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This version of the presentation includes corrections to errors in the original presentation contained on slide 22 clarifying footnotes on slides 20 amp 21 and a post-meeting addition (slide 23)
2
This presentation contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws including statements regarding Agenus and AgenTus clinical development and regulatory plans and timelines expected timing for clinical trials and releasing clinical data anticipated milestones from partnership transactions and goals for 2020 These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially These risks and uncertainties include among others the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission filed with the Securities and Exchange Commission and made available on our website at wwwagenusbiocom Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this presentation These statements speak only as of the date of this presentation and Agenus undertakes no obligation to update or revise the statements other than to the extent required by law All forward-looking statements are expressly qualified in their entirety by this cautionary statement
Forward-Looking Statements
3
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER
AND BETTER
bull Pivotal Trial Clinical Data on Balstilimab and Zalifrelimabbull AGEN1181 Beyond a Next-Generation CTLA-4bull New Discoveries
Investor Day
Tyler Curiel MD MPH FACPThe Daisy M Skinner Professor of Cancer Immunology ResearchProfessor of Medicine Microbiology Immunology amp Medical GeneticsUT Health San AntonioMays Cancer Center
From AgenusFrom the Experts
Bradley Monk MD FACS FACOGProfessor Division of Gynecologic Oncology Arizona Oncology (US Oncology Network)Co-Director of GOG Partners
Charles Drake MD PhDCo-Director Cancer Immunotherapy Program Columbia University Herbert Irving Comprehensive Cancer Center
Garo Armen PhDChairman and CEO
Jennifer Buell PhDPresident and COO
Julie DeSanderVice President Business Development amp Alliance Management
Dhan Chand PhDHead of Drug Discovery
Mark Exley PhDVice President Cellular Immunology
Anna Wijatyk MDHead of Clinical Development
5
Delivering Some of Our 2020 Goals Today
bull 6 Clinical Data Readoutsthorn Zalifrelimab and Balstilimab thorn Balstilimabthorn AGEN1181
AGEN1223AGEN2373GS-1423
2020 Objectives Shared at Agenusrsquo November 2019 RampD Day
bull 2 INDsbull 2 BLA filings
6
Dr Bradley J Monk MD FACOG FACS
bull Professor of Gynecologic Oncologybull University of Arizonabull Arizona Oncology (US Oncology Network)bull Co-Director gt GOG Partnersbull Chair Cervical Cancer Committee gt Gynecologic
Cancer Intergroup (GCIG)
7
The Enemy
8
Three Decades Recurrent amp Metastatic Cervical Cancer
bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over
24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with
cisplatin-based chemoradiation for locally advanced disease (1999 onwards)
Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93
9
New England Journal of Medicineand THE LANCET
Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663
Articles
wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1
Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk
SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events
Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062
Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death
Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer
Funding National Cancer Institute
Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0
See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7
Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of
IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer
continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1
FDA approved for 1-L metastatic disease Aug 14 2014
10
FDA Accelerated Approval of Pembrolizumab(June 12 2018)
FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019
Companion DiagnosticPD-L1 IHC 22C3CPSge1
ORR 143(95 CI 74 241)
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
2
This presentation contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws including statements regarding Agenus and AgenTus clinical development and regulatory plans and timelines expected timing for clinical trials and releasing clinical data anticipated milestones from partnership transactions and goals for 2020 These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially These risks and uncertainties include among others the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission filed with the Securities and Exchange Commission and made available on our website at wwwagenusbiocom Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this presentation These statements speak only as of the date of this presentation and Agenus undertakes no obligation to update or revise the statements other than to the extent required by law All forward-looking statements are expressly qualified in their entirety by this cautionary statement
Forward-Looking Statements
3
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER
AND BETTER
bull Pivotal Trial Clinical Data on Balstilimab and Zalifrelimabbull AGEN1181 Beyond a Next-Generation CTLA-4bull New Discoveries
Investor Day
Tyler Curiel MD MPH FACPThe Daisy M Skinner Professor of Cancer Immunology ResearchProfessor of Medicine Microbiology Immunology amp Medical GeneticsUT Health San AntonioMays Cancer Center
From AgenusFrom the Experts
Bradley Monk MD FACS FACOGProfessor Division of Gynecologic Oncology Arizona Oncology (US Oncology Network)Co-Director of GOG Partners
Charles Drake MD PhDCo-Director Cancer Immunotherapy Program Columbia University Herbert Irving Comprehensive Cancer Center
Garo Armen PhDChairman and CEO
Jennifer Buell PhDPresident and COO
Julie DeSanderVice President Business Development amp Alliance Management
Dhan Chand PhDHead of Drug Discovery
Mark Exley PhDVice President Cellular Immunology
Anna Wijatyk MDHead of Clinical Development
5
Delivering Some of Our 2020 Goals Today
bull 6 Clinical Data Readoutsthorn Zalifrelimab and Balstilimab thorn Balstilimabthorn AGEN1181
AGEN1223AGEN2373GS-1423
2020 Objectives Shared at Agenusrsquo November 2019 RampD Day
bull 2 INDsbull 2 BLA filings
6
Dr Bradley J Monk MD FACOG FACS
bull Professor of Gynecologic Oncologybull University of Arizonabull Arizona Oncology (US Oncology Network)bull Co-Director gt GOG Partnersbull Chair Cervical Cancer Committee gt Gynecologic
Cancer Intergroup (GCIG)
7
The Enemy
8
Three Decades Recurrent amp Metastatic Cervical Cancer
bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over
24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with
cisplatin-based chemoradiation for locally advanced disease (1999 onwards)
Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93
9
New England Journal of Medicineand THE LANCET
Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663
Articles
wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1
Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk
SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events
Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062
Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death
Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer
Funding National Cancer Institute
Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0
See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7
Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of
IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer
continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1
FDA approved for 1-L metastatic disease Aug 14 2014
10
FDA Accelerated Approval of Pembrolizumab(June 12 2018)
FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019
Companion DiagnosticPD-L1 IHC 22C3CPSge1
ORR 143(95 CI 74 241)
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
3
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER
AND BETTER
bull Pivotal Trial Clinical Data on Balstilimab and Zalifrelimabbull AGEN1181 Beyond a Next-Generation CTLA-4bull New Discoveries
Investor Day
Tyler Curiel MD MPH FACPThe Daisy M Skinner Professor of Cancer Immunology ResearchProfessor of Medicine Microbiology Immunology amp Medical GeneticsUT Health San AntonioMays Cancer Center
From AgenusFrom the Experts
Bradley Monk MD FACS FACOGProfessor Division of Gynecologic Oncology Arizona Oncology (US Oncology Network)Co-Director of GOG Partners
Charles Drake MD PhDCo-Director Cancer Immunotherapy Program Columbia University Herbert Irving Comprehensive Cancer Center
Garo Armen PhDChairman and CEO
Jennifer Buell PhDPresident and COO
Julie DeSanderVice President Business Development amp Alliance Management
Dhan Chand PhDHead of Drug Discovery
Mark Exley PhDVice President Cellular Immunology
Anna Wijatyk MDHead of Clinical Development
5
Delivering Some of Our 2020 Goals Today
bull 6 Clinical Data Readoutsthorn Zalifrelimab and Balstilimab thorn Balstilimabthorn AGEN1181
AGEN1223AGEN2373GS-1423
2020 Objectives Shared at Agenusrsquo November 2019 RampD Day
bull 2 INDsbull 2 BLA filings
6
Dr Bradley J Monk MD FACOG FACS
bull Professor of Gynecologic Oncologybull University of Arizonabull Arizona Oncology (US Oncology Network)bull Co-Director gt GOG Partnersbull Chair Cervical Cancer Committee gt Gynecologic
Cancer Intergroup (GCIG)
7
The Enemy
8
Three Decades Recurrent amp Metastatic Cervical Cancer
bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over
24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with
cisplatin-based chemoradiation for locally advanced disease (1999 onwards)
Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93
9
New England Journal of Medicineand THE LANCET
Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663
Articles
wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1
Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk
SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events
Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062
Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death
Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer
Funding National Cancer Institute
Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0
See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7
Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of
IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer
continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1
FDA approved for 1-L metastatic disease Aug 14 2014
10
FDA Accelerated Approval of Pembrolizumab(June 12 2018)
FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019
Companion DiagnosticPD-L1 IHC 22C3CPSge1
ORR 143(95 CI 74 241)
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
bull Pivotal Trial Clinical Data on Balstilimab and Zalifrelimabbull AGEN1181 Beyond a Next-Generation CTLA-4bull New Discoveries
Investor Day
Tyler Curiel MD MPH FACPThe Daisy M Skinner Professor of Cancer Immunology ResearchProfessor of Medicine Microbiology Immunology amp Medical GeneticsUT Health San AntonioMays Cancer Center
From AgenusFrom the Experts
Bradley Monk MD FACS FACOGProfessor Division of Gynecologic Oncology Arizona Oncology (US Oncology Network)Co-Director of GOG Partners
Charles Drake MD PhDCo-Director Cancer Immunotherapy Program Columbia University Herbert Irving Comprehensive Cancer Center
Garo Armen PhDChairman and CEO
Jennifer Buell PhDPresident and COO
Julie DeSanderVice President Business Development amp Alliance Management
Dhan Chand PhDHead of Drug Discovery
Mark Exley PhDVice President Cellular Immunology
Anna Wijatyk MDHead of Clinical Development
5
Delivering Some of Our 2020 Goals Today
bull 6 Clinical Data Readoutsthorn Zalifrelimab and Balstilimab thorn Balstilimabthorn AGEN1181
AGEN1223AGEN2373GS-1423
2020 Objectives Shared at Agenusrsquo November 2019 RampD Day
bull 2 INDsbull 2 BLA filings
6
Dr Bradley J Monk MD FACOG FACS
bull Professor of Gynecologic Oncologybull University of Arizonabull Arizona Oncology (US Oncology Network)bull Co-Director gt GOG Partnersbull Chair Cervical Cancer Committee gt Gynecologic
Cancer Intergroup (GCIG)
7
The Enemy
8
Three Decades Recurrent amp Metastatic Cervical Cancer
bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over
24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with
cisplatin-based chemoradiation for locally advanced disease (1999 onwards)
Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93
9
New England Journal of Medicineand THE LANCET
Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663
Articles
wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1
Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk
SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events
Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062
Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death
Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer
Funding National Cancer Institute
Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0
See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7
Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of
IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer
continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1
FDA approved for 1-L metastatic disease Aug 14 2014
10
FDA Accelerated Approval of Pembrolizumab(June 12 2018)
FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019
Companion DiagnosticPD-L1 IHC 22C3CPSge1
ORR 143(95 CI 74 241)
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
5
Delivering Some of Our 2020 Goals Today
bull 6 Clinical Data Readoutsthorn Zalifrelimab and Balstilimab thorn Balstilimabthorn AGEN1181
AGEN1223AGEN2373GS-1423
2020 Objectives Shared at Agenusrsquo November 2019 RampD Day
bull 2 INDsbull 2 BLA filings
6
Dr Bradley J Monk MD FACOG FACS
bull Professor of Gynecologic Oncologybull University of Arizonabull Arizona Oncology (US Oncology Network)bull Co-Director gt GOG Partnersbull Chair Cervical Cancer Committee gt Gynecologic
Cancer Intergroup (GCIG)
7
The Enemy
8
Three Decades Recurrent amp Metastatic Cervical Cancer
bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over
24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with
cisplatin-based chemoradiation for locally advanced disease (1999 onwards)
Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93
9
New England Journal of Medicineand THE LANCET
Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663
Articles
wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1
Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk
SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events
Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062
Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death
Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer
Funding National Cancer Institute
Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0
See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7
Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of
IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer
continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1
FDA approved for 1-L metastatic disease Aug 14 2014
10
FDA Accelerated Approval of Pembrolizumab(June 12 2018)
FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019
Companion DiagnosticPD-L1 IHC 22C3CPSge1
ORR 143(95 CI 74 241)
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
6
Dr Bradley J Monk MD FACOG FACS
bull Professor of Gynecologic Oncologybull University of Arizonabull Arizona Oncology (US Oncology Network)bull Co-Director gt GOG Partnersbull Chair Cervical Cancer Committee gt Gynecologic
Cancer Intergroup (GCIG)
7
The Enemy
8
Three Decades Recurrent amp Metastatic Cervical Cancer
bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over
24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with
cisplatin-based chemoradiation for locally advanced disease (1999 onwards)
Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93
9
New England Journal of Medicineand THE LANCET
Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663
Articles
wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1
Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk
SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events
Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062
Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death
Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer
Funding National Cancer Institute
Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0
See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7
Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of
IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer
continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1
FDA approved for 1-L metastatic disease Aug 14 2014
10
FDA Accelerated Approval of Pembrolizumab(June 12 2018)
FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019
Companion DiagnosticPD-L1 IHC 22C3CPSge1
ORR 143(95 CI 74 241)
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
7
The Enemy
8
Three Decades Recurrent amp Metastatic Cervical Cancer
bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over
24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with
cisplatin-based chemoradiation for locally advanced disease (1999 onwards)
Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93
9
New England Journal of Medicineand THE LANCET
Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663
Articles
wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1
Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk
SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events
Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062
Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death
Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer
Funding National Cancer Institute
Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0
See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7
Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of
IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer
continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1
FDA approved for 1-L metastatic disease Aug 14 2014
10
FDA Accelerated Approval of Pembrolizumab(June 12 2018)
FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019
Companion DiagnosticPD-L1 IHC 22C3CPSge1
ORR 143(95 CI 74 241)
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
8
Three Decades Recurrent amp Metastatic Cervical Cancer
bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over
24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with
cisplatin-based chemoradiation for locally advanced disease (1999 onwards)
Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93
9
New England Journal of Medicineand THE LANCET
Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663
Articles
wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1
Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk
SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events
Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062
Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death
Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer
Funding National Cancer Institute
Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0
See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7
Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of
IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer
continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1
FDA approved for 1-L metastatic disease Aug 14 2014
10
FDA Accelerated Approval of Pembrolizumab(June 12 2018)
FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019
Companion DiagnosticPD-L1 IHC 22C3CPSge1
ORR 143(95 CI 74 241)
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
9
New England Journal of Medicineand THE LANCET
Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663
Articles
wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1
Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk
SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events
Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062
Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death
Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer
Funding National Cancer Institute
Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0
See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7
Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of
IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer
continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1
FDA approved for 1-L metastatic disease Aug 14 2014
10
FDA Accelerated Approval of Pembrolizumab(June 12 2018)
FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019
Companion DiagnosticPD-L1 IHC 22C3CPSge1
ORR 143(95 CI 74 241)
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
10
FDA Accelerated Approval of Pembrolizumab(June 12 2018)
FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019
Companion DiagnosticPD-L1 IHC 22C3CPSge1
ORR 143(95 CI 74 241)
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
11
R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14
Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358
1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA
Colead authors
Proof of Concept for Combo PD-1 + CTLA-4 in Cervical
Abstract Number 5630
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
12
Study Design and Current Analysis
Treatment(until toxicity or progression or a
maximum of 24 mo)
Current AnalysisScreening Follow-up
NIVO+IPI Regimen
NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg
q3w x 4 followed by NIVO 240 mg q2w
bull Imaging every 8 wks for yr 1 of treatment
bull Imaging every 12 wks beyond yr 1
R
bull Histologically confirmedSCC of the cervixbull RM disease
bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown
Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease
Database lockJune 26 2019
Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)
ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma
bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response
bull Study start date October 2015bull Estimated completion date December 2019
NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +
IPI 1 mgkg q6w
CheckMate 358
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
13
Patient Characteristics
Baseline characteristicsNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Age median (range) y 480 (32ndash76) 445 (26ndash74)
ECOG PS n ()01
23 (511)22 (489)
26 (565)20 (435)
AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)
3 (66)1 (22)
41 (911)
0 (00)8 (174)
38 (826)
Tumor cell PD-L1 expression dagger n ()Evaluable
ge1lt1
Not evaluablenot reported
37 (822)23 (622)14 (378)8 (178)
34 (739)23 (676)11 (324)12 (260)
13
Prior therapiesNIVO3+IPI1
(n = 45)NIVO1+IPI3
(n = 46)
Prior therapy n ()PlatinumBevacizumab
39 (867)24 (533)
42 (913)25 (543)
Prior radiotherapy n () 38 (844) 39 (848)
Prior systemic therapy in the RM setting n ()0ge1
19 (422)26 (578)
24 (522)22 (478)
Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity dagger Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer
Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting
CheckMate 358
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
14
Change from Baseline in Target Lesion SizeCheckMate 358
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100
minus75
minus50minus25
0
255075
Patient
Max
imum
cha
nge
from
ba
selin
e in
targ
et le
sion
s (
)
100
minus100minus75minus50minus25
0255075
Patient
NIVO3+IPI1 NIVO1+IPI3
No PST for RM diseasePST for RM disease
Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy
No PST for RM diseasePST for RM disease
ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
15
Complete Response to Treatment withNivolumab + Ipilimumab
42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1
Base
line
95
mo
2 m
o
CD4
CD8
Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio
All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy
Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies
ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017
ndash Documented disease progression
CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019
(7 mo post-treatment completion)
CheckMate 358
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
16
CheckMate 358 Safety Summary
bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to
treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths
SAE serious adverse event TRAE treatment-related adverse event
Event n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4
TRAEs 36 (800) 13 (289) 38 (826) 17 (370)
Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)
TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)
Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)
CheckMate 358
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
17
CheckMate 358 TRAEs with Incidence ge5
bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose
bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each
TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class
TRAEs by SOC n ()
NIVO3+IPI1(n = 45)
NIVO1+IPI3(n = 46)
Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0
Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)
Skin 16 (356) 0 16 (348) 2 (43)
Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)
Endocrine 13 (289) 2 (44) 20 (435) 0
Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)
Metabolism 5 (111) 1 (22) 5 (109) 0
Nervous system 4 (89) 0 6 (130) 0
Musculoskeletal 2 (44) 1 (22) 9 (196) 0
Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)
CheckMate 358
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
18
Why CTLA-4 and PD-1 have Best-in-Class Potential
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
19
CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors
2-3x improved ORR with CTLA4 in certain tumors
34
45
37
36
21
28
12
20
19
12
12
7
5
5
58
57
45
41
38
36
31
31
28
23
21
20
16
10
Previously treated MSI-H CRC
1L Melanoma
1L NSCLC (ge50 PD-L1)
1L RCC
2L+ Bladder cancer
1L NSCLC (ge1 PD-L1)
Ovarian cancer
2L+ Hepatocellular cancer
Mesothelioma
Cervical cancer
2L+ SCLC
2L+ Gastric esophageal cancer
Sarcoma
Prostate cancer (mCRPC)
PD1 ORR
PD1CTLA4 ORR
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
20
CRs amp PRs show durability gt70wks
Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries
CRs amp PRs show durability gt50wks
Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads
Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
22
Sponsor Agent of Patients
ORR CR PR Related AEs (Grade 3+)
Agenus Balstilimab 42 119 24 95 91
Merck Pembrolizumab 98 122 31 92 122
Agenus Balstilimab + Zalifrelimab
34 206 88 118 146
BMS Ipilimumab + Nivolumab
26 231 38 192 289
Seattle Genetics Genmab
Tisotumab vedotin 55 22 2 20 56
Iovance LN-145 27 444 111 333 963
Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)
Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile
Addition to original presentation
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
23
Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer
Sponsor Treatment of
PatientsComplete Response
Partial Response
Overall Response Rate
Combination of PD-1 and CTLA-4
Agenus Balstilimab + Zalifrelimab 34 88 118 206
BMS Ipilimumab + Nivolumab 26 38 192 231
PD-1 Monotherapy
Agenus Balstilimab 42 24 95 119
Merck Pembrolizumab 77 31 112 143
Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline)
Corrected Slide
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019
Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)
Balstilimab+Zalifrelimab
(N=41)
Balstilimab(N=44)
Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]
Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]
Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]
Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
25
1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a
pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15
a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable
safety a) Including Zalifrelimab to Balstilimab
5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely
Conclusions
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
26
Anna Wijatyk MDHead of Clinical Development
WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND
BETTER
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
27
On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
28
Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018
Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on
Non-t lesions none
Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus
Demographics 64 yo White
Primary tumor FIGO-IIIa SCC
Prior treatment carbotax in 2016
Screening Cycle 36 ndash CR0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Independent review
T
umor
size
Weeks
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
29
Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)
Screening
Week 27 ndash CR from week 6-on
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40
T
umor
size
Weeks
Baseline On-treatmentTarget lesions Vaginal stump 47 mm
inguinal ln 19 mmCR on wk 6
Non-target lesions none -
Related AEs G2 hypothyroidism
Demographics 57 yo white
Primary tumor FIGO-IIIB SCC nonkeratinizing
Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
30
2 Interim AnalysesPivotal Trial Analysis
Underway
25 Countries120 Sites
8 Studies Open
Clinical Development and Operations
~300 Patients Treated
54 Agenus Team Members
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
31
Balstilimab Balstilimab + Zalifrelimab
AGEN1181AGEN1223AGEN2373
Deliver Clinical Data on Multiple Discoveries
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
32
IND Cleared Sites Activated Patients Dosed
New Discoveries to Patients with Path-breaking Speed
Industry Standard 168 days
Agenus timelines - 65 Days
Speed to clinic speed to patients speed to market
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
33
Jennifer Buell PhDPresident and COO
Agenus
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
34
Agenus Discoveries In The Clinic
Option programs w GILD
Agenus PartnersCommercial QS-21 (SHINGRIX)1
Pivotal(Planned BLA 2020)
Balstilimab (PD-1) Balstilimab + Zalifrelimab
(CTLA-4)
Phase 12AGEN1181
AGEN1223AGEN2373
GS-1423MK-4830
INCAGN1876INCAGN1949INCAGN2390INCAGN2385
More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
35
Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
36
Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment
CD8 T cellTumour cell
MHC
PD-L1- - -
PD-L2PD-1- - -
Tumourantigen
TCR
PD-1
+++
PD-L1 expression on tumor cells OR
Myeloid cells SEND a negative signal
CD8 T cellTumour cellMHC
TCR
+++
Suppressive Factors
Regulatory CD4 T Cell
(FoxP3+)
-- - --
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
37
Targeted Treg Depletion Treats Cold Tumors(in mice)
Klages K et al Cancer Research 2010
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
38
High Risk PC
Arm AAndrogen Deprivation Therapy(ADT)
Arm BADT Plus Vaccine
Surgery on day 28 (+-3)
Safety Tolerability
T Cell infiltration of prostate gland
Profile the Tumor Microenvironment Post-Treatment
Randomize
n=16 n=16
Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin
Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer
Endpoints
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
39
In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance
UntreatedControlN = 13
AndrogenDeprivation
TherapyN=15
AndrogenDeprivation
PLUS VaccineN=13
CD8+ T cell density(mean 95CI)
96 (72ndash120) 205 (121ndash289) 263 (129ndash397)
Treg celldensity(mean 95CI)
29 (21ndash36) 59 (34ndash85) 78 (48ndash107)
CD8+ Tregratio(mean 95CI)
37 (29ndash46)
40 (27ndash53) 39 (22ndash57)
Obradovic Dallos Drake et al in review
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
40
CD45
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Fold
cha
nge
rela
tive
to P
re-C
CD4
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
CD8a
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
Ptprc(CD45)
Cd4 Cd8a
Eomes Tbx21(T-bet)
Foxp3
Tbx21 (Tbet)
Pre-C
Post-C
D7
C-Res
istan
t10-1
100
101
102
FoxP3
Pre-C
Post-C
D7
C-Res
istan
t100
101
102
103
EOMES
Pre-C
Post-C D
7
C-Res
istan
t100
101
102
103
Fold
cha
nge
rela
tive
to P
re-C
153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other
Pre-C
237 Treg
CD4+ T
119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other
C-Resistant
134 Treg
CD4+ T
106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other
Post-C D7
395 Treg
CD4+ T
Shen and Drake Prostate Cancer Neoplastic Disease 2017
In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx
Adaptive Treg Resistance
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
41
pm
e F
PK
M C
TL
A4
Ex
pre
ss
ion
PBMC N
aive C
D4
PBMC A
ctivate
d CD4
PBMC T
reg
TIL T
reg
PBMC N
aive C
D8
PBMC A
ctivate
d CD8
PBMC A
g Experie
nced CD8
TIL A
g Experie
nced CD8
0
250
500
750
1000
1250
Nirschl T and Drake CIn Preparation
CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
42
A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer
00 10 20 30 40 50 60 70
0
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix + αPD-1
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (ND)
0
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Degarelix + αCTLA-4 (D)
167
0 10 20 30 40 50 60 700
500
1000
1500
2000
Days after degarelix
Tum
or v
olum
e (m
m3 )
Degarelix
0
Shen and Drake Prostate Cancer Neoplastic Disease 2017
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
43
Radiation TherapyDrives
Adaptive TregResistance
Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017
Contro
lRT
Contro
lRT
Contro
lRT
0
10
20
30
40
50
B16 RENCA MC38
C
D4+
Fox
p3+C
D4+
cells
Contro
lRT
Contro
lRT
Contro
lRT
0
200
400
600
800
B16 RENCA MC38
MF
I of
Fox
p3
Control
RT
B16F10 RENCA MC38
0 102 103 104 105
0102
103
104
105
156
0 102 103 104 105
0102
103
104
105
317
0 102 103 104 105
0102
103
104
105
227
0 102 103 104 105
0102
103
104
105
418
0 102 103 104 105
0102
103
104
105
230
0 102 103 104 105
0102
103
104
105
500
Foxp
3
CD4
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
44
A Depleting aCTLA-4Plus Radiation
Cures The MajorityOf Treated Animals
Marisciano Drake et al Clinical Cancer Res 2018
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
45
100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection
Not the Case for RT + aPD-1
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
46
Selected aCTLA-4 Agents in the Clinic
46
Ipilimumab Tremilimumab BMS 928218 MK 1308
IgG Isotype IgG1 IgG2 AfucosylatedIgG1
Not Reported
TregDepletion
+- No Not Reported Not Reported
Grade III IVIRAE
asymp25 asymp15 Not Reported Not Reported
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
47
bull High Affinity for CTLA-4
bull Fc Optimized to Enhance Depletion
bull Enhanced T Cell Activation
bull Promote T Cell Memory
bull Reasonable Tolerability
Optimized aCTLA-4 Product Profile
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
48
The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants
Waight JD et al Cancer Cell 2018
IgG1 aCTLA-4 Fc Engineered aCTLA-4
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
49
Enhanced Treg Depletion with AGEN1181
Source Agenus Data
Parental IgG1
Isotype Control
AGEN1181
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
50
Enhanced T Cell Activation with AGEN1181
Source Agenus Data
Increased FcgRIIIa Binding (hIgG1-DLE)
WT FcgRIIIa Binding (hIgG1)
Absent FcgRIIIa Binding (hIgG1-N297A)
Waight JD et al Cancer Cell 2018
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
51
Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4
51
Source Agenus dataWaight et al Cancer Cell 2018
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
52
Early Clinical Activity with AGEN1181
bull Ongoing Dose-Escalation Trial
bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019
bull 20 patients treated to date on monotherapy and in combination with balstilimab
bull 1 CR and disease stabilization in majority of response evaluable patients
bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)
52
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
53
bull 73 yo Female with Endometrial Carcinoma (Uterine)
ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment
bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation
bull Metastatic progression lymph node + sigmoid colon
bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR
Metastatic Endometrial CancerConfirmed Complete Response
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
54
A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors
Ipilimumab Monotherapy
bull Most CRs in solid tumors are in melanoma
bull All CRs in solid tumors were at dosed at 3 or 10 mgkg
bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma
AGEN1181 Monotherapy
bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)
bull CRSD were at low doses 1 mgkg or less
bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)
bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody
1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
55
bull AGEN1181 is an Fc Enhanced Anti-CTLA-4
bull Well-documented enhanced in vitro activity (Waight et al)
bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies
Summary Forward Looking
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
56
Dr Tyler CurielMD MPH FACP
bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research
bull Professor of Medicine and Microbiology Immunology amp Medical Genetics
bull University of Texas Health San Antonio TX
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
57
A Deeper Look
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
58
Endometrial Cancer Patient Complete Response
bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype
PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
59
AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro
AGEN1181AGEN1884
analog Isotype
Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181
Resting Memory T cells 1
Resting Memory T cells 2
CD8 cytotoxic T cells
CD8 γδNK-like T cells
Proliferating cells
Dendritic cells
Source Agenus data
1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog
isotype
2 Conditional cell type differences
3 Key insight AGEN1181 selectively expands an IFN type 1 responding
memory T cell
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
60
AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients
γδ T cells
bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab
bull Single cells were sequenced using Smart-seq2
bull AGEN analysis drives new mechanistic insight
All other clusters
Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers
0
002
004
006
008
01
012
pre post pre post
γ
δT
cells
Pre Post Post
Non-responders Responders
Pre
Key insight γδ T cell population is expanded in ipi + nivo responders
Normalized expression
-10 20
Data source Sade-Feldman et al Cell 2018Data analysis Agenus
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
61
Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4
0
168
284
0
05
1
15
2
25
3
ISOTY
PE 3M
AGEN1884
AGEN1181
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
AGEN
1181
isoty
peAG
EN18
84 an
alog
AGEN
1181
AGEN
1181
isoty
peAG
EN18
84 an
alog
All other clusters
Identify γδ T cell populationComparable to intratumoral population
Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro
γ
δT
cells
to
tal C
D8+
IFNG
NKp301
FcεRIγ1
i Frequency of γδ T cells
AGEN
1181
isoty
pe
AGEN
1181
AGEN
1884
analo
g
Normalized expression
-10 10
Normalized expression
-10 201Activated NK cell receptor markersCorreia et al PNAS 2018
ii Selected activation markers
Intrat
umora
l γδ
In vit
ro γδ
Source Agenus data
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
62
bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset
bull Next experiments will expand observations to patients on AGEN1181
Conclusions
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
63
Next Steps
1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction
2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble
factors or direct signals)
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
64
Dhan Chand PhDHead of Drug Discovery
OUR NEXT WAVEOF INNOVATION
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
66
CD73-adenosine and TGFβ are Major Contributors to Therapeutic
Resistance
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
67
AGEN Solution A Bi-functional Tumor Conditioning Agent
GS-1423 is potentially a first-in-class bi-functional antibody
TGFb-Trap
CD73 binding region
GS linker
Phase I initiatedQ2 2019
(licensed to Gilead)
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
68
GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment
0 20 40 60 800
20
40
60
80
Time (hours)
T
umor
Cel
l Killi
ng
IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1
Phase I initiated Q2 2019
GS-1423 is licensed to Gilead by Agenus
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
69
Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-
tumor Immune Responses
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
70
AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation
AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety
Fc-optimized ldquoback-endrdquo
Target Y
Phase I initiatedDecember 2019
Target X
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
71
AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs
0 2 4 60
1 0
2 0
3 0
4 0
5 0
Treg
H o u rs
AD
CC
ac
tiv
ity
A G E N 1 2 2 3
A n ti-G IT R (IN C A G N 0 1 8 7 6 )
A n ti-G IT R (M K 4 1 6 6 )
A n ti-G IT R (T R X -5 1 8 )
A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )
A n ti-O X 4 0 (A G E N 2 0 4 9 )
A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )
A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )
C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )
AGEN1223
Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs
0 2 4 6
50
40
30
20
10
0
Hours
A
DCC
activ
ity
Phase I initiated December 2019
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
72
Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity
SHP-12
ITIMs
PhagocytosisM1 pro-inflammatory phenotype
Inhibitoryreceptor
Ligand expressed broadly across tumor types
Tumor Macrophage
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
73
AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams
Ligand
SHP-12
ITIMs
AGEN1531
PhagocytosisM1 pro-inflammatory phenotype
AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages
towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral
T amp NK cellsbull Overcome dendritic cell tolerogenicity
Inhibitoryreceptor
Tumor
Macrophage
IND Projected 2020
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
74
AGEN1531 Antagonizes a Key Immunosuppressive Interface
-3 -2 -1 0 1 2
0
200000
400000
600000
Antibody (log microgmL)
RLU
AGEN1531
Isotype
AGEN1531 relieves target-mediated inhibition of FcγR signalling
AGEN1531 converts macrophages from immune suppressing to tumor fighting
M
1 m
acro
phag
es
AGEN1531
Isotyp
e con
trol
M1-enri
ched
contr
ol
M2-enri
ched
contr
ol0
20
40
60
80
IND Projected 2020
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
75
Patient Progression on Anti-PD-1 Driven by Secondary Immune
Checkpoints
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
76
AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation
AGEN1777 is a potential first-in-class dual antagonist bispecific
APC
T NK cellCo-stimulatory
receptorLigand
Tumor cell
AGEN1777
FcγR
Ligand
Enhanced co-stimulatory signaling
Inhibitory receptors
IND Projected 2020
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
77
AGEN1777 Controls Tumors in a Mouse Colon Tumor Model
10 20 30 40 500
500
1000
1500
2000
AGEN1777 Bispecific(mouse surrogate)
Days post implantation
Tum
or v
olum
e (m
m3 ) CR 1315
10 20 30 40 500
500
1000
1500
2000
Isotype Control(Bispecific)
Days post implantation
Tum
or v
olum
e (m
m3 )
10 20 30 40 500
500
1000
1500
2000
anti-PD-1(mAb)
Days post implantationTu
mor
vol
ume
(mm
3 ) CR 215
IND Projected 2020Source Agenus data
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
78
Data Accepted forPresentation at AACR 2020
(Abstract 922)
Novel Combinations AddressTherapeutic Resistance
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
79
Our next disruptors exemplify innovation and smart design
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
80
Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
81
Tumor cell
Cytotoxicity
NK cell
IL-12
IFNɣ
iNKT cell
IL-12
Cytotoxicity
GzmBFasL
TAM or APC
IFNɣActivation
Mark Exley PhDPrincipal
INVARIANT NKT CELLS BOOST
IMMUNE RESPONSE NATURALLY
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
82
Tumor cell
Cytotoxicity
GzmBFasL
IFNɣ
iNKT cell
IL-12
Tumor associated
macrophages
Tumor cell
Cytotoxicity
NK or T cell
IL-12
IFNɣActivation
Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system
iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000
fold (1 healthy donor ~ 1000 doses)
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
83
bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL
bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors
Some cancers over-express CD1d
iNKTs May be Effective in Solid and Hematologic Tumors
Allogeneic iNKTs expected to enter clinic
as mono and CPI combinations in 2020
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
84
Julie DeSanderHead of Business Development
SMART COLLABORATIONS
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
85
Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received
$1725Mreceived1
$145Mreceived2
$9Mreceived
$190Mreceived
More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026
$10Mreceived
Eligiblebull $200M milestonesbull Royalties
Eligiblebull $85M milestonesbull Royalties
Eligiblebull $40M milestones3
Eligiblebull $17Bn milestonesbull Royalties
Eligiblebull $450M milestonesbull Royalties
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
86
2020 Partnering Strategy
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations
In-licensing
Ex-US Partnerships
Clinical Collaborations
Platform Collaborations
Research Collaborations In-licensing
87
QampA
87
QampA