Does ATLAS have broad

shoulders?

Jean-Luc Bodmer Vaccine Technology V, Playa del Carmen

The Need for and Challenges of T Cell-Enabled Vaccines

• C. trachomatis

• CMV

• Dengue fever

• Gonococci

• HSV-1

• HSV-2

• Malaria

• Pneumococci

• Pseudomonas

• S. aureus

• Tuberculosis

Pathogens where T cells contribute to

protection

T cells pose new challenges

Impact on discovery

• Up to 1,000X increase in potential targets

• Diversity of human T cell responses – Greater variability than

antibody

– Difficult to model in animals

• Time, cost

• Less predictive

power

A large need . . . but significant discovery hurdles

2

Potential T cell antigens – a vastly increased pool of

candidates

David Goodsell watercolor – cross-section of E. coli http://www.hhmi.org/bulletin/winter-2013/structural-revolution

Antibody targets limited to: • Surface proteins & carbohydrates • Secreted proteins & toxins

How do you define which targets are the best antigens for T cell responses?

T cells targets comprise a much larger repertoire: • Any protein or pieces thereof expressed on or in a pathogen • Dozens to thousands of potential targets

3

Antigen Recognition: Greater Variability in presentation

• There are nearly 2000 known alleles of HLA (MHC) genes

• Grouped into HLA supertypes – each HLA molecule within a supertype binds essentially

the same peptide epitope

– MHC-I :HLA-A1, -A2, -A3, -A24, -B7, -B27, -B44, -B58, -B62

– MHC-II :HLA-DQ1, -DQ2, -DQ3, -DQ4, -DQ5 (95% coverage)

• Antigen processing, presentation and recognition is highly diverse and depends on the

genetics of each subject.

http://sph.bu.edu/otlt/MPH-Modules/EH/EH_Immunity_B/BindingAntigenEpiptopes.png

Antibody T cell

4

Final Ag

Vaccine

ATLAS™: Antigen Lead Acquisition System

Further in vivo

validation and development

Antigen ranking

High throughput screening

Full length, full

proteome libraries

Clinical cohorts

Full Proteome Top Candidates Leads

5

6

ATLASTM Screening Technology Flowchart

7

ATLASTM: Screening for responses against CD4+ T cells

8

ATLASTM: Screening for responses against CD8+ T cells

Addressing intractable diseases at Genocea

9

GEN-004: Streptococcus pneumoniae

Inhibition of mucosal colonization

GEN-005: Plasmodium falciparum

Elimination of infected hepatocytes

GEN-001: Chlamydia trachomatis

Elimination of infected epithelial cells

GEN-003: Herpes Simplex Virus-2

Elimination of infected epithelial cells

Genome Size – Probing the Proteome of diverse pathogens

with ATLAS screening libraries

10

Pathogen Disease(s) # Clones

Expression

Rate

Program

status

Herpes Virus

Simplex 2 Genital Herpes 85 100% Phase Ia/II

Chlamydia

trachomatis

PID, urethritis,

lymphogranuloma

venereum

960 97% Pre-clinical

Plasmodium

falciparum Malaria 1189 88% Antigen ID

Streptococcus

pneumoniae

(otitis media, pneumonia, sepsis, meningitis)

2,218 95% Phase I/II pneumococcal disease

GEN-003 (HSV-2 Immunotherapy)

GEN-004 (Pneumococcus Px)

GEN-002 (HSV-2 Px)

GEN-001 (Chlamydia)

Malaria

Discovery

Genocea’s Pipeline of T Cell-Enabled Product Candidates

11

Pre-clinical Phase 1 Phase 2 Phase 3

Oncology

GEN-003: Therapeutic Vaccine against HSV-2

• Lifelong sexually transmitted disease – Painful, recurrent genital ulcers

– Significant emotional distress

• Public health epidemic – 500 million people infected worldwide (16% of U.S. adults)

– Contributes to transmission of HIV-1

– Serious complications from maternal-to-infant transmission

• Standard of care (oral anti-viral drugs) has limitations – Incomplete control of recurring ulcers

– Continued risk of transmission

– Compliance burden to maintain effect

12

• Reduce viral shedding: – To improve

symptom control – To reduce

transmission risk

• Convenient dosing regimen

• Novel mechanism of action

GEN-003 Composition

GEN-003: A Novel HSV-2 Therapeutic Vaccine Candidate

Intervening against HSV-2

Matrix- M2

adjuvant

T Cell Antigen

ICP4.2

B Cell Antigen

gD2DTMR

GEN-003 Proposition

Novel T cell antigen prioritized via ATLAS

Points of potential T cell intervention

Point of potential B cell intervention

Virus moves

from nerve cell

to skin and

mucosa

13

GEN-003: Highly Significant, Durable Impact on HSV-2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Baseline After dose 3 After 6 months

14

10 µg

100 µg

30 µg

Placebo

Proteins only

*** ***

***

Genital Lesion Rate (a)

*** = p<0.001 (a) Normalized so that rate at baseline = 1

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Baseline After dose 3 After 6 months

*** ***

***

Viral Shedding Rate (a)

10 µg

100 µg

30 µg

Placebo

Proteins only

GEN-004: Significant Need for a New Vaccine

• Pathogenic bacterium causing pneumonia, sepsis,

meningitis, otitis media

– A leading cause of infectious disease mortality

• Global vaccine market value of $5 billion in 2013

– Led by Prevnar/Prevenar (Pfizer): $4 billion

• Commercially available vaccines sub-optimal

– Limited serotype coverage

– “Non-vaccine serotypes” increasing in incidence

– Manufacturing complexity

15

Natural clearance (TH17 CD4+ T cell-mediated)

Prevnar et al (antibody-mediated)

Intervening against

Pneumococcus

http://www.ohiohealth.com/

http://www.childrenscentralcal.org/HealthE/P02

948/Pages/P02950.aspx

GEN-004 composition

Alum

adjuvant

Novel T cell antigens

prioritized via ATLAS

T Cell

Antigen

SP1912

T Cell

Antigen

SP2108

T Cell

Antigen

SP0148

• Cover all pneumococcus serotypes

• Reduce colonization via TH17

• Complement antibody

MoA

GEN-004 Proposition

16

GEN-004: T Cell-Enabled Impact on Colonization

0

50

100

150

200

250

Alum GEN-004 WCV

Am

ou

nt

of

Co

lon

iza

tio

n

(CF

Us

)

Parenteral administration

WCV = non-encapsulated killed whole bacteria

+ Alum

p<0.001 p<0.001

Nasopharyngeal colonization after 3 immunizations

GEN-004: Effect in Mouse Colonization Model

17

GEN-004: Phase 1 Trial

• Patients: 90 healthy adult volunteers ages 18-50

• Trial design: – Randomized, double-blind, dose-escalation

– 5 dosing groups of ~18: • Placebo

• Proteins only

• GEN-004 (10 µg of each protein + 350 µg alum)

• GEN-004 (30/350)

• GEN-004 (100/350)

– 3 doses at 1 month intervals

• Objectives: – Safety and tolerability

– Immune responses: especially T cell (IL-17)

18

Potentially the first protein subunit pneumococcus vaccine to demonstrate TH17 response

GEN-001: An elusive vaccine against Chlamydia

trachomatis

• C. trachomatis development cycle poses challenges

to development of immune response

• Compelling evidence that both B cell and T cell

immunity play a role in developing protection

• A vaccine that effectively stimulates both B cell and

T cell responses to specific C. trachomatis antigens

may help confer protection

19

GEN-001: Cohort-based screening identify a small number of Ag

0

5

10

15

20

25

30

35

40

45

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39

Per

cen

t R

esp

on

der

s

Clone (arbitrary)

** **

CD4+

0

5

10

15

20

25

30

35

40

45

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52

Per

cen

t R

esp

on

der

s

Clone (arbitrary)

Protected

Unprotected

** **

CD8+

**p<0.05; all others p<0.1

(Spont. resolution + Exposed)

(Persisting Infection + PID)

20

15

17

19

21

23

25

27

29

31

33

35

0 50 100 150 200

Pe

rce

nt

Re

spo

nd

ers

Clone (arbitrary)

CD8

CD4

GEN-001: Immunodominance and Protection Do Not

Correlate

“Protective” Antigen

TFI Antigen

+

+

21

Co

py

Nu

mb

er

DN

APBS

UVEB

GB04

2

GB04

2 +

MM

GB04

4

GB04

4 +

MM

10

100

1000

10000

100000 p<0.065

NS

• Design

– Mice immunized with GB042 (top CD4 antigen) and GB044 (TFI associated immunogenic antigen)

– Quantitative PCR to detect Chlamydia DNA in oviducts

• Results

– GB042 significantly decreased bacterial burden in the oviducts

– GB044 increased bacterial burden in oviduct

• Takeaway: “Bad” antigens associated with pathology do not clear Chlamydia even if they are immunogenic

GEN-001: Pathology-associated Antigens May Not Protect

22

GEN-005: Malaria, a global Unmet Medical Need

• Endemic to over 100 nations and territories

– Over 200 million cases annually

– Estimated 600,000 deaths annually.

– 90% of these deaths occur in sub-Saharan Africa, (mostly children > 5yo)

– ~ $12B in annual expenses in Africa

• Prevention

– Insecticide-treated mosquito nets (ITNs), indoor spraying with residual insecticides

– Draining of swamps / marshes

– Chemoprophylaxis available, but cumbersome.

• Standard of care

– Artemisinin-based combination therapy (ACT, current std of care)

– Rise of Antimalarial drug resistance

• Vaccines against Malaria

– There are currently no licensed vaccines against malaria………….

24

GEN-005 : targeting the hepatic stage of P. falciparum

Plasmodium in liver

5-16 days after

mosquito bite Plasmodium in

bloodstream for

~30 min

Plasmodium in

blood 17-20 days

post bite.

Recurrent fevers

(1-3 days)

Liver Stage: CD8+ T-Cell

25

GEN-005 in the context of the MVI portfolio

12

14

1

RTS,S/AS01E-GSK CSP based

Phase III trial ongoing: 25%~50%

protection(Oct, 2013 updated)

Strong antibody response, lack of

cellular response

Prevent and

reduce

clinical

illness

No clinical

symptoms Block

transmission

ATLAS screening

GEN-005

26

GEN-005: pre-erythrocytic Proteome Library Design

Complete Proteome

5,300 ORF

Build 3:

+430 ORF

Build 2:

+288 ORF

Build 1:

901 ORF

27

Human Plasmodium in

human liver cells

Murine Plasmodium

in murine liver cells

GEN-005: Clinical cohorts exhibiting sterilizing immunity

RAS

radiation-attenuated sporozoites

immunization by mosquito bites, large # infected bites

CPS

Live non-attenuated sporozoites

Immunization by mosquito bites, small # infected bites

Administered during chloroquine prophylaxis

PfSPZ

Cryo-, purified radiation-attenuated sporozoites

Immunization by intravenous injection (IV), high dose

All three approaches have been shown to induce

100% sterilizing immunity against Controlled

Human Malaria Challenges (CHMI)

28

GEN-005: Genocea’s Screening Plan

Sample Set Institution Samples Library scale Significance Completion

PfRAS NMRC

(Richie) 24 735 ORF

Vaccination, 50% sterilizing immunity (19??)

3Q2013

Endemic (US immigrants)

ASC (Bronx, NY)

100 735 ORF Natural Immunity 3Q2013

CPS RUNMC

(R. Sauerwein) 42 132 ORF

Vaccination, 100% sterilizing immunity (2011)

2Q2014

Endemic (Mali)

NIAID (P. Crompton)

40 735 ORF Natural Immunity 3Q2014

PfSPZ NIAID, Sanaria

(Seder/Hoffman) ~40 ~1,000 ORF

Vaccination, 100% sterilizing immunity (2013)

4Q2014*

PfSPZ NHP NIAID

(Seder) TBD ~1,000 ORF

Peripheral vs. Hepatic responses

4Q2014

PfRAS (IMRAS) NMRC, BMGF 88 >1,500 ORF Vaccination (2014-15) 4Q2105

CPS RUNMC

(R. Sauerwein) 20 >1,500 ORF Vaccination (2015) 2Q2015

29

GEN-005: screening of 8 RAS patients provisionally

identifies novel candidates not previously considered

30 June 24, 2014

Confidential

Gene Class N Percentage

DNA & RNA metabolism 15 (12.4%)

Signaling 8 (6.6%)

Unknown or hypothetical 51 (42.1%)

Cellular Transactions 21 (17.4%)

Energy Metabolism 19 (15.7%)

Structural 3 (2.5%)

Pathogenicity 4 (3.3%)

Genocea’s ATLASTM platform…

• Has broad shoulders – Can identify new Antigen Candidates (GEN-003/4/1)

– Can be customized to address various effector mechanisms (Cytotoxic CD8 T cells, Th1 CD4, Th17 CD4).

– Has generated POC in Phase Ia clinical trials (GEN-003)

• Can do the heavy-lifting – The team at Genocea has successfully built expression libraries

containing FL ORF from organisms as divergent as viruses, bacteria, protozoans and now human.

– Many hundred samples were successfully screened

– Two programs completed pre-clinical development and PhI manufacturing campaigns

• Can make a difference

31

Acknowledgements

32

Richard Malley

Kristin Moffitt

Yingjie Lu

GEN-003: HSV-2

GEN-003-001 trial participants

University of Washington

Westover Heights Clinic

Indiana University School of Medicine

Center for Clinical Studies, Houston TX

Center for Clinical Studies, Webster TX

IND 2 Results

University of Alabama Birmingham

Cincinnati Children’s Medical Center

Rho, Inc.

William Geisler Edward W. Hook

Amy Scurlock Suzanne Trupin

Jeff Klausner

Toni Darville

CAPT Thomas Richie

CAPT Eileen Villasante

Joao Aguiar

Noelle Patterson

Jessica Bolton

Stefan Kappe

Alexis Kaushansky

Kim Nichols

GEN-005: Malaria GEN-001: Chlamydia

GEN-004: S. pneumoniae Robert Seder

Andrew Ishizuka

Peter Crompton

Robert Sauerwein

Else Bijker

..And the team

at Genocea…

Acknowledgements

33 June 2014

Summer 2013

Winter 2011