A better immunotoxin

against cancer

C 3

C 2

C 3

C 2

C 1

CkH

H

H

H

H

VH VL

C 1

Ck

HIgG

VH

VL

Monoclonal antibodies

Gets cancer cells to commit suicideGet immune system to kill cancer cellsExamples: Rituximab, Alemtuzumab, Herceptin

C 3

C 2

C 3

C 2

C 1

CkH

H

H

H

H

VH VL

C 1

Ck

HIgG

VH

VL

Radiolabeled Monoclonal antibodies

Targets radiation to the cancer cellExamples: Zevalin, Bexxar

C 3

C 2

C 3

C 2

C 1

CkH

H

H

H

H

VH VL

C 1

Ck

HIgG

VH

VL

Immunotoxins

Inhibition of protein synthesisCell death

TOXIN

C 3

C 2

C 3

C 2

C 1

CkH

H

H

H

H

VH VL

C 1

Ck

H

RFB4

Ib III IIIa

PE

BL22

VL VH

Ib III IIC 3

VH

VL

RECOMBINANT IMMUNOTOXINS

-s-s-

IIIII

ER

ENDOSOMES

GOLGI

COATED PIT

III

IaII

SS

II

REDL

SH

III S HREDL

III

II

III II

III II

III II

EF2

III II

SHUTTLE

CYTOSOL

KDELRECEPTOR

IIIIa

II

REDL

IIIIIIRFB4(dsFv)-PE38 (BL22)

VL VH

-s-s- III II

IIIII

CD22

III IIIa

PSEUDOMONAS EXOTOXIN

BL22

III II

PE38

HAIRY CELL LEUKEMIAB-cell leukemia2% of all Leukemias Low blood countsSplenomegaly (large spleen)Cytoplasmic projections

Treatment of HCLCladribine (CdA) and Pentostatin (DCF) can induce long term CRs but have not been shown to cure the disease. They have decreased efficacy with each repeated course.

Phase I Trial of BL22 in CdA-Resistant HCLSummary

• Response:

• CR rate 86% at high doses, 41% at low doses

• Most (11/19) CRs were after just 1 cycle • Toxicity: Most commonly temporary fluid retention

Kreitman et al., NEJM, 345:241, 2001, Kreitman et al., JCO, 23:6719, 2005

Phase II Trial of BL22 in HCLResults

Conclusions: • One cycle highly active • Retreatment improved best response

Retreat 56%

CR: Complete remissionHR: Hematologic remission (good blood counts)PR: Partial remission (>50% improvement)SD: Stable disease PD: Progressive disease

Phase II Disease-free survival

Months from beginning BL220 10 20 30 40 50 60

n=17 (Patients achieving CR)

Median CR duration = 31+ (5-59+) mo

12/17 (71%) still in CR

Dis

ease

-Fre

e S

urv

ival

(%

)

0

20

40

60

80

100

| || || | | | | | | |

CE

LL

S/m

m3 x

10

-3g

/dl

/mm

3

ANC

Col 4 vs Col 10

ANC

01234

PLATELETS0

50100150200250300 C1 C2 C3

HGB12141618

C1 C2 C3

HCL

DAY OF BL22 PROTOCOL0 50 100 150 200 250 300

0500

100015002000 C1 C2 C3

PLATELETS

HGB

HCL

29003100

Complete remission with BL22

Resolution of Splenomegaly with BL22

Pre C7D1(Height = 250 mm) (Height = 125 mm)

CD4 counts in HCL Pre and Post BL22

Pre Post

CD

4 co

un

t (c

ells

/ul)

0

200

400

600

800

1000

Conclusions:

• Hairy cell leukemia is a chronic leukemia which shows no evidence of cure with standard chemotherapy, so patients who are young may die of this disease without alternative treatment.

• BL22 is highly active in HCL despite patients not responding to standard HCL therapy.

• Compared to standard chemotherapy, BL22 is not toxic to normal T-cells and does not even have prolonged damage to normal B-cells.

• HA22 (CAT-8015), an improved version of BL22, is completing Phase I testing in HCL.

COLLABORATORS: BL22LMB: MEDICINE / PED BRANCH:IRA PASTAN G. SALVATORE WYNDHAM H. WILSON DAVID J.P. FITZGERALD B.K. LEE ALAN WAYNEQ.C. WANGMASANORI ONDA

CLINICAL IMMUNOTHERAPY SECTION, LMBINGER MARGULIES EVGENY ARONSKAKUSHI MATSUSHITA ROBERTA TRAINITARA SUNUM RAJAT SINGH MARP FACILITY (DTP):rIMMUNOTOXIN CLINICAL TEAM (CCR) STEVE GIARDINALINDA ELLISON ELIZABETH MAESTRI DANIEL COFFMANRAFFIT HASSAN RITA MINCEMOYER TOBY HECHTBARBARA DEBORAH SONYA DUKE

EMORY: HARRY FINDLEY MedImmune: BOB LECHLEIDERKATHERINE KAUCIC

PATHOLOGY: MARYALICE STETLER- STEVENSON PHARMACY:ELAINE S. JAFFE MARK RAFFELD GEORGE GRIMES

DAVID KOHLERHEMATOLOGY: PIERRE NOEL, MARGARET RICK, JAY LOZIER

ANC (Neutrophils)

BL22 PATIENT BH20

CE

LL

S /

mm

3 x 1

0-3

0123

C1

PLATELETS0

100200300 C1

Hemoglobin (Red cells)

g/d

l

8101214 C1

Hairy cell count

-25 0 25 50 75 100

DAY OF BL22 PROTOCOL

/mm

3

0

5

10 C1

ANC (Neutrophils)

PLATELETS

Hemoglobin (Red cells)

Hairy cell count

500 1000