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A better immunotoxin against cancer

A better immunotoxin against cancer. V. L. V. H. V. V. H. L. Monoclonal antibodies Gets cancer cells to commit suicide Get immune system to kill cancer cells Examples: Rituximab, Alemtuzumab, Herceptin. C 3. H. C. C 3. k. C 2. H. H. C 2. C 1. H. H. C. C 1. H. k.

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A better immunotoxin against cancer

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  1. A better immunotoxin against cancer

  2. V L V H V V H L Monoclonal antibodies Gets cancer cells to commit suicide Get immune system to kill cancer cells Examples: Rituximab, Alemtuzumab, Herceptin C 3 H C C 3 k C 2 H H C 2 C 1 H H C C 1 H k IgG

  3. V L V H V V H L Radiolabeled Monoclonal antibodies Targets radiation to the cancer cell Examples: Zevalin, Bexxar C 3 H C C 3 k C 2 H H C 2 C 1 H H C C 1 H k IgG

  4. V L V H V V H L Immunotoxins Inhibition of protein synthesis Cell death C 3 H C C 3 k C 2 H H C 2 C 1 H H C C 1 H k IgG TOXIN

  5. V L V H V V V H L L RECOMBINANT IMMUNOTOXINS C 3 H C C 3 k C 2 H H C 2 C 1 H H RFB4 C C 1 H k V H C Ib III II -s-s- 3 BL22 Ib III Ia II PE

  6. II II III III V L CD22 BL22 REDL S III S II II Ia V H ENDOSOMES REDL II III -s-s- II REDL III H S III Ia H S RFB4(dsFv)-PE38 (BL22) II II II COATED PIT III GOLGI II III II PE38 ER Ia III II III II III III II II SHUTTLE PSEUDOMONAS EXOTOXIN III II KDEL RECEPTOR EF2 CYTOSOL

  7. HAIRY CELL LEUKEMIA B-cell leukemia 2% of all Leukemias Low blood counts Splenomegaly (large spleen) Cytoplasmic projections Treatment of HCL Cladribine (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.

  8. Phase I Trial of BL22 in CdA-Resistant HCL • Summary • 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

  9. Phase II Trial of BL22 in HCL Results Retreat 56% CR: Complete remission HR: Hematologic remission (good blood counts) PR: Partial remission (>50% improvement) SD: Stable disease PD: Progressive disease • Conclusions: • One cycle highly active • Retreatment improved best response

  10. Phase II Disease-free survival 100 80 | | | | | | | | | | | | 60 Disease-Free Survival (%) 40 n=17 (Patients achieving CR) 20 Median CR duration = 31+ (5-59+) mo 12/17 (71%) still in CR 0 0 10 20 30 40 50 60 Months from beginning BL22

  11. 3 /mm 3 -3 CELLS/mm x10 Complete remission with BL22 4 3 ANC 2 ANC 1 0 300 C1 C2 C3 250 200 150 100 PLATELETS PLATELETS Col 4 vs Col 10 50 0 18 C1 C2 C3 16 g/dl 14 HGB 12 HGB 2000 C1 C2 C3 1500 HCL 1000 HCL 500 0 0 50 100 150 200 250 300 2900 3100 DAY OF BL22 PROTOCOL

  12. Resolution of Splenomegaly with BL22 Pre C7D1 (Height = 250 mm) (Height = 125 mm)

  13. 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.

  14. COLLABORATORS: BL22 LMB: MEDICINE / PED BRANCH: IRA PASTAN G. SALVATORE WYNDHAM H. WILSON DAVID J.P. FITZGERALD B.K. LEE ALAN WAYNE Q.C. WANG MASANORI ONDA CLINICAL IMMUNOTHERAPY SECTION, LMB INGER MARGULIES EVGENY ARONS KAKUSHI MATSUSHITA ROBERTA TRAINI TARA SUNUM RAJAT SINGH MARP FACILITY (DTP): rIMMUNOTOXIN CLINICAL TEAM (CCR) STEVE GIARDINA LINDA ELLISON ELIZABETH MAESTRI DANIEL COFFMAN RAFFIT HASSAN RITA MINCEMOYER TOBY HECHT BARBARA DEBORAH SONYA DUKE EMORY: HARRY FINDLEY MedImmune: BOB LECHLEIDER KATHERINE KAUCIC PATHOLOGY: MARYALICE STETLER- STEVENSON PHARMACY: ELAINE S. JAFFE MARK RAFFELD GEORGE GRIMES DAVID KOHLER HEMATOLOGY: PIERRE NOEL, MARGARET RICK, JAY LOZIER

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