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A better immunotoxin against cancer Monoclonal antibodies VL Ck VH C 1 H CH1 Ck IgG VH VL Gets cancer cells to commit suicide Get immune system to kill cancer cells Examples: Rituximab, Alemtuzumab, Herceptin Radiolabeled Monoclonal antibodies VL Ck VH C 1 H CH1 Ck IgG VH VL Targets radiation to the cancer cell Examples: Zevalin, Bexxar Immunotoxins VL Ck VH C 1 H CH1 Ck IgG VH VL Inhibition of protein synthesis Cell death TOXIN RECOMBINANT IMMUNOTOXINS VL Ck VH C 1 H CH1 Ck RFB4 VH VL VL VH -s-s- C 3 II Ib III Ib III BL22 Ia II PE CD22 BL22 III II REDL II III S III S II Ia VL VH -s-s- II III RFB4(dsFv)-PE38 (BL22) ENDOSOMES REDL III II REDL III Ia II SH H S II COATED PIT III PE38 III III III SHUTTLE II PSEUDOMONAS EXOTOXIN III II III II II ER II Ia GOLGI III II II EF2 KDEL RECEPTOR CYTOSOL 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. Phase I Trial of BL22 in CdA-Resistant HCL Summary • Response: Total CR PR CR+PR 31 19 (61%) 6 (19%) 25 (81%) • 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 HCL Results Retreat 56% CR: HR: PR: SD: Complete remission Hematologic remission (good blood counts) Partial remission (>50% improvement) Stable disease PD: Progressive disease Conclusions: • One cycle highly active • Retreatment improved best response Disease-Free Survival (%) Phase II Disease-free survival 100 80 | | | || | | | | | | | 60 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 Months from beginning BL22 60 /mm 3 g/dl CELLS/mm 3 x10 -3 Complete remission with BL22 4 3 2 1 0 300 C1 250 200 150 100 50 0 18 16 C1 14 12 2000 C1 1500 1000 500 0 0 ANC C2 C3 PLATELETS Col 4 vs Col 10 C2 HGB C3 HCL 50 PLATELETS C3 HGB C2 ANC 100 150 200 250 HCL 300 29003100 DAY OF BL22 PROTOCOL Resolution of Splenomegaly with BL22 Pre (Height = 250 mm) C7D1 (Height = 125 mm) CD4 counts in HCL Pre and Post BL22 CD4 count (cells/ul) 1000 800 600 400 200 0 Pre Post 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: BL22 LMB: IRA PASTAN DAVID J.P. FITZGERALD Q.C. WANG MASANORI ONDA G. SALVATORE B.K. LEE CLINICAL IMMUNOTHERAPY SECTION, LMB INGER MARGULIES EVGENY ARONS KAKUSHI MATSUSHITA ROBERTA TRAINI TARA SUNUM RAJAT SINGH rIMMUNOTOXIN CLINICAL TEAM (CCR) LINDA ELLISON ELIZABETH MAESTRI RAFFIT HASSAN RITA MINCEMOYER BARBARA DEBORAH SONYA DUKE EMORY: HARRY FINDLEY PATHOLOGY: MARYALICE STETLER- STEVENSON ELAINE S. JAFFE MARK RAFFELD MEDICINE / PED BRANCH: WYNDHAM H. WILSON ALAN WAYNE MARP FACILITY (DTP): STEVE GIARDINA DANIEL COFFMAN TOBY HECHT MedImmune: BOB LECHLEIDER KATHERINE KAUCIC PHARMACY: GEORGE GRIMES DAVID KOHLER HEMATOLOGY: PIERRE NOEL, MARGARET RICK, JAY LOZIER /mm 3 C1 3 2 1 0 300 200 100 0 g/dl CELLS / mm3 x 10-3 BL22 PATIENT BH20 ANC (Neutrophils) ANC (Neutrophils) C1 PLATELETS PLATELETS C1 14 12 10 8 10 Hemoglobin (Red cells) Hemoglobin (Red cells) C1 Hairy cell count Hairy cell count 5 0 -25 0 25 50 75 100 500 DAY OF BL22 PROTOCOL 1000