A CD123-targeting Antibody-Drug Conjugate (ADC), IMGN632, designed to eradicate Acute Myeloid Leukemia (AML) cells while sparing normal bone marrow

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1 A CD123-targeting Antibody-Drug Conjugate (ADC), IMGN632, designed to eradicate Acute Myeloid Leukemia (AML) cells while sparing normal bone marrow Yelena Kovtun, Gregory Jones, Charlene Audette, Lauren Harvey, Alan Wilhelm, Chen Bai, Sharlene Adams, Ravi Chari, Thomas Chittenden ASH 216

2 CD123 as a target for AML therapy CD123 is the alpha-subunit of the IL-3 receptor Expression in AML >9% of patients express CD123 on blasts and leukemic stem cells Higher levels associated with aggressive disease and poor prognosis Expression on normal tissues Low levels on normal hematopoietic stem cells Significant levels on normal myeloid progenitors Potential for CD123-targeted therapy to produce durable responses in AML, but also cause myelosuppression 2

3 ADCs of anti-cd123 antibody with IGN payload Antibody humanized IgG1 binding to an unique epitope on CD123 engineered for precise conjugation of two payload molecules Payload novel DNA targeting Indolino-benzodiazepine dimers (termed IGNs) Cross-linking IGN (C-ADC payload) Alkylating IGN (A-ADC payload) Linker peptide, stable in circulation 3

4 Proposed mechanism of cell killing by Antibody-IGN conjugates 1. ADC binding to CD123 triggers internalization and trafficking to lysosomes 2. In lysosomes, antibody and linker are catabolized releasing cytotoxic payload 3. The payload diffuses into the nucleus and binds, alkylates or cross-links DNA, inducing cell cycle arrest and 4. apoptotic cell death 4

5 Alkylating ADC (A-ADC) and cross-linking ADC (C-ADC) are active in multiple CD123-positive AML cell lines in vitro IC 5, M Eleven AML CD123-positive cell lines with poor prognostic factors (FLT3-ITD, P53, EVI1, MDR1) were tested ADC cytotoxicity 1-1 Both ADCs are highly active Blocking CD123 reduced ADC potency ~ 5-fold CD123 block A-ADC C-ADC 5

6 Both A-ADC and C-ADC are ~ 1-fold more active than Mylotarg on primary AML samples IC 9, M Samples from 17 AML patients, including 4 relapsed/refractory and 1 with multi-drug resistance tested in CFU assays ADC cytotoxicity 1-1 Unlike Mylotarg, A-ADC and C- ADC are highly active against all samples A -A D C C -A D C M y lo ta r g 6

7 M e d ia n T u m o r V o lu m e (m m 3 ) Comparable activity of A-ADC and C-ADC in AML xenograft models in vivo P e rc e n t s u rv iv a l Model resistant to SoC* EOL-1 subcutaneous * Cytarabine and Azacitidine Model with FLT3-ITD MV4-11 disseminated D a y s P o s t In o c u la tio n V e h ic le A -A D C - 4 m c g /k g A -A D C - 8 m c g /k g C -A D C - 4 m c g /k g C -A D C - 8 m c g /k g Ab dose D a y (p o s t in o c u la tio n ) Both ADCs at 8 mcg/kg single dose are highly active At 4 mcg/kg - A-ADC is at least as active as C-ADC 7

8 B o d y W e ig h t C h a n g e (% ) B o d y W e ig h t C h a n g e (% ) 8 A-ADC is better tolerated than C-ADC in tumor free CD-1 mice At 6, mcg/kg A-ADC is well tolerated in mice, C-ADC is toxic 6 A-ADC, 6, mcg/kg 6 C-ADC, 6, mcg/kg At lower doses mice treated with C-ADC lose weight weeks after dosing 6 4 C-ADC, 4, mcg/kg 6 4 C-ADC, 2,8 mcg/kg D a y s P o s t In je c tio n D a y s P o s t In je c tio n

9 C D le v e ls Normal human myeloid progenitors are affected by C-ADC in vitro 1 5 CD123 levels on normal bone marrow cells (n=1) Apoptotic (C-caspase-3) signal CMP C-ADC treated cells Monocytes 1 5 MPP CLP Black no treatment Green cells treated with 1pM A-ADC Blue cells treated with 1pM C-ADC Neither ADC affects Multi-Potent Progenitors (MPP), Common Lymphoid Progenitors (CLP) or monocytes C-ADC, but not A-ADC, induces apoptosis of Common Myeloid Progenitors (CMP) H S C M P P C L P C M P M o n o c y te s 9

10 IC 9, [ADC, M] A-ADC, but not C-ADC or Mylotarg, displays pronounced preferential killing of AML over normal myeloid progenitors Normal bone marrow (n=12) and AML (n=17) samples tested in GM-CFU assays A-ADC is ~ 5 fold less cytotoxic than C-ADC to normal myeloid progenitors 1-7 A-ADC C-ADC Mylotarg fold fold fold N o r m a l A M L. N o r m a l A M L. N o r m a l A M L 1

11 % S u rv iv a l A-ADC (IMGN632) is highly active in multiple AML models with poor prognostic factors in vivo Kasumi-3-Luciferase model (P53 and MDR) * IMGN632 reduced tumor burden and extended survival in 6/6 mice Control non-binding ADC 1 IM G N IMGN632 V e h ic le C o n tro l A D C D a y s P o s t In o c u la tio n * Y.Kovtun et al., EHA 216 poster 4122 IMGN632 high activity in additional in vivo models ** ** S. Adams et al., ASH 216 poster

12 Summary The alkylating ADC (IMGN632) is better tolerated in mice and less cytotoxic to normal myeloid progenitors than the crosslinking ADC IMGN632 is highly active in: AML cell lines with poor prognostic factors in vitro multiple AML models in vivo samples from all AML patients in vitro at concentrations that are non-toxic to bone marrow cells and 1-fold lower than Mylotarg Phase 1 trial for IMGN632 in AML and other CD123-positive malignancies is planned for