IMGN632 is a novel CD123-targeting antibody-drug conjugate composed of a humanized anti-CD123 antibody and a DNA-alkylating IGN payload. IMGN632 is currently in Phase I dose escalation in patients with relapsed/refractory AML or BPDCN (NCT03386513), demonstrating responses across a wide range of doses. Venetoclax, a BCL-2 inhibitor, lowers the apoptotic threshold and was recently approved for elderly AML patients in combination with azacitidine. By combining these potentially synergistic anti-leukemic mechanisms in pre-clinical AML models, the increased pro-apoptotic signaling enabled by BCL-2 inhibition would act in concert with the pro-apoptotic effects of DNA damage caused by IMGN632.
The combination of IMGN632 and venetoclax was evaluated in pre-clinical AML models.
The IMGN632 plus venetoclax combination was evaluated in vitro in four AML cell lines (MV4–11, MOLM-13, KG-1, EOL-1), in vivo in two subcutaneous AML xenograft models (EOL-1, KG-1), and in vivo in two AML PDX models. In subcutaneous models, tumor volume was measured, complete regressions (CRs) were noted, and endpoint was determined by either clinical observations or when tumor volume reached 1000 mm3. In PDX models, survival was measured.
In vitro synergy was observed in 3 of the 4 cell lines tested at doses ranging from 0.5 pM to 8 pM for IMGN632, and 0.625 nM to 20 nM for venetoclax (MV4–11, MOLM-13, EOL-1), and 1 nM to 1 μM for IMGN632, and 100 nM to 1 μM for venetoclax in the KG-1 cell line, with optimal combination indexes (CI) of 0.023 (KG-1), 0.497 (MV4–11), 0.377 (MOLM-13), and 0.67 (EOL-1), indicating strong synergy across most of the cell lines tested. In the EOL-1 model (see Figure Panel A), the combination [IMGN632 (80 μg/kg, one intravenous dose) plus venetoclax (100 mg/kg, orally, daily x28)] was highly active, resulting in 4/6 CRs and a 0% T/C (percent treatment to control of the median tumor volume, at control endpoint), compared to the corresponding inactive venetoclax (1/6 CR, 69% T/C) and active IMGN632 (2/6 CRs, 11% T/C) single agents. Importantly, the four mice treated with the combination who achieved CRs remained in remission through the end of the study at >60 days. In the IMGN632-resistant KG-1 model, the combination [IMGN632 (800 μg/kg, intravenous, weekly x3) plus venetoclax (100 mg/kg, orally, daily x28)] was active (40% T/C) while corresponding single agent IMGN632 (73% T/C) and venetoclax (81% T/C) were inactive. In a venetoclax-responsive AML PDX model (NRASm, EZH2m; see Figure Panel B), the combination [low dose IMGN632 (24 μg/kg, intravenous, weekly x3) plus venetoclax (100 mg/kg, orally, daily x28)] showed 124% ILS (% increased life span), with a median survival of 148 days. This was superior to venetoclax alone (77% ILS; median survival of 117 days) and IMGN632 alone (0% ILS; median survival of 65 days). Similarly, this same combination regimen was active (40% ILS; median survival of 108 days) in a second AML PDX model (FLT3-ITD, IDH1m), while IMGN632 (10% ILS; median survival of 85 days) and venetoclax (6% ILS; median survival of 82 days) single agents were inactive.
The combination of IMGN632 and venetoclax demonstrated synergistic cytotoxicity in vitro and greater tumor growth inhibition and prolonged survival in vivo. Collectively, these results provide support for testing the combination of IMGN632 and venetoclax in AML patients.