Abstract 1160: Debio 1562M, a 2ndgeneration ADC targeting CD37, shows high potency against AML and MDS and safe toxicological profile for future clinical development

Abstract CD37 is a trans-membrane protein exclusively expressed in hematopoietic tissues. Increased CD37 expression has been measured on malignant B-cells and its relevance as an attractive therapeutic target has been confirmed in several clinical trials. In acute myeloid leukemia (AML), increased CD37 expression on blasts and leukemic stem cells (LSCs) has also been reported, both at protein and mRNA levels. This increased expression is restricted to malignant cells compared to hematopoietic stem cells and correlates with poor patient outcome.We confirmed broad expression of CD37 across patients in 53 AML and 15 MDS primary samples and observed a strong internalization capability particularly suitable for an ADC therapy. Debio 1562M, a 2nd generation CD37-targeting ADC, is active at sub-nanomolar level across all AML models evaluated, irrespective of their treatment history, physiological subtype, genetic alterations, or mutation background. Sensitivity to Debio 1562M was not correlated with CD37 expression level suggesting a development in all comer’s population.We assessed the effect of Debio 1562M on LSCs derived from 14 primary AML samples, where a 10nM treatment was able to decrease the number of colony formation by 80% compared to control. Additionally, we confirmed the capacity of Debio 1562M to reach tumor cells present in the bone marrow (BM) of NSG mice inoculated with MOLM-13 AML cells, suggesting that tumor cells in the BM can be targeted by Debio 1562M to allow LSCs elimination. Debio 1562M activity was benchmarked against several targeted therapies such as menin, FLT3, IDH1 and IDH2 inhibitors or gemtuzumab ozogamicin (GO) CD33-targeting ADC, in different in vivo models. In MOLM-13 xenografted mice, Debio 1562M induced tumor regression after a single injection similarly to GO, while the menin inhibitor revumenib achieved tumor stasis with twice daily administrations and the FLT3 inhibitor gilteritinib only achieved partial response after daily administrations. Similarly, in 4 patient-derived xenograft models bearing FLT3, IDH1 or IDH2 mutations, Debio 1562M led to greater circulating blast reduction compared to gilteritinib, ivosidenib IDH1 inhibitor and enasidenib IDH2 inhibitor. In summary, Debio 1562M monotherapy shows superior activity than targeted therapies in preclinical AML models.The toxicological profile of Debio 1562M in mice showed expected off-target toxicity related to the payload’s activity. On-target toxicity profile of Debio 1562M could not be evaluated due to lack of cross-reactive species, however no significant toxicity on human PBMCs was observed in vitro. In conclusion, the promising antitumor activity and tolerability of Debio 1562M in preclinical models pave the way for entering clinical development in AML in 2025. Citation Format: Lisa Ivanschitz, Josée Hue-Perron, Alain Monjardet, Noemie Luong, Esthela Artiga, Karilyn T. Larkin, Leo Marx. Debio 1562M, a 2ndgeneration ADC targeting CD37, shows high potency against AML and MDS and safe toxicological profile for future clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1160.