S227928: A Novel Anti-CD74 ADC with MCL-1 Inhibitor Payload for the Treatment of Acute Myeloid Leukemia (AML) and Other Hematologic Malignancies

• Published in: Blood 2024-11, Vol.144, p.1381-1381
• Main Authors: Maragno, Ana-Leticia, Seiss, Katherine, Newcombe, Rick, Mistry, Prakash, Schnell, Christian R, Von Arx, Fabian, Koenig, Julie, Malamas, Anthony S, Le Toumelin-Braizat, Gaetane, Bresson, Laura, Rocchetti, Francesca, Demarles, Didier, Kurth, Esther, Renteria, Lorena, Hainzl, Dominik, Engelhardt, Volker, Liot, Caroline, Madelain, Vincent, Kostova, Vesela, Starck, Jérôme-Benoit, Valour, Damien, Franzetti, Georges-Alain, Colland, Frederic, Vostiarova, Helena, Tschantz, William R, Bachmann, Nicholas, Palacio-Ramirez, Sebastian, Burger, Matthew T, Campbell, Jennifer M, Chen, Zhuoliang, Koenig, Robert, McNeill, Eric, Mo, Ruowei, Nakajima, Katsumasa, Palermo, Mark G, Shen, Yiping, Yu, Bing, Zambrowski, Mark, Zhang, Alan, Zecri, Frederic, Broniscer, Alberto, Geneste, Olivier, Horton, Kristin, D'Alessio, Joseph A
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-210048

Introduction Overexpression of MCL-1 is a well-known mechanism of resistance to venetoclax (ven), a BCL-2 inhibitor. MCL-1 inhibition has shown promising responses in preclinical models of AML in combination with BCL-2 inhibitors leading to tumor regression and prolonged survival. Despite the enthusiasm in testing MCL-1 inhibitors as a treatment strategy in AML, clinical development of MCL-1 inhibitors has been limited by cardiac and gastrointestinal toxicities, which have precluded the delivery of therapeutic doses and led to the discontinuation in clinical evaluation of multiple agents. Hence, new strategies are warranted to achieve MCL-1 inhibition with higher therapeutic margin. Results S227928 is an ADC that couples an MCL-1 inhibitor payload, S64315 (aka MIK665), to an anti-CD74 monoclonal antibody via a cleavable valine-citrulline polyethylene glycol (PEG24) linker. Analysis of RNAseq expression databases and surface expression analysis by flow cytometry (FC) demonstrates that CD74 is highly expressed in several hematologic neoplasms, including AML. CD74 is expressed on the cell surface as the invariant chain of MHC class II and is the receptor for macrophage migration inhibitory factor. Evaluation of 28 primary AML samples by FC revealed CD74 expression in myeloid cells and leukemic blasts, with >60% of patients showing >50% of myeloid cells positive for the target. RNAseq and immunohistochemistry (IHC) analyses showed that physiological expression of CD74 is mainly restricted to cells of hematologic origin, with no expression in liver, gastrointestinal tract, or cardiomyocytes. S227928 demonstrates CD74-specific binding and cell-killing in CD74-expressing AML cell lines as compared to an isotype control ADC. Cytotoxicity correlates with MCL-1 inhibition. Intracellular payload release and target engagement were confirmed by detection of payload measured by LC MS/MS (liquid chromatography tandem mass spectrometry) and a dose-dependent disruption of MCL-1/BIM complex measured via AlphaLISA assay, respectively. In the AML-derived EOL-1 cell line, the MCL-1/BIM complex was more potently disrupted by the ADC compared to the S64315 payload (IC50 0.03 nM vs 0.41 nM), demonstrating enhanced intracellular accumulation of payload via ADC deliverythan with the small-molecule inhibitor. While single agent S227928 showed modest activity in in vitro and in vivo AML preclinical models, S227928 demonstrated potent anti-tumor activity when combined with ven in AML