Abstract 1068: Anti-DR5 agonist IgM antibody IGM-8444 combined with SMAC mimetic birinapant induces strong synergistic tumor cytotoxicity
Authors: Wang Beatrice T. , Desbois Melanie , Calhoun Susan E. , Matthew Thomas J. , Yakkundi Poonam , Wang Ling , Chen Xingjie , Kothambawala Tasnim , Oyasu Miho , Kotturi Maya F. , Hernandez Genevive , Liu Xiaohan , Peterson Marvin S. , Humke Eric W. , Keyt Bruce A. , Sinclair Angus M. 
Published: June 2022

Abstract
Apoptosis is induced through extrinsic and intrinsic signaling pathways. Extrinsic apoptosis can be activated through multimerization of death receptor 5 (DR5), a tumor necrosis factor (TNF) receptor family member highly expressed in many cancers. However, cellular resistance mechanisms within the intrinsic pathway may limit DR5 activity, including inhibitor of apoptosis proteins (IAPs) that block caspase activity or promote pro-survival NFκB signaling. Second mitochondria-derived activator of caspases (SMAC) is an endogenous bivalent IAP antagonist. Birinapant, a bivalent SMAC mimetic that binds and degrades IAPs, has been evaluated through Phase 2, demonstrating good safety and on target activity but minimal efficacy as a monotherapy. We hypothesized that simultaneously targeting the extrinsic apoptotic pathway with IGM-8444, an anti-DR5 multivalent IgM agonist, and the intrinsic apoptotic pathway with birinapant could enhance tumor cell apoptosis. Human cancer cell lines including triple negative breast cancer (TNBC), head and neck, ovarian, colorectal, lung, and sarcomas, were screened for sensitivity to IGM-8444 and birinapant combination. Strong synergistic cytotoxicity was observed in vitro in 36/45 (80%) cancer cell lines, as measured by both Bliss synergy score and maximal killing. IGM-8444 and birinapant combination also induced synergistic cytotoxicity in cells with acquired resistance to DR5 agonist antibodies. By contrast, IGM-8444 and birinapant did not kill primary human hepatocytes in vitro, demonstrating the potential clinical safety for this combination. In vivo, the IGM-8444 and birinapant combination dose-dependently reduced tumor growth in a MDA-MB-231 TNBC model, with 8/10 tumor-free mice at the highest dose of birinapant tested. By comparison, birinapant combination with an anti-DR5 IgG agonist showed a modest response. IGM-8444 and birinapant also showed significant anti-tumor responses in additional cell line and patient-derived xenograft models, including 7/9 tumor-free animals in a HT-1080 fibrosarcoma model and 9/10 complete responses in a EBC-1 lung squamous cell lung carcinoma model. Lastly, pharmacodynamic biomarkers including cIAP1 degradation, caspase activation, and caspase-cleaved cytokeratin 18 in tumor and serum correlated with anti-tumor response. In summary, combined targeting of the extrinsic and intrinsic apoptotic pathways with IGM-8444 and birinapant respectively enhances tumor cytotoxicity in multiple preclinical models. The combination of IGM-8444 with birinapant is currently under evaluation in a Phase 1 study in patients with relapsed and/or refractory solid cancers (NCT04553692).
Citation Format: Beatrice T. Wang, Melanie Desbois, Susan E. Calhoun, Thomas J. Matthew, Poonam Yakkundi, Ling Wang, Xingjie Chen, Tasnim Kothambawala, Miho Oyasu, Maya F. Kotturi, Genevive Hernandez, Xiaohan Liu, Marvin S. Peterson, Eric W. Humke, Bruce A. Keyt, Angus M. Sinclair. Anti-DR5 agonist IgM antibody IGM-8444 combined with SMAC mimetic birinapant induces strong synergistic tumor cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1068.