Abstract B144: MUC16-directed DR5 activation by IMV-M induces selective tumor cell apoptosis and tumor regression and enhances the activity of KRAS inhibitors in preclinical pancreatic cancer models

Abstract

Bispecific apoptosis triggers (BATs) are a novel class of bispecific antibodies designed to target both a tumor-associated antigen and death receptor 5 (DR5) that have shown improved efficacy and reduced toxicity compared to conventional DR5 antibody therapeutics in preclinical models. IMV-M is a novel bivalent BAT that targets the tumor-associated antigen Mucin 16 (MUC16) and DR5 (Goldmacher, et al. Sci. Rep., 2025). MUC16 is a tumor-associated cell surface glycoprotein overexpressed in multiple malignancies, and its shed extracellular domain, CA125, is used as a biomarker in ovarian and pancreatic cancer. In this study, we demonstrate that IMV-M selectively induces apoptosis in a panel of MUC16-positive pancreatic cancer cell lines in vitro. The extent of apoptosis induction and inhibition of cell proliferation by IMV-M were concentration-dependent and correlated with cell surface MUC16 expression and CA125 levels in conditioned media. Single-agent IMV-M demonstrated potent antitumor activity in pancreatic cancer models, achieving sub-nanomolar potency in vitro (IC50 <0.05 nM in MUC16+ cell lines) and inducing complete tumor regressions following single-dose (5 mg/kg, i.v.) treatment in mouse xenograft models. Furthermore, the antitumor activity of IMV-M was enhanced when combined with the RAS inhibitors RMC-6236 and RMC-9805, supporting the potential development of combination regimens with KRAS-directed therapies that have demonstrated promising clinical activity in pancreatic cancer. Collectively, these findings demonstrate that IMV-M exhibits potent and selective antitumor activity against MUC16-positive pancreatic cancer models through targeted DR5 activation. Given that MUC16 is expressed in approximately 80% of pancreatic ductal adenocarcinomas (Streppel et al. Hum. Pathol. 2011), these results support clinical evaluation of IMV-M as a potential therapeutic strategy for patients with this devastating disease. Haiyong Han, Matthew S. Zucker, Sanjana Tripuraneni, Ruben M. Munoz, Kuntal Halder, Arnav Hingorani, Iosif Gershteyn, Victor S. Goldmacher, Daniel D. Von Hoff. MUC16-directed DR5 activation by IMV-M induces selective tumor cell apoptosis and tumor regression and enhances the activity of KRAS inhibitors in preclinical pancreatic cancer models [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B144.