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.