A bispecific anti-MUC16/anti-death receptor 5 antibody achieves effective and tumor-selective death receptor 5-mediated tumor regression.

The bispecific antibody IMV-M was designed to selectively bind and cluster death receptor 5 (DR5) upon engaging the tumor antigen MUC16 through a novel mechanism-clustering multiple IMV-M molecules on a single MUC16 molecule. IMV-M demonstrated potent, MUC16-selective anti-tumor activity in vitro and in xenograft models without requiring secondary crosslinking, and a pilot non-human primate toxicity study detected no toxicity. Our findings suggest that antibody clustering effectively induces DR5 clustering, resulting in anti-tumor activity. Unlike anti-MUC16 antibody-drug conjugates (ADCs), which rely on cytotoxic payloads, this approach offers a safer and more effective therapeutic strategy. Notably, MUC16 is overexpressed in substantial subsets of ovarian, pancreatic, and lung cancers, with minimal expression in normal tissues, suggesting the broad applicability of this bispecific antibody.