A bispecific antibody overcomes limitations of prior strategies to achieve effective and tumor-selective Death Receptor 5 (DR5) clustering

The bispecific antibody IMV-M was designed to bind and cluster Death Receptor 5 (DR5) specifically upon engaging the tumor antigen MUC16. This dual-binding mechanism induces apoptosis in MUC16-positive tumor cells through a novel enhancement process. IMV-M exhibited potent, MUC16-selective anti-tumor activity in vitro and in xenograft models, achieving efficacy at safe therapeutic doses without requiring secondary crosslinking. In contrast, earlier DR5-targeting tumor-selective bispecific antibodies either demonstrated limited anti-tumor activity or relied on secondary crosslinking, highlighting that binding of a bispecific antibody to a tumor antigen and DR5 alone is insufficient for effective DR5 clustering. Our findings reveal that an additional crowding mechanism for efficient DR5 clustering by bispecific antibodies is required. In contrast to the targeted delivery approach with antibody-drug conjugates (ADCs), our approach offers a pathway for developing more effective and safer cancer therapies. Importantly, the MUC16 antigen is overexpressed in substantial subsets of ovarian, pancreatic, and lung cancers while being almost completely absent in normal tissues, with highly limited expression in certain epithelial cells, indicating broad applicability of this bispecific antibody.