Abstract 6073: IDP-002 is a PD-1xCD6 bispecific antibody that enables complete PD-1 receptor occupancy and enhances cytotoxic over regulatory T cell responses

Abstract High response rates observed with PD-1/L1 antagonists have advanced immunotherapy to the forefront of treatment options for multiple cancer types; however, a substantial proportion of partial and non-responders warrants development of novel and more effective approaches. Poor responses to current PD-1/L1 antagonists may result from incomplete receptor occupancy, partial reversal of T cell exhaustion, and proliferative responses in PD-1+ FOXP3+ immunosuppressive regulatory T cells (Tregs) which will suppress anti-tumor effector T cell responses. Importantly, the recently demonstrated superiority of the PD-1xVEGF bispecific antibody (bsAb) ivonescimab over pembrolizumab in PD-L1+ advanced NSCLC suggests greater PD-1 receptor occupancy (achieved through high-avidity PD-1 binding of ivonescimab/VEGF multivalent complexes) leads to significantly deeper clinical responses. Enhanced PD-1 receptor occupancy may also be achieved with cis-acting bsAbs that target PD-1 and an abundant T cell surface protein, enabling more efficient PD-1 blockade compared to that achieved with conventional mAbs. Furthermore, candidate co-targets can be evaluated not only by expression level, but also for co-stimulatory capacity and differential cell subset expression. For example, low co-target expression on Tregs or co-target signaling that attenuates Treg fitness would skew PD-1 antagonist activity towards effector T cells and reduce therapy-induced Treg responses. Here, we present IDP-002, a PD-1xCD6 bsAb that facilitates complete PD-1 receptor occupancy and promotes greater proliferative and cytotoxic responses in vitro and in tumor-bearing humanized mice compared to current PD-1 antagonist mAbs. Tregs, which express lower levels of CD6, proliferate less efficiently than effector CD4 and CD8 T cells in response to IDP-002. Enhanced effector T cell responses observed with IDP-002 derive from a combination of complete PD-1 blockade and the engagement of unique signaling pathways downstream of CD6. IDP-002 has the potential to become a leading therapeutic option for the next generation of PD-1 antagonists. Citation Format: Marc Gavin, Tsadik Habtetsion, Christie Mortales, Hayley Ma, Aniruddh Saxena, Mikaela Rusnak, Jing Song, Ben Setter, Robert Gene, Heath Klock, Carina Xu, Ertan Eryilmaz, Pamela Holland, Scott Lesley. IDP-002 is a PD-1xCD6 bispecific antibody that enables complete PD-1 receptor2 occupancy and enhances cytotoxic over regulatory T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6073.