Abstract 526: Novel mechanisms of Neuropilin-1 inhibition result in improved tumor growth inhibition in vivo

Abstract Background Cygnal Therapeutics, pioneer in exoneuronal biology, has identified the neuronal protein, Neuropilin-1 (NRP1) as a critical regulator of tumor growth and anti-tumor immunity. NRP1 is a co-receptor that complexes with diverse ligands and their cognate receptors. As such, it plays a role in multiple different biological processes, including axon guidance and angiogenesis. NRP1 contains two CUB domains (a1 and a2) involved in binding the ligand Semaphorin3A (SEMA3A), two Factor V/VIII domains (b1 and b2) involved in VEGF ligand binding and one MAM domain (c domain). While functional antibodies with anti-tumor activity have been generated against the SEMA3A and VEGF binding domains, targeting other domains of NRP1 has not been well-studied. For example, the c-domain of NRP1 has been implicated in the dimerization of NRP1, a prerequisite for functionality. Thus c-domain blockers might inhibit multiple signaling pathways required for tumor growth. Alternatively, binders targeting the interface of two different domains might allow for simultaneous blocking of multiple ligands. We therefore hypothesized that these novel binders to alternative regions of NRP1 such as the b1/b2 interface and the c-domain would have improved and significant anti-tumor activity. Methods Antibodies with diverse binding characteristics were tested for in vivo anti-tumor activity in multiple syngeneic models, including anti-PD1 non-responsive models. Ability of these of the anti-NRP1 antibodies to elicit an adaptive immune response was evaluated. Results Novel binders to alternative regions of NRP1 such as domain interfaces and the c-domain resulted in significant tumor growth inhibition in multiple syngeneic models. Additionally, the NRP1 antagonists induced a robust CD8 T cell response, indicating immune-stimulatory role of these antibodies. Conclusions Cygnal has developed fully human monoclonal antibodies against previously untargeted domains of NRP1. These novel domain binders show remarkable inhibition of tumor growth in multiple syngeneic models and offer a novel means of therapeutic intervention in patients. Citation Format: Shalini Sethumadhavan, Eric Zhu, Aaron Fulgham, Mandana Abbassi, Ameya Apte, Tiffany Liao, Chengfeng Merriman, Katherine Molloy, Caitlin Stein, Amber Hanna, James Geoghegan, Bianka Prinz, Hongyue Dai, Jonathan Hurov, Pearl Huang, Daniel Blom. Novel mechanisms of Neuropilin-1 inhibition result in improved tumor growth inhibition in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 526.