Bispecific Targeting of PD-1 and PD-L1 Enhances T cell Activation and Antitumor Immunity

The programmed cell death protein 1 receptor (PD-1) and programmed death ligand 1 (PD-L1) co-inhibitory pathway suppresses T cell mediated immunity. We hypothesized that co-targeting of PD-1 and PD-L1 with a bispecific antibody molecule could provide an alternative therapeutic approach, with enhanced antitumor activity, compared to monospecific PD-1 and PD-L1 antibodies. Here, we described LY3434172, a bispecific IgG1 monoclonal antibody with ablated Fc immune effector function that targets both human PD-1 and PD-L1. LY3434172 fully inhibited the major inhibitory receptor:ligand interactions in the PD-1 pathway. LY3434172 enhanced functional activation of T cells in vitro compared to the parent anti-PD-1 and anti-PD-L1 antibody combination or respective monotherapies. In mouse tumor models reconstituted with human immune cells, LY3434172 therapy induced dramatic and potent antitumor activity compared to each parent antibody or their combination. Collectively, these results demonstrated the enhanced immunomodulatory (immune blockade) properties of LY3434172, which improved antitumor immune response in preclinical studies, thus supporting its evaluation as a novel bispecific cancer immunotherapy.