Kotanides et al. developed a bispecific monoclonal antibody (LY3434172) that co-targets human (and cynomolgus nhp) PD-1 and PD-L1 with high specificity and comparable binding affinity to each parental antibody. LY3434172 induced bridging of PD-1- and PD-L1-expressing cells and enhanced T cell activation compared to each parental antibody and their combination. In xenograft tumor models (HCC827 and NCI-H292) complemented with human immune cells (T cells or PBMCs), LY3434172 demonstrated enhanced antitumor activity compared to each parental antibody and their combination at considerably lower doses.
Contributed by Shishir Pant
ABSTRACT: The programmed cell death protein 1 receptor (PD-1) and programmed death ligand 1 (PD-L1) coinhibitory pathway suppresses T-cell-mediated immunity. We hypothesized that cotargeting of PD-1 and PD-L1 with a bispecific antibody molecule could provide an alternative therapeutic approach, with enhanced antitumor activity, compared with monospecific PD-1 and PD-L1 antibodies. Here, we describe LY3434172, a bispecific IgG1 mAb 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 with 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 with 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.