PT - JOURNAL ARTICLE AU - Kotanides, Helen AU - Li, Yiwen AU - Malabunga, Maria AU - Carpenito, Carmine AU - Eastman, Scott W. AU - Shen, Yang AU - Wang, George AU - Inigo, Ivan AU - Surguladze, David AU - Pennello, Anthony L. AU - Persaud, Krishnadatt AU - Hindi, Sagit AU - Topper, Michael AU - Chen, Xinlei AU - Zhang, Yiwei AU - Bulaon, Danielle K. AU - Bailey, Tim AU - Lao, Yanbin AU - Han, Bing AU - Torgerson, Stacy AU - Chin, Darin AU - Sonyi, Andreas AU - Haidar, Jaafar N. AU - Novosiadly, Ruslan D. AU - Moxham, Christopher M. AU - Plowman, Gregory D. AU - Ludwig, Dale L. AU - Kalos, Michael TI - Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity AID - 10.1158/2326-6066.CIR-20-0304 DP - 2020 Oct 01 TA - Cancer Immunology Research PG - 1300--1310 VI - 8 IP - 10 4099 - http://cancerimmunolres.aacrjournals.org/content/8/10/1300.short 4100 - http://cancerimmunolres.aacrjournals.org/content/8/10/1300.full SO - Cancer Immunol Res2020 Oct 01; 8 AB - 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.