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

Autor: Michael Kalos, Dale L. Ludwig, Gregory D. Plowman, Christopher M. Moxham, Ruslan D. Novosiadly, Jaafar N. Haidar, Andreas Sonyi, Darin Chin, Stacy Torgerson, Bing Han, Yanbin Lao, Tim Bailey, Danielle K. Bulaon, Yiwei Zhang, Xinlei Chen, Michael Topper, Sagit Hindi, Krishnadatt Persaud, Anthony L. Pennello, David Surguladze, Ivan Inigo, George Wang, Yang Shen, Scott W. Eastman, Carmine Carpenito, Maria Malabunga, Yiwen Li, Helen Kotanides
Rok vydání: 2023
DOI: 10.1158/2326-6066.c.6550090
Popis: 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.
Databáze: OpenAIRE