RT Journal Article
SR Electronic
T1 Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 1300
OP 1310
DO 10.1158/2326-6066.CIR-20-0304
VO 8
IS 10
A1 Kotanides, Helen
A1 Li, Yiwen
A1 Malabunga, Maria
A1 Carpenito, Carmine
A1 Eastman, Scott W.
A1 Shen, Yang
A1 Wang, George
A1 Inigo, Ivan
A1 Surguladze, David
A1 Pennello, Anthony L.
A1 Persaud, Krishnadatt
A1 Hindi, Sagit
A1 Topper, Michael
A1 Chen, Xinlei
A1 Zhang, Yiwei
A1 Bulaon, Danielle K.
A1 Bailey, Tim
A1 Lao, Yanbin
A1 Han, Bing
A1 Torgerson, Stacy
A1 Chin, Darin
A1 Sonyi, Andreas
A1 Haidar, Jaafar N.
A1 Novosiadly, Ruslan D.
A1 Moxham, Christopher M.
A1 Plowman, Gregory D.
A1 Ludwig, Dale L.
A1 Kalos, Michael
YR 2020
UL http://cancerimmunolres.aacrjournals.org/content/8/10/1300.abstract
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.