Journal
ISCIENCE
Volume 14, Issue -, Pages 113-+Publisher
CELL PRESS
DOI: 10.1016/j.isci.2019.03.017
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Funding
- Strategic Priority Research Program of Chinese Academy of Sciences (CAS) [XDA12020358, XDB29040201]
- National Science and Technology Major Project [2018ZX09711003-002-001]
- NSFC Innovative Research Group [81621091]
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Programmed cell death 1 (PD-1)/PD-1 ligand-1 (PD-L1)-blocking monoclonal antibodies (mAbs) have taken center stage for tumor immune checkpoint therapy. Identification of the hotspots on PD-1 for mAbs will help to develop next-generation oral deliverable agents with long-lasting efficacy. Here, we identified two PD-1-targeting mAbs, GY-5 and GY-14, with PD-1/PD-L1-blocking efficacy. Complex structural information revealed that both mAbs mainly bind to the FG loop of PD-1, which also contributes multiple interactions with PD-L1 The FG loop adopts substantially varied conformations upon binding to different mAbs, providing a novel targetable region for the development of PD-1-specific biologics and small chemical molecules, Glycosylation modifications of PD-1 could be observed in three of the four potential N-linked glycosylation sites. However, the binding of GY-5 and GY-14 to PD-1 was not affected by glycosylation. These findings broaden our understanding of the mechanism of anti-PD-1 mAbs and provide insight into the development of agents targeting PD-1.
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