Chen Danqing, Tan Shuguang, Zhang Hao, Wang Haiyuan, He Weiwu, Shi Rui, Tong Zhou, Zhu Jianhua, Cheng Hao, Gao Shan, Chai Yan, Qi Jianxun, Xiao Minghui, Yan Jinghua, Gao George F
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
iScience. 2019 Apr 26;14:113-124. doi: 10.1016/j.isci.2019.03.017. Epub 2019 Mar 21.
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.
程序性细胞死亡蛋白1（PD-1）/PD-1配体-1（PD-L1）阻断单克隆抗体（mAb）已成为肿瘤免疫检查点治疗的核心。确定mAb在PD-1上的“热点”将有助于开发具有持久疗效的下一代口服给药制剂。在此，我们鉴定出两种具有PD-1/PD-L1阻断功效的靶向PD-1的mAb，即GY-5和GY-14。复杂的结构信息表明，这两种mAb主要与PD-1的FG环结合，而FG环也与PD-L1有多种相互作用。FG环在与不同mAb结合时会呈现出显著不同的构象，为开发PD-1特异性生物制剂和小分子化学物质提供了一个新的可靶向区域。在四个潜在的N-连接糖基化位点中的三个位点可观察到PD-1的糖基化修饰。然而，GY-5和GY-14与PD-1的结合不受糖基化的影响。这些发现拓宽了我们对抗PD-1 mAb作用机制的理解，并为靶向PD-1的药物开发提供了思路。
