The FG Loop of PD-1 Serves as a "Hotspot" for Therapeutic Monoclonal Antibodies in Tumor Immune Checkpoint Therapy

Danqing Chen; Shuguang Tan; Hao Zhang; Haiyuan Wang; Weiwu He; Rui Shi; Zhou Tong; Jianhua Zhu; Hao Cheng; Shan Gao; Yan Chai; Jianxun Qi; Minghui Xiao; Jinghua Yan; George F Gao

doi:10.1016/j.isci.2019.03.017

The FG Loop of PD-1 Serves as a "Hotspot" for Therapeutic Monoclonal Antibodies in Tumor Immune Checkpoint Therapy

iScience. 2019 Apr 26:14:113-124. doi: 10.1016/j.isci.2019.03.017. Epub 2019 Mar 21.

Authors

Danqing Chen¹, Shuguang Tan¹, Hao Zhang², Haiyuan Wang³, Weiwu He⁴, Rui Shi², Zhou Tong², Jianhua Zhu⁵, Hao Cheng⁶, Shan Gao⁷, Yan Chai¹, Jianxun Qi¹, Minghui Xiao⁸, Jinghua Yan⁹, George F Gao¹⁰

Affiliations

¹ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
² CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
³ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Laboratory of Animal Infectious Diseases, College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning 530004, China.
⁴ OriGene Technologies, Inc., Rockville 20850, USA.
⁵ Department of Oncology, Fourth Medical Center of PLA General Hospital, Beijing 100048, China.
⁶ Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
⁷ CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China.
⁸ Shanxi Weiqida Guangming Pharmaceutical Co. Ltd., Datong 037301, China.
⁹ 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; Shanxi Weiqida Guangming Pharmaceutical Co. Ltd., Datong 037301, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: yanjh@im.ac.cn.
¹⁰ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: gaof@im.ac.cn.

Abstract

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.

Keywords: Biological Sciences; Immunobiological Therapy Center; Structural Biology.