PD-1 N58-Glycosylation-Dependent Binding of Monoclonal Antibody Cemiplimab for Immune Checkpoint Therapy

Frontiers in Immunology

Min Jiang¹  George F. Gao¹  Dan Lu¹  Yan Chai¹  Shuguang Tan¹  Kefang Liu¹  Juanhua He²  Zepeng Xu³  Ding Zhang⁵  Dongli Ma⁶  Xiaopeng Ma⁶ 

[1] CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China;College of Life Sciences, Jiangxi Science and Technology Normal University, Nanchang, China;Faculty of Health Sciences, University of Macau, Macau, Macau SAR, China;Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China;Shanxi Academy of Advanced Research and Innovation, Taiyuan, China;Shenzhen Children’s Hospital, Shenzhen, China;

关键词: PD-1;    antibody;    N58 glycosylation;    cemiplimab;    immune checkpoint therapy (ICT);   

DOI  :  10.3389/fimmu.2022.826045

来源: DOAJ

【 摘 要 】

Immune checkpoint therapy (ICT) with a monoclonal antibody (MAb) against programmed cell death protein 1 (PD-1) is a powerful clinical treatment for tumors. Cemiplimab is a human IgG4 antibody approved in 2018 and is the first MAb proven to be effective for locally advanced basal cell carcinoma. Here, we report the crystal structure of cemiplimab bound to PD-1 and the effects of PD-1 N-glycosylation on the interactions with cemiplimab. The structure of the cemiplimab/PD-1 complex shows that cemiplimab mainly binds to PD-1 with its heavy chain, whereas the light chain serves as the predominant region to compete with the binding of PD-L1 to PD-1. The interaction network of cemiplimab to PD-1 resembles that of camrelizumab (another PD-1-binding MAb), and the N58 glycan on the BC loop of PD-1 may be involved in the interaction with cemiplimab. The binding affinity of cemiplimab with PD-1 was substantially decreased with N58-glycan-deficient PD-1, whereas the PD-1/PD-L1 blocking efficiency of cemiplimab was attenuated upon binding to the N58-glycosylation-deficient PD-1. These results indicate that both the binding and blocking efficacy of cemiplimab require the N58 glycosylation of PD-1. Taken together, these findings expand our understanding of the significance of PD-1 glycosylation in the interaction with cemiplimab.

【 授权许可】

Unknown