The FG Loop of PD-1 Serves as a 'Hotspot' for Therapeutic Monoclonal Antibodies in Tumor Immune Checkpoint Therapy
| Autor: | Shuguang Tan, Jianhua Zhu, Yan Chai, Rui Shi, Zhou Tong, He Weiwu, George F. Gao, Jianxun Qi, Shan Gao, Chen Danqing, Jinghua Yan, Minghui Xiao, Hao Zhang, Hao Cheng, Haiyuan Wang |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Glycosylation medicine.drug_class 02 engineering and technology Monoclonal antibody Article 03 medical and health sciences chemistry.chemical_compound Immune system Structural Biology Programmed cell death 1 medicine lcsh:Science Biological sciences Multidisciplinary biology Immunobiological Therapy Center Biological Sciences 021001 nanoscience & nanotechnology Immune checkpoint 030104 developmental biology chemistry Structural biology Cancer research biology.protein lcsh:Q 0210 nano-technology |
| Zdroj: | iScience iScience, Vol 14, Iss, Pp 113-124 (2019) |
| ISSN: | 2589-0042 |
| Popis: | Summary 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. Graphical Abstract Highlights • GY-5 and GY-14 show efficient anti-tumor efficacy in NCG mouse model • Both GY-5 and GY-14 bind to the FG loop of PD-1 • Glycosylation is observed in PD-1, but not involved in binding to GY-5 and GY-14 • The loops of PD-1 may serve as “hotspot” for development of PD-1-targeting biologics Biological Sciences; Immunobiological Therapy Center; Structural Biology |
| Databáze: | OpenAIRE |
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