An unexpected N-terminal loop in PD-1 dominates binding by nivolumab

• Published in: Nature communications 2017-02, Vol.8 (1), p.14369-14369, Article 14369
• Main Authors: Tan, Shuguang, Zhang, Hao, Chai, Yan, Song, Hao, Tong, Zhou, Wang, Qihui, Qi, Jianxun, Wong, Gary, Zhu, Xiaodong, Liu, William J., Gao, Shan, Wang, Zhongfu, Shi, Yi, Yang, Fuquan, Gao, George F., Yan, Jinghua
• Format: Article
• Language: English
• Subjects: 13/31; 631/250/251; 631/45/535/1266; 82/1; 82/103; 82/80; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized - chemistry; Antibodies, Monoclonal, Humanized - pharmacology; Antineoplastic Agents, Immunological - pharmacology; B7-H1 Antigen - metabolism; Cancer; Crystallography, X-Ray; Disease control; Drug Design; Glycosylation; Humanities and Social Sciences; Humans; Immunotherapy; Immunotherapy - methods; Laboratories; Life sciences; Ligands; Melanoma; Monoclonal antibodies; multidisciplinary; Neoplasms - drug therapy; Nivolumab; Peptides; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - chemistry; Programmed Cell Death 1 Receptor - metabolism; Protein Binding; Protein Domains; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14369

Cancer immunotherapy by targeting of immune checkpoint molecules has been a research ‘hot-spot’ in recent years. Nivolumab, a human monoclonal antibody targeting PD-1, has been widely used clinically since 2014. However, the binding mechanism of nivolumab to PD-1 has not yet been shown, despite a recent report describing the complex structure of pembrolizumab/PD-1. It has previously been speculated that PD-1 glycosylation is involved in nivolumab recognition. Here we report the complex structure of nivolumab with PD-1 and evaluate the effects of PD-1 N-glycosylation on the interactions with nivolumab. Structural and functional analyses unexpectedly reveal an N-terminal loop outside the IgV domain of PD-1. This loop is not involved in recognition of PD-L1 but dominates binding to nivolumab, whereas N-glycosylation is not involved in binding at all. Nivolumab binds to a completely different area than pembrolizumab. These results provide the basis for the design of future inhibitory molecules targeting PD-1. Programmed cell death 1 (PD-1) is a key target for cancer immunotherapy. Here the authors present the crystal structure of the extracellular PD-1 domain with the clinically approved monoclonal antibody nivolumab, which shows that the N-terminal PD-1 loop is crucial for antibody binding.