7WVM

The complex structure of PD-1 and cemiplimab

Summary for 7WVM

• Entry DOI: 10.2210/pdb7wvm/pdb
• Descriptor: Heavy Chain of Cemiplimab, Light Chain of Cemiplimab, Programmed cell death protein 1 (3 entities in total)
• Functional Keywords: pd-1, antibody, n58 glycosylation, cemiplimab, immune checkpoint therapy (ict), antitumor protein, immune system-antitumor protein complex, immune system/antitumor protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 74873.37

Authors

Lu, D.,Xu, Z.P.,Liu, K.F.,Tan, S.G.,Gao, G.F.,Chai, Y. (deposition date: 2022-02-10, release date: 2022-04-20, Last modification date: 2024-11-20)

Primary citation

Lu, D.,Xu, Z.,Zhang, D.,Jiang, M.,Liu, K.,He, J.,Ma, D.,Ma, X.,Tan, S.,Gao, G.F.,Chai, Y.
PD-1 N58-Glycosylation-Dependent Binding of Monoclonal Antibody Cemiplimab for Immune Checkpoint Therapy.
Front Immunol, 13:826045-826045, 2022

PubMed Abstract: 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.

PubMed: 35309324
DOI: 10.3389/fimmu.2022.826045

Experimental method

X-RAY DIFFRACTION (3.4 Å)