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

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. Her...

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Autores principales: Lu, Dan, Xu, Zepeng, Zhang, Ding, Jiang, Min, Liu, Kefang, He, Juanhua, Ma, Dongli, Ma, Xiaopeng, Tan, Shuguang, Gao, George F., Chai, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8924070/
https://www.ncbi.nlm.nih.gov/pubmed/35309324
http://dx.doi.org/10.3389/fimmu.2022.826045
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author Lu, Dan
Xu, Zepeng
Zhang, Ding
Jiang, Min
Liu, Kefang
He, Juanhua
Ma, Dongli
Ma, Xiaopeng
Tan, Shuguang
Gao, George F.
Chai, Yan
author_facet Lu, Dan
Xu, Zepeng
Zhang, Ding
Jiang, Min
Liu, Kefang
He, Juanhua
Ma, Dongli
Ma, Xiaopeng
Tan, Shuguang
Gao, George F.
Chai, Yan
author_sort Lu, Dan
collection PubMed
description 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.
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spelling pubmed-89240702022-03-17 PD-1 N58-Glycosylation-Dependent Binding of Monoclonal Antibody Cemiplimab for Immune Checkpoint Therapy Lu, Dan Xu, Zepeng Zhang, Ding Jiang, Min Liu, Kefang He, Juanhua Ma, Dongli Ma, Xiaopeng Tan, Shuguang Gao, George F. Chai, Yan Front Immunol Immunology 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. Frontiers Media S.A. 2022-03-02 /pmc/articles/PMC8924070/ /pubmed/35309324 http://dx.doi.org/10.3389/fimmu.2022.826045 Text en Copyright © 2022 Lu, Xu, Zhang, Jiang, Liu, He, Ma, Ma, Tan, Gao and Chai https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Lu, Dan
Xu, Zepeng
Zhang, Ding
Jiang, Min
Liu, Kefang
He, Juanhua
Ma, Dongli
Ma, Xiaopeng
Tan, Shuguang
Gao, George F.
Chai, Yan
PD-1 N58-Glycosylation-Dependent Binding of Monoclonal Antibody Cemiplimab for Immune Checkpoint Therapy
title PD-1 N58-Glycosylation-Dependent Binding of Monoclonal Antibody Cemiplimab for Immune Checkpoint Therapy
title_full PD-1 N58-Glycosylation-Dependent Binding of Monoclonal Antibody Cemiplimab for Immune Checkpoint Therapy
title_fullStr PD-1 N58-Glycosylation-Dependent Binding of Monoclonal Antibody Cemiplimab for Immune Checkpoint Therapy
title_full_unstemmed PD-1 N58-Glycosylation-Dependent Binding of Monoclonal Antibody Cemiplimab for Immune Checkpoint Therapy
title_short PD-1 N58-Glycosylation-Dependent Binding of Monoclonal Antibody Cemiplimab for Immune Checkpoint Therapy
title_sort pd-1 n58-glycosylation-dependent binding of monoclonal antibody cemiplimab for immune checkpoint therapy
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8924070/
https://www.ncbi.nlm.nih.gov/pubmed/35309324
http://dx.doi.org/10.3389/fimmu.2022.826045
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