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Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections
The ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutralizing antibodies against SARS-CoV-2 are an option for drug development for treating COVID-19. Here, we report the identification and characterization of two g...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801428/ https://www.ncbi.nlm.nih.gov/pubmed/33431876 http://dx.doi.org/10.1038/s41467-020-20465-w |
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author | Zhang, Chao Wang, Yifan Zhu, Yuanfei Liu, Caixuan Gu, Chenjian Xu, Shiqi Wang, Yalei Zhou, Yu Wang, Yanxing Han, Wenyu Hong, Xiaoyu Yang, Yong Zhang, Xueyang Wang, Tingfeng Xu, Cong Hong, Qin Wang, Shutian Zhao, Qiaoyu Qiao, Weihua Zang, Jinkai Kong, Liangliang Wang, Fangfang Wang, Haikun Qu, Di Lavillette, Dimitri Tang, Hong Deng, Qiang Xie, Youhua Cong, Yao Huang, Zhong |
author_facet | Zhang, Chao Wang, Yifan Zhu, Yuanfei Liu, Caixuan Gu, Chenjian Xu, Shiqi Wang, Yalei Zhou, Yu Wang, Yanxing Han, Wenyu Hong, Xiaoyu Yang, Yong Zhang, Xueyang Wang, Tingfeng Xu, Cong Hong, Qin Wang, Shutian Zhao, Qiaoyu Qiao, Weihua Zang, Jinkai Kong, Liangliang Wang, Fangfang Wang, Haikun Qu, Di Lavillette, Dimitri Tang, Hong Deng, Qiang Xie, Youhua Cong, Yao Huang, Zhong |
author_sort | Zhang, Chao |
collection | PubMed |
description | The ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutralizing antibodies against SARS-CoV-2 are an option for drug development for treating COVID-19. Here, we report the identification and characterization of two groups of mouse neutralizing monoclonal antibodies (MAbs) targeting the receptor-binding domain (RBD) on the SARS-CoV-2 spike (S) protein. MAbs 2H2 and 3C1, representing the two antibody groups, respectively, bind distinct epitopes and are compatible in formulating a noncompeting antibody cocktail. A humanized version of the 2H2/3C1 cocktail is found to potently neutralize authentic SARS-CoV-2 infection in vitro with half inhibitory concentration (IC50) of 12 ng/mL and effectively treat SARS-CoV-2-infected mice even when administered at as late as 24 h post-infection. We determine an ensemble of cryo-EM structures of 2H2 or 3C1 Fab in complex with the S trimer up to 3.8 Å resolution, revealing the conformational space of the antigen–antibody complexes and MAb-triggered stepwise allosteric rearrangements of the S trimer, delineating a previously uncharacterized dynamic process of coordinated binding of neutralizing antibodies to the trimeric S protein. Our findings provide important information for the development of MAb-based drugs for preventing and treating SARS-CoV-2 infections. |
format | Online Article Text |
id | pubmed-7801428 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78014282021-01-21 Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections Zhang, Chao Wang, Yifan Zhu, Yuanfei Liu, Caixuan Gu, Chenjian Xu, Shiqi Wang, Yalei Zhou, Yu Wang, Yanxing Han, Wenyu Hong, Xiaoyu Yang, Yong Zhang, Xueyang Wang, Tingfeng Xu, Cong Hong, Qin Wang, Shutian Zhao, Qiaoyu Qiao, Weihua Zang, Jinkai Kong, Liangliang Wang, Fangfang Wang, Haikun Qu, Di Lavillette, Dimitri Tang, Hong Deng, Qiang Xie, Youhua Cong, Yao Huang, Zhong Nat Commun Article The ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutralizing antibodies against SARS-CoV-2 are an option for drug development for treating COVID-19. Here, we report the identification and characterization of two groups of mouse neutralizing monoclonal antibodies (MAbs) targeting the receptor-binding domain (RBD) on the SARS-CoV-2 spike (S) protein. MAbs 2H2 and 3C1, representing the two antibody groups, respectively, bind distinct epitopes and are compatible in formulating a noncompeting antibody cocktail. A humanized version of the 2H2/3C1 cocktail is found to potently neutralize authentic SARS-CoV-2 infection in vitro with half inhibitory concentration (IC50) of 12 ng/mL and effectively treat SARS-CoV-2-infected mice even when administered at as late as 24 h post-infection. We determine an ensemble of cryo-EM structures of 2H2 or 3C1 Fab in complex with the S trimer up to 3.8 Å resolution, revealing the conformational space of the antigen–antibody complexes and MAb-triggered stepwise allosteric rearrangements of the S trimer, delineating a previously uncharacterized dynamic process of coordinated binding of neutralizing antibodies to the trimeric S protein. Our findings provide important information for the development of MAb-based drugs for preventing and treating SARS-CoV-2 infections. Nature Publishing Group UK 2021-01-11 /pmc/articles/PMC7801428/ /pubmed/33431876 http://dx.doi.org/10.1038/s41467-020-20465-w Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zhang, Chao Wang, Yifan Zhu, Yuanfei Liu, Caixuan Gu, Chenjian Xu, Shiqi Wang, Yalei Zhou, Yu Wang, Yanxing Han, Wenyu Hong, Xiaoyu Yang, Yong Zhang, Xueyang Wang, Tingfeng Xu, Cong Hong, Qin Wang, Shutian Zhao, Qiaoyu Qiao, Weihua Zang, Jinkai Kong, Liangliang Wang, Fangfang Wang, Haikun Qu, Di Lavillette, Dimitri Tang, Hong Deng, Qiang Xie, Youhua Cong, Yao Huang, Zhong Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections |
title | Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections |
title_full | Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections |
title_fullStr | Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections |
title_full_unstemmed | Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections |
title_short | Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections |
title_sort | development and structural basis of a two-mab cocktail for treating sars-cov-2 infections |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801428/ https://www.ncbi.nlm.nih.gov/pubmed/33431876 http://dx.doi.org/10.1038/s41467-020-20465-w |
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