Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections

Chao Zhang, Yifan Wang, Yuanfei Zhu, Caixuan Liu, Chenjian Gu, Shiqi Xu, Yalei Wang, Yu Zhou, Yanxing Wang, Wenyu Han, Xiaoyu Hong, Yong Yang, Xueyang Zhang, Tingfeng Wang, Cong Xu, Qin Hong, Shutian Wang, Qiaoyu Zhao, Weihua Qiao, Jinkai Zang, Liangliang Kong, Fangfang Wang, Haikun Wang, Di Qu, Dimitri Lavillette, Hong Tang, Qiang Deng (), Youhua Xie (), Yao Cong () and Zhong Huang ()
Additional contact information
Chao Zhang: University of Chinese Academy of Sciences
Yifan Wang: University of Chinese Academy of Sciences
Yuanfei Zhu: Fudan University
Caixuan Liu: University of Chinese Academy of Sciences
Chenjian Gu: Fudan University
Shiqi Xu: University of Chinese Academy of Sciences
Yalei Wang: University of Chinese Academy of Sciences
Yu Zhou: University of Chinese Academy of Sciences
Yanxing Wang: University of Chinese Academy of Sciences
Wenyu Han: University of Chinese Academy of Sciences
Xiaoyu Hong: University of Chinese Academy of Sciences
Yong Yang: University of Chinese Academy of Sciences
Xueyang Zhang: University of Chinese Academy of Sciences
Tingfeng Wang: University of Chinese Academy of Sciences
Cong Xu: University of Chinese Academy of Sciences
Qin Hong: University of Chinese Academy of Sciences
Shutian Wang: University of Chinese Academy of Sciences
Qiaoyu Zhao: University of Chinese Academy of Sciences
Weihua Qiao: University of Chinese Academy of Sciences
Jinkai Zang: University of Chinese Academy of Sciences
Liangliang Kong: The National Facility for Protein Science in Shanghai (NFPS)
Fangfang Wang: The National Facility for Protein Science in Shanghai (NFPS)
Haikun Wang: University of Chinese Academy of Sciences
Di Qu: Fudan University
Dimitri Lavillette: University of Chinese Academy of Sciences
Hong Tang: University of Chinese Academy of Sciences
Qiang Deng: Fudan University
Youhua Xie: Fudan University
Yao Cong: University of Chinese Academy of Sciences
Zhong Huang: University of Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20465-w

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