Nat Commun
. 2021 Jan 11;12(1):264.
doi: 10.1038/s41467-020-20465-w.
Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections
Chao Zhang 1 , Yifan Wang 2 , Yuanfei Zhu 3 , Caixuan Liu 2 , Chenjian Gu 3 , Shiqi Xu 1 , Yalei Wang 1 , Yu Zhou 1 , Yanxing Wang 2 4 , Wenyu Han 2 , Xiaoyu Hong 2 , Yong Yang 1 , Xueyang Zhang 1 , Tingfeng Wang 1 , Cong Xu 2 , Qin Hong 2 , Shutian Wang 2 , Qiaoyu Zhao 2 , Weihua Qiao 1 , Jinkai Zang 1 , Liangliang Kong 5 , Fangfang Wang 5 , Haikun Wang 1 , Di Qu 3 6 , Dimitri Lavillette 1 , Hong Tang 1 , Qiang Deng 7 , Youhua Xie 8 , Yao Cong 9 10 , Zhong Huang 11
Affiliations
- PMID: 33431876
- DOI: 10.1038/s41467-020-20465-w
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 ? 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.