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

[tetano]

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.