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

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.