Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

Lv, Zhe; Deng, Yong-Qiang; Ye, Qing; Cao, Lei; Sun, Chun-Yun; Fan, Changfa; Huang, Weijin; Sun, Shihui; Sun, Yao; Zhu, Ling; Chen, Qi; Wang, Nan; Nie, Jianhui; Cui, Zhen; Zhu, Dandan; Shaw, Neil; Li, Xiao-Feng; Li, Qianqian; Xie, Liangzhi; Wang, Youchun; Rao, Zihe; Qin, Cheng-Feng; Wang, Xiangxi

The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we reported a humanized monoclonal antibody, H014, efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nM level by engaging the S receptor binding domain (RBD). Importantly, H014 administration reduced SARS-CoV-2 titers in the infected lungs and prevented pulmonary pathology in hACE2 mouse model. Cryo-EM characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a novel conformational epitope, which is only accessible when the RBD is in open conformation. Biochemical, cellular, virological and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncover broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19. One sentence summary A potent neutralizing antibody conferred protection against SARS-CoV-2 in an hACE2 humanized mouse model by sterically blocking the interaction of the virus with its receptor.