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

• Published in: Nature communications Vol. 12; no. 1; pp. 264 - 16
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/326; 631/535; 82/1; ACE2; Allosteric properties; Angiotensin-converting enzyme 2; Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibodies, Neutralizing - immunology; Antibodies, Viral - chemistry; Antibodies, Viral - immunology; Antibodies, Viral - pharmacology; Antibodies, Viral - therapeutic use; Antigens; Antiviral agents; Antiviral drugs; Binding; Coronaviridae; Coronaviruses; COVID-19; COVID-19 - drug therapy; Cryoelectron Microscopy; Drug development; Emerging diseases; Epitope Mapping; Epitopes; Female; Human health and pathology; Humanities and Social Sciences; Immunology; Immunotherapy; Infectious diseases; Life Sciences; Mice; Mice, Inbred BALB C; Microbiology and Parasitology; Models, Molecular; Monoclonal antibodies; multidisciplinary; Neutralizing; Pandemics; Prophylaxis; Protein Binding - drug effects; Protein Conformation; Proteins; Respiratory diseases; SARS-CoV-2 - drug effects; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - immunology; Spike protein; Trimers; Viral diseases; Virology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20465-w

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. Here, the authors identify and characterize two mouse-derived monoclonal antibodies against SARS-CoV-2 spike protein that target different epitopes in RBD and block the interaction S/ACE2 and show that a formulated humanized version cocktail exhibits prophylaxis and therapeutic antiviral effects in an hACE2-adenovector expressed mouse model.