Cell Research, 1 December, 2020, DOI：https://doi.org/10.1038/s41422-020-00444-y
Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection
Hangping Yao, Yao Sun, Yong-Qiang Deng, Nan Wang, Yongcong Tan, Na-Na Zhang, Xiao-Feng Li, Chao Kong, Yan-Peng Xu, Qi Chen, Tian-Shu Cao, Hui Zhao, Xintian Yan, Lei Cao, Zhe Lv, Dandan Zhu, Rui Feng, Nanping Wu, Wenhai Zhang, Yuhao Hu, Keda Chen, Rong-Rong Zhang, Qingyu Lv, Shihui Sun, Yunhua Zhou, Run Yan, Guan Yang, Xinglu Sun, Chanjuan Liu, Xiangyun Lu, Linfang Cheng, Hongying Qiu, Xing-Yao Huang, Tianhao Weng, Danrong Shi, Weidong Jiang, Junbin Shao, Lei Wang, Jie Zhang, Tao Jiang, Guojun Lang, Cheng-Feng Qin, Lanjuan Li & Xiangxi Wang
Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.