H. Yao, Yao Sun, Yongqiang Deng, N. Wang, Yongcong Tan, N. Zhang, Xiao-Feng Li, Chao Kong, Yan-Peng Xu, Qi Chen, Tian-Shu Cao, H. Zhao, Xin-tian Yan, Lei Cao, Zhe Lv, Dandan Zhu, Rui Feng, N. Wu, Wenhai Zhang, Yuhao Hu, Keda Chen, Rong-Rong Zhang, Qingyu Lv, Shihui Sun, Yun-hua Zhou, R. Yan, G. Yang, Xing Sun, Chanjuan Liu, Xiangyun Lu, L. Cheng, H. Qiu, Xing-Yao Huang, Tianhao Weng, Danrong Shi, Weidong Jiang, Junbin Shao, Lei Wang, Jie Zhang, T. Jiang, Guojun Lang, C. Qin, Lanjuan Li, X. Wang
Cell research, 2020
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.
Cited by 25 publications.
Field of study: Biology