Volume 31, No 1, Jan 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 1, January 2021: 25-36

ORIGINAL ARTICLES

Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection

Hangping Yao¹ , Yao Sun² , Yong-Qiang Deng³ , Nan Wang² , Yongcong Tan⁴ , Na-Na Zhang³ , Xiao-Feng Li³ , Chao Kong⁴ , Yan-Peng Xu³ , Qi Chen³ , Tian-Shu Cao³ , Hui Zhao³ , Xintian Yan⁴ , Lei Cao² , Zhe Lv² , Dandan Zhu² , Rui Feng² , Nanping Wu¹ , Wenhai Zhang⁴ , Yuhao Hu⁴ , Keda Chen⁵ , Rong-Rong Zhang³ , Qingyu Lv³ , Shihui Sun³ , Yunhua Zhou⁴ , Run Yan⁴ , Guan Yang⁶ , Xinglu Sun⁴ , Chanjuan Liu⁴ , Xiangyun Lu¹ , Linfang Cheng¹ , Hongying Qiu³ , Xing-Yao Huang³ , Tianhao Weng¹ , Danrong Shi¹ , Weidong Jiang⁷ , Junbin Shao⁸ , Lei Wang² , Jie Zhang⁸ , Tao Jiang³ , Guojun Lang^4,* , Cheng-Feng Qin^3,* , Lanjuan Li^1,* , Xiangxi Wang^2,9,*

¹State Key Laboratory for Diagnosis and Treatment of Infectious Diseases/National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
²CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
³State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, AMMS, Beijing 100071, China
⁴Sanyou Biopharmaceuticals (Shanghai) Co., Ltd., Shanghai 201114, China
⁵Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang 310015, China
⁶State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
⁷Shanghai Henlius Biotech, Inc, Shanghai 200233, China
⁸Shanghai ZJ Bio-Tech Co., Ltd., Shanghai 201114, China
⁹Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, Guangdong 510200, China
These authors contributed equally: Hangping Yao, Yao Sun, Yong-Qiang Deng, Nan Wang, Yongcong Tan, Na-Na Zhang. Correspondence: Guojun Lang(guojun.lang@sunyoubio.com)Cheng-Feng Qin(qincf@bmi.ac.cn)Lanjuan Li(ljli@zju.edu.cn)Xiangxi Wang(xiangxi@ibp.ac.cn)

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.

https://doi.org/10.1038/s41422-020-00444-y

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