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

被引：71

作者：

Yao, Hangping ^{[1
]}

Sun, Yao ^{[2
]}

Deng, Yong-Qiang ^{[3
]}

Wang, Nan ^{[2
]}

Tan, Yongcong ^{[4
]}

Zhang, Na-Na ^{[3
]}

Li, Xiao-Feng ^{[3
]}

Kong, Chao ^{[4
]}

Xu, Yan-Peng ^{[3
]}

Chen, Qi ^{[3
]}

Cao, Tian-Shu ^{[3
]}

Zhao, Hui ^{[3
]}

Yan, Xintian ^{[4
]}

Cao, Lei ^{[2
]}

Lv, Zhe ^{[2
]}

Zhu, Dandan ^{[2
]}

Feng, Rui ^{[2
]}

Wu, Nanping ^{[1
]}

Zhang, Wenhai ^{[4
]}

Hu, Yuhao ^{[4
]}

Chen, Keda ^{[5
]}

Zhang, Rong-Rong ^{[3
]}

Lv, Qingyu ^{[3
]}

Sun, Shihui ^{[3
]}

Zhou, Yunhua ^{[4
]}

Yan, Run ^{[4
]}

Yang, Guan ^{[6
]}

Sun, Xinglu ^{[4
]}

Liu, Chanjuan ^{[4
]}

Lu, Xiangyun ^{[1
]}

Cheng, Linfang ^{[1
]}

Qiu, Hongying ^{[3
]}

Huang, Xing-Yao ^{[3
]}

Weng, Tianhao ^{[1
]}

Shi, Danrong ^{[1
]}

Jiang, Weidong ^{[7
]}

Shao, Junbin ^{[8
]}

Wang, Lei ^{[2
]}

Zhang, Jie ^{[8
]}

Jiang, Tao ^{[3
]}

Lang, Guojun ^{[4
]}

Qin, Cheng-Feng ^{[3
]}

Li, Lanjuan ^{[1
]}

Wang, Xiangxi ^{[2
,9
]}

机构：

[1] Zhejiang Univ, Affiliated Hosp 1, State Key Lab Diag & Treatment Infect Dis, Natl Clin Res Ctr Infect Dis,Sch Med, Hangzhou 310003, Zhejiang, Peoples R China

[2] Chinese Acad Sci, Inst Biophys, CAS Key Lab Infect & Immun, Natl Lab Macromol, Beijing 100101, Peoples R China

[3] Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, AMMS, Beijing 100071, Peoples R China

[4] Sanyou Biopharmaceut Shanghai Co Ltd, Shanghai 201114, Peoples R China

[5] Zhejiang Shuren Univ, Shulan Int Med Coll, Hangzhou 310015, Zhejiang, Peoples R China

[6] Beijing Inst Life, Natl Ctr Prot Sci Beijing, Beijing Proteome Res Ctr, State Key Lab Prote, Beijing 102206, Peoples R China

[7] Shanghai Henlius Biotech Inc, Shanghai 200233, Peoples R China

[8] Shanghai ZJ Biotech Co Ltd, Shanghai 201114, Peoples R China

[9] Guangzhou Regenerat Med & Hlth, Guangdong Lab, Guangzhou 510200, Guangdong, Peoples R China

来源：

CELL RESEARCH | 2021年 / 31卷 / 01期

基金：

中国国家自然科学基金; 上海市自然科学基金;

关键词：

CRYO-EM STRUCTURE; STRUCTURAL BASIS; SPIKE PROTEIN; NEUTRALIZATION; VALIDATION; BINDING;

D O I：

10.1038/s41422-020-00444-y

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：25 / 36

页数：12

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