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

doi: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 HuKeda 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

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	25-36
Number of pages	12
Journal	Cell Research
Volume	31
Issue number	1
DOIs	https://doi.org/10.1038/s41422-020-00444-y
State	Published - Jan 2021
Externally published	Yes

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Yao, H., Sun, Y., Deng, Y. Q., Wang, N., Tan, Y., Zhang, N. N., Li, X. F., Kong, C., Xu, Y. P., Chen, Q., Cao, T. S., Zhao, H., Yan, X., Cao, L., Lv, Z., Zhu, D., Feng, R., Wu, N., Zhang, W., ... Wang, X. (2021). Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection. Cell Research, 31(1), 25-36. https://doi.org/10.1038/s41422-020-00444-y

@article{003b4d262a8f413db9805b05aca72298,

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

abstract = "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.",

author = "Hangping Yao and Yao Sun and Deng, {Yong Qiang} and Nan Wang and Yongcong Tan and Zhang, {Na Na} and Li, {Xiao Feng} and Chao Kong and Xu, {Yan Peng} and Qi Chen and Cao, {Tian Shu} and Hui Zhao and Xintian Yan and Lei Cao and Zhe Lv and Dandan Zhu and Rui Feng and Nanping Wu and Wenhai Zhang and Yuhao Hu and Keda Chen and Zhang, {Rong Rong} and Qingyu Lv and Shihui Sun and Yunhua Zhou and Run Yan and Guan Yang and Xinglu Sun and Chanjuan Liu and Xiangyun Lu and Linfang Cheng and Hongying Qiu and Huang, {Xing Yao} and Tianhao Weng and Danrong Shi and Weidong Jiang and Junbin Shao and Lei Wang and Jie Zhang and Tao Jiang and Guojun Lang and Qin, {Cheng Feng} and Lanjuan Li and Xiangxi Wang",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2021",

month = jan,

doi = "10.1038/s41422-020-00444-y",

language = "English",

volume = "31",

pages = "25--36",

journal = "Cell Research",

issn = "1001-0602",

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Yao, H, Sun, Y, Deng, YQ, Wang, N, Tan, Y, Zhang, NN, Li, XF, Kong, C, Xu, YP, Chen, Q, Cao, TS, Zhao, H, Yan, X, Cao, L, Lv, Z, Zhu, D, Feng, R, Wu, N, Zhang, W, Hu, Y, Chen, K, Zhang, RR, Lv, Q, Sun, S, Zhou, Y, Yan, R, Yang, G, Sun, X, Liu, C, Lu, X, Cheng, L, Qiu, H, Huang, XY, Weng, T, Shi, D, Jiang, W, Shao, J, Wang, L, Zhang, J, Jiang, T, Lang, G, Qin, CF, Li, L & Wang, X 2021, 'Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection', Cell Research, vol. 31, no. 1, pp. 25-36. https://doi.org/10.1038/s41422-020-00444-y

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T1 - Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection

AU - Yao, Hangping

AU - Sun, Yao

AU - Deng, Yong Qiang

AU - Wang, Nan

AU - Tan, Yongcong

AU - Zhang, Na Na

AU - Li, Xiao Feng

AU - Kong, Chao

AU - Xu, Yan Peng

AU - Chen, Qi

AU - Cao, Tian Shu

AU - Zhao, Hui

AU - Yan, Xintian

AU - Cao, Lei

AU - Lv, Zhe

AU - Zhu, Dandan

AU - Feng, Rui

AU - Wu, Nanping

AU - Zhang, Wenhai

AU - Hu, Yuhao

AU - Chen, Keda

AU - Zhang, Rong Rong

AU - Lv, Qingyu

AU - Sun, Shihui

AU - Zhou, Yunhua

AU - Yan, Run

AU - Yang, Guan

AU - Sun, Xinglu

AU - Liu, Chanjuan

AU - Lu, Xiangyun

AU - Cheng, Linfang

AU - Qiu, Hongying

AU - Huang, Xing Yao

AU - Weng, Tianhao

AU - Shi, Danrong

AU - Jiang, Weidong

AU - Shao, Junbin

AU - Wang, Lei

AU - Zhang, Jie

AU - Jiang, Tao

AU - Lang, Guojun

AU - Qin, Cheng Feng

AU - Li, Lanjuan

AU - Wang, Xiangxi

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41422-020-00444-y

DO - 10.1038/s41422-020-00444-y

M3 - Article

C2 - 33262452

AN - SCOPUS:85097023850

SN - 1001-0602

VL - 31

SP - 25

EP - 36

JO - Cell Research

JF - Cell Research

IS - 1

ER -

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

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