An ultrapotent pan-β-coronavirus lineage B (β-CoV-B) neutralizing antibody locks the receptor-binding domain in closed conformation by targeting its conserved epitope.

Zezhong Liu; Wei XU; Zhenguo Chen; Wangjun FU; Wuqiang Zhan; Yidan Gao; Jie Zhou; Yunjiao Zhou; Jianbo WU; Qian Wang; Xiang Zhang; Aihua Hao; Wei WU; Qianqian Zhang; Yaming LI; Kaiyue Fan; Ruihong Chen; Qiaochu Jiang; Christian T Mayer; Till Schoofs; Youhua Xie; Shibo Jiang; Yumei Wen; Zhenghong Yuan; Kang Wang; Lu LU; Lei Sun; Qiao Wang

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An ultrapotent pan-β-coronavirus lineage B (β-CoV-B) neutralizing antibody locks the receptor-binding domain in closed conformation by targeting its conserved epitope.

Author: Zezhong LIU ^{1
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6} ; Wei XU ^{1
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6} ; Zhenguo CHEN ^{1
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6} ; Wangjun FU ⁷ ; Wuqiang ZHAN ^{1
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6} ; Yidan GAO ^{1
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6} ; Jie ZHOU ^{1
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6} ; Yunjiao ZHOU ^{1
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6} ; Jianbo WU ^{1
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6} ; Qian WANG ^{1
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4
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6} ; Xiang ZHANG ^{1
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6} ; Aihua HAO ^{1
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6} ; Wei WU ^{1
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6} ; Qianqian ZHANG ^{1
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6} ; Yaming LI ^{1
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6} ; Kaiyue FAN ⁷ ; Ruihong CHEN ⁷ ; Qiaochu JIANG ^{1
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6} ; Christian T MAYER ⁸ ; Till SCHOOFS ⁹ ; Youhua XIE ^{1
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6} ; Shibo JIANG ^{1
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6} ; Yumei WEN ^{1
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6} ; Zhenghong YUAN ^{1
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10} ; Kang WANG ¹¹ ; Lu LU ^{1
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12} ; Lei SUN ^{1
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13} ; Qiao WANG ^{1
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14}
Author Information

1. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences
2. Shanghai Institute of Infectious Disease and Biosecurity
3. the Fifth People's Hospital of Shanghai
4. Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology)
5. Institutes of Biomedical Sciences
6. Biosafety Level 3 Laboratory, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
7. CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
8. Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
9. GSK Vaccines, 1300, Wavre, Belgium.
10. Biosafety Level 3 Laboratory, Shanghai Medical College, Fudan University, Shanghai, 200032, China. zhyuan@shmu.edu.cn.
11. CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. wangkangup@163.com.
12. Biosafety Level 3 Laboratory, Shanghai Medical College, Fudan University, Shanghai, 200032, China. lul@fudan.edu.cn.
13. Biosafety Level 3 Laboratory, Shanghai Medical College, Fudan University, Shanghai, 200032, China. llsun@fudan.edu.cn.
14. Biosafety Level 3 Laboratory, Shanghai Medical College, Fudan University, Shanghai, 200032, China. wangqiao@fudan.edu.cn.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: SARS-CoV-2; XG014; antibody-dependent cell-cell fusion; neutralizing antibody; receptor-binding domain
MeSH: Angiotensin-Converting Enzyme 2; Antibodies, Neutralizing; Antibodies, Viral; COVID-19; Epitopes; Humans; SARS-CoV-2/genetics*; Spike Glycoprotein, Coronavirus/genetics*
From: Protein & Cell 2022;13(9):655-675
CountryChina
Language:English
Abstract: New threats posed by the emerging circulating variants of SARS-CoV-2 highlight the need to find conserved neutralizing epitopes for therapeutic antibodies and efficient vaccine design. Here, we identified a receptor-binding domain (RBD)-binding antibody, XG014, which potently neutralizes β-coronavirus lineage B (β-CoV-B), including SARS-CoV-2, its circulating variants, SARS-CoV and bat SARSr-CoV WIV1. Interestingly, antibody family members competing with XG014 binding show reduced levels of cross-reactivity and induce antibody-dependent SARS-CoV-2 spike (S) protein-mediated cell-cell fusion, suggesting a unique mode of recognition by XG014. Structural analyses reveal that XG014 recognizes a conserved epitope outside the ACE2 binding site and completely locks RBD in the non-functional "down" conformation, while its family member XG005 directly competes with ACE2 binding and position the RBD "up". Single administration of XG014 is effective in protection against and therapy of SARS-CoV-2 infection in vivo. Our findings suggest the potential to develop XG014 as pan-β-CoV-B therapeutics and the importance of the XG014 conserved antigenic epitope for designing broadly protective vaccines against β-CoV-B and newly emerging SARS-CoV-2 variants of concern.