A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants
Abstract The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years. The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-11-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-021-00810-1 |
| _version_ | 1818838285072465920 |
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| author | Zhenlin Yang Yulu Wang Yujia Jin Yuanfei Zhu Yanling Wu Cheng Li Yu Kong Wenping Song Xiaolong Tian Wuqiang Zhan Ailing Huang Shanshan Zhou Shuai Xia Xiaoxu Tian Chao Peng Cuicui Chen Yibing Shi Gaowei Hu Shujuan Du Yuyan Wang Youhua Xie Shibo Jiang Lu Lu Lei Sun Yuanlin Song Tianlei Ying |
| author_facet | Zhenlin Yang Yulu Wang Yujia Jin Yuanfei Zhu Yanling Wu Cheng Li Yu Kong Wenping Song Xiaolong Tian Wuqiang Zhan Ailing Huang Shanshan Zhou Shuai Xia Xiaoxu Tian Chao Peng Cuicui Chen Yibing Shi Gaowei Hu Shujuan Du Yuyan Wang Youhua Xie Shibo Jiang Lu Lu Lei Sun Yuanlin Song Tianlei Ying |
| author_sort | Zhenlin Yang |
| collection | DOAJ |
| description | Abstract The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years. The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants. Here we show that the bivalency of an affinity maturated fully human single-domain antibody (n3113.1-Fc) exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus, and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2 (ACE2) humanized mice. The crystal structure of n3113 in complex with the receptor-binding domain (RBD) of SARS-CoV-2, combined with the cryo-EM structures of n3113 and spike ecto-domain, reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2. The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion, expanding our recognition of neutralization by antibodies against SARS-CoV-2. Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) for n3113.1-Fc with Y58L mutation, demonstrating the potential of n3113.1-Fc (Y58L) as a promising candidate for clinical development to treat COVID-19. |
| first_indexed | 2024-12-19T03:35:58Z |
| format | Article |
| id | doaj.art-06f49be0a9fe4fccae87b81c545ff0ab |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-12-19T03:35:58Z |
| publishDate | 2021-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-06f49be0a9fe4fccae87b81c545ff0ab2022-12-21T20:37:24ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352021-11-01611810.1038/s41392-021-00810-1A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variantsZhenlin Yang0Yulu Wang1Yujia Jin2Yuanfei Zhu3Yanling Wu4Cheng Li5Yu Kong6Wenping Song7Xiaolong Tian8Wuqiang Zhan9Ailing Huang10Shanshan Zhou11Shuai Xia12Xiaoxu Tian13Chao Peng14Cuicui Chen15Yibing Shi16Gaowei Hu17Shujuan Du18Yuyan Wang19Youhua Xie20Shibo Jiang21Lu Lu22Lei Sun23Yuanlin Song24Tianlei Ying25Department of Pulmonary Medicine, Zhongshan Hospital, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityShanghai Engineering Research Center for Synthetic ImmunologyMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityThe Fifth People’s Hospital of Shanghai, Fudan University and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan UniversityShanghai Engineering Research Center for Synthetic ImmunologyMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityNational Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of ScienceNational Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of ScienceDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityMOE/NHC Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityThe Fifth People’s Hospital of Shanghai, Fudan University and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan UniversityDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan UniversityShanghai Engineering Research Center for Synthetic ImmunologyAbstract The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years. The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants. Here we show that the bivalency of an affinity maturated fully human single-domain antibody (n3113.1-Fc) exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus, and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2 (ACE2) humanized mice. The crystal structure of n3113 in complex with the receptor-binding domain (RBD) of SARS-CoV-2, combined with the cryo-EM structures of n3113 and spike ecto-domain, reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2. The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion, expanding our recognition of neutralization by antibodies against SARS-CoV-2. Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) for n3113.1-Fc with Y58L mutation, demonstrating the potential of n3113.1-Fc (Y58L) as a promising candidate for clinical development to treat COVID-19.https://doi.org/10.1038/s41392-021-00810-1 |
| spellingShingle | Zhenlin Yang Yulu Wang Yujia Jin Yuanfei Zhu Yanling Wu Cheng Li Yu Kong Wenping Song Xiaolong Tian Wuqiang Zhan Ailing Huang Shanshan Zhou Shuai Xia Xiaoxu Tian Chao Peng Cuicui Chen Yibing Shi Gaowei Hu Shujuan Du Yuyan Wang Youhua Xie Shibo Jiang Lu Lu Lei Sun Yuanlin Song Tianlei Ying A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants Signal Transduction and Targeted Therapy |
| title | A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants |
| title_full | A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants |
| title_fullStr | A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants |
| title_full_unstemmed | A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants |
| title_short | A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants |
| title_sort | non ace2 competing human single domain antibody confers broad neutralization against sars cov 2 and circulating variants |
| url | https://doi.org/10.1038/s41392-021-00810-1 |
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