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An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants

The wide transmission and host adaptation of SARS-CoV-2 have led to the rapid accumulation of mutations, posing significant challenges to the effectiveness of vaccines and therapeutic antibodies. Although several neutralizing antibodies were authorized for emergency clinical use, convalescent patien...

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Autores principales: Chi, Xiaojing, Zhang, Xinhui, Pan, Shengnan, Yu, Yanying, Shi, Yujin, Lin, Tianli, Duan, Huarui, Liu, Xiuying, Chen, Wenfang, Yang, Xuehua, Chen, Lan, Dong, Xiaoqian, Ren, Lili, Ding, Qiang, Wang, Jianwei, Yang, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828845/
https://www.ncbi.nlm.nih.gov/pubmed/35140196
http://dx.doi.org/10.1038/s41392-022-00912-4
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author Chi, Xiaojing
Zhang, Xinhui
Pan, Shengnan
Yu, Yanying
Shi, Yujin
Lin, Tianli
Duan, Huarui
Liu, Xiuying
Chen, Wenfang
Yang, Xuehua
Chen, Lan
Dong, Xiaoqian
Ren, Lili
Ding, Qiang
Wang, Jianwei
Yang, Wei
author_facet Chi, Xiaojing
Zhang, Xinhui
Pan, Shengnan
Yu, Yanying
Shi, Yujin
Lin, Tianli
Duan, Huarui
Liu, Xiuying
Chen, Wenfang
Yang, Xuehua
Chen, Lan
Dong, Xiaoqian
Ren, Lili
Ding, Qiang
Wang, Jianwei
Yang, Wei
author_sort Chi, Xiaojing
collection PubMed
description The wide transmission and host adaptation of SARS-CoV-2 have led to the rapid accumulation of mutations, posing significant challenges to the effectiveness of vaccines and therapeutic antibodies. Although several neutralizing antibodies were authorized for emergency clinical use, convalescent patients derived natural antibodies are vulnerable to SARS-CoV-2 Spike mutation. Here, we describe the screen of a panel of SARS-CoV-2 receptor-binding domain (RBD) targeted nanobodies (Nbs) from a synthetic library and the design of a biparatopic Nb, named Nb1–Nb2, with tight affinity and super-wide neutralization breadth against multiple SARS-CoV-2 variants of concern. Deep-mutational scanning experiments identify the potential binding epitopes of the Nbs on the RBD and demonstrate that biparatopic Nb1–Nb2 has a strong escape-resistant feature against more than 60 tested RBD amino acid substitutions. Using pseudovirion-based and trans-complementation SARS-CoV-2 tools, we determine that the Nb1–Nb2 broadly neutralizes multiple SARS-CoV-2 variants at sub-nanomolar levels, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Kappa (B.1.617.1), and Mu (B.1.621). Furthermore, a heavy-chain antibody is constructed by fusing the human IgG1 Fc to Nb1–Nb2 (designated as Nb1–Nb2-Fc) to improve its neutralization potency, yield, stability, and potential half-life extension. For the new Omicron variant (B.1.1.529) that harbors unprecedented multiple RBD mutations, Nb1–Nb2-Fc keeps a firm affinity (KD < 1.0 × 10(−12) M) and strong neutralizing activity (IC(50) = 1.46 nM for authentic Omicron virus). Together, we developed a tetravalent biparatopic human heavy-chain antibody with ultrapotent and broad-spectrum SARS-CoV-2 neutralization activity which highlights the potential clinical applications.
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spelling pubmed-88288452022-02-24 An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants Chi, Xiaojing Zhang, Xinhui Pan, Shengnan Yu, Yanying Shi, Yujin Lin, Tianli Duan, Huarui Liu, Xiuying Chen, Wenfang Yang, Xuehua Chen, Lan Dong, Xiaoqian Ren, Lili Ding, Qiang Wang, Jianwei Yang, Wei Signal Transduct Target Ther Article The wide transmission and host adaptation of SARS-CoV-2 have led to the rapid accumulation of mutations, posing significant challenges to the effectiveness of vaccines and therapeutic antibodies. Although several neutralizing antibodies were authorized for emergency clinical use, convalescent patients derived natural antibodies are vulnerable to SARS-CoV-2 Spike mutation. Here, we describe the screen of a panel of SARS-CoV-2 receptor-binding domain (RBD) targeted nanobodies (Nbs) from a synthetic library and the design of a biparatopic Nb, named Nb1–Nb2, with tight affinity and super-wide neutralization breadth against multiple SARS-CoV-2 variants of concern. Deep-mutational scanning experiments identify the potential binding epitopes of the Nbs on the RBD and demonstrate that biparatopic Nb1–Nb2 has a strong escape-resistant feature against more than 60 tested RBD amino acid substitutions. Using pseudovirion-based and trans-complementation SARS-CoV-2 tools, we determine that the Nb1–Nb2 broadly neutralizes multiple SARS-CoV-2 variants at sub-nanomolar levels, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Kappa (B.1.617.1), and Mu (B.1.621). Furthermore, a heavy-chain antibody is constructed by fusing the human IgG1 Fc to Nb1–Nb2 (designated as Nb1–Nb2-Fc) to improve its neutralization potency, yield, stability, and potential half-life extension. For the new Omicron variant (B.1.1.529) that harbors unprecedented multiple RBD mutations, Nb1–Nb2-Fc keeps a firm affinity (KD < 1.0 × 10(−12) M) and strong neutralizing activity (IC(50) = 1.46 nM for authentic Omicron virus). Together, we developed a tetravalent biparatopic human heavy-chain antibody with ultrapotent and broad-spectrum SARS-CoV-2 neutralization activity which highlights the potential clinical applications. Nature Publishing Group UK 2022-02-09 /pmc/articles/PMC8828845/ /pubmed/35140196 http://dx.doi.org/10.1038/s41392-022-00912-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Chi, Xiaojing
Zhang, Xinhui
Pan, Shengnan
Yu, Yanying
Shi, Yujin
Lin, Tianli
Duan, Huarui
Liu, Xiuying
Chen, Wenfang
Yang, Xuehua
Chen, Lan
Dong, Xiaoqian
Ren, Lili
Ding, Qiang
Wang, Jianwei
Yang, Wei
An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants
title An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants
title_full An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants
title_fullStr An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants
title_full_unstemmed An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants
title_short An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants
title_sort ultrapotent rbd-targeted biparatopic nanobody neutralizes broad sars-cov-2 variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828845/
https://www.ncbi.nlm.nih.gov/pubmed/35140196
http://dx.doi.org/10.1038/s41392-022-00912-4
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