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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Medicine R Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/06f49be0a9fe4fccae87b81c545ff0ab
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spelling	oai:doaj.org-article:06f49be0a9fe4fccae87b81c545ff0ab2021-11-07T12:14:06ZA non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants10.1038/s41392-021-00810-12059-3635https://doaj.org/article/06f49be0a9fe4fccae87b81c545ff0ab2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41392-021-00810-1https://doaj.org/toc/2059-3635Abstract 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.Zhenlin YangYulu WangYujia JinYuanfei ZhuYanling WuCheng LiYu KongWenping SongXiaolong TianWuqiang ZhanAiling HuangShanshan ZhouShuai XiaXiaoxu TianChao PengCuicui ChenYibing ShiGaowei HuShujuan DuYuyan WangYouhua XieShibo JiangLu LuLei SunYuanlin SongTianlei YingNature Publishing GrouparticleMedicineRBiology (General)QH301-705.5ENSignal Transduction and Targeted Therapy, Vol 6, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Biology (General) QH301-705.5
spellingShingle	Medicine R Biology (General) QH301-705.5 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
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.
format	article
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
title	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_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_sort	non-ace2 competing human single-domain antibody confers broad neutralization against sars-cov-2 and circulating variants
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/06f49be0a9fe4fccae87b81c545ff0ab
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A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants

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