Broad-Spectrum Engineered Multivalent Nanobodies Against SARS-CoV-1/2

文献类型： 外文期刊

第一作者： Wang, Zhihong

作者： Wang, Zhihong;Zhao, Pinnan;Shi, Ning;Wang, Jie;Qiao, Chunxia;Li, Xin ying;Gao, Xiang;Feng, Jiannan;Luo, Longlong;Shi, Zhuangzhuang;Wang, Tiecheng;Liao, Xiaochen;Dong, Hui;Zhou, Yangyihua;Wang, Zekun;Quan, Guiqi;Wu, Yahui;Zhang, Ran

作者机构：

关键词： antibody engineering; de novo design; multivalent nanobodies; nanobody; SARS-CoV-1; SARS-CoV-2

期刊名称：ADVANCED SCIENCE （ 影响因子：14.1； 五年影响因子：15.6 ）

ISSN：

年卷期： 2024 年 11 卷 45 期

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收录情况： SCI

摘要： SARS-CoV-2 Omicron sublineages escape most preclinical/clinical neutralizing antibodies in development, suggesting that previously employed antibody screening strategies are not well suited to counteract the rapid mutation of SARS-CoV-2. Therefore, there is an urgent need to screen better broad-spectrum neutralizing antibody. In this study, a comprehensive approach to design broad-spectrum inhibitors against both SARS-CoV-1 and SARS-CoV-2 by leveraging the structural diversity of nanobodies is proposed. This includes the de novo design of a fully human nanobody library and the camel immunization-based nanobody library, both targeting conserved epitopes, as well as the development of multivalent nanobodies that bind nonoverlapping epitopes. The results show that trivale B11-E8-F3, three nanobodies joined tandemly in trivalent form, have the broadest spectrum and efficient neutralization activity, which spans from SARS-CoV-1 to SARS-CoV-2 variants. It is also demonstrated that B11-E8-F3 has a very prominent preventive and some therapeutic effect in animal models of three authentic viruses. Therefore, B11-E8-F3 has an outstanding advantage in preventing SARS-CoV-1/SARS-CoV-2 infections, especially in immunocompromised populations or elderly people with high-risk comorbidities. This study presents the design and development of multivalent nanobodies targeting conserved epitopes of SARS-CoV-1 and SARS-CoV-2. The trivalent nanobody B11-E8-F3 exhibits broad-spectrum neutralization against SARS-CoV-1 and multiple SARS-CoV-2 variants, including Omicron sublineages, and demonstrates significant preventive and therapeutic efficacy in animal models. image

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