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A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration

View ORCID ProfileXilin Wu, Lin Cheng, Ming Fu, Bilian Huang, Linjing Zhu, Shijie Xu, Haixia Shi, Doudou Zhang, Huanyun Yuan, Waqas Nawaz, Ping Yang, Qinxue Hu, Yalan Liu, Zhiwei Wu
doi: https://doi.org/10.1101/2021.02.08.429275
Xilin Wu
1Center for Public Health Research, Medical School, Nanjing University, Nanjing, P.R. China
2Abrev Biotechnology Co., Ltd. Nanjing, P.R. China
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  • ORCID record for Xilin Wu
Lin Cheng
3Institute for Hepatology, Shenzhen Third People’s Hospital
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Ming Fu
4State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China
5Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou 510623, China
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Bilian Huang
1Center for Public Health Research, Medical School, Nanjing University, Nanjing, P.R. China
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Linjing Zhu
2Abrev Biotechnology Co., Ltd. Nanjing, P.R. China
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Shijie Xu
1Center for Public Health Research, Medical School, Nanjing University, Nanjing, P.R. China
2Abrev Biotechnology Co., Ltd. Nanjing, P.R. China
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Haixia Shi
6Y-clone Medical Science Co. Ltd. Suzhou, P.R. China
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Doudou Zhang
2Abrev Biotechnology Co., Ltd. Nanjing, P.R. China
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Huanyun Yuan
2Abrev Biotechnology Co., Ltd. Nanjing, P.R. China
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Waqas Nawaz
1Center for Public Health Research, Medical School, Nanjing University, Nanjing, P.R. China
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Ping Yang
4State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China
7University of Chinese Academy of Sciences, Beijing, China
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Qinxue Hu
4State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China
8Institute for Infection and Immunity, St George’s University of London, London, SW17 0RE, UK
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Yalan Liu
4State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China
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  • For correspondence: wzhw@nju.edu.cn liuyl@wh.iov.cn
Zhiwei Wu
1Center for Public Health Research, Medical School, Nanjing University, Nanjing, P.R. China
9School of Life Sciences, Ningxia University, Yinchuan, P.R. China
10Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, P.R. China
11State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, P.R. China
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  • For correspondence: wzhw@nju.edu.cn liuyl@wh.iov.cn
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Abstract

The dramatically expanding COVID-19 needs multiple effective countermeasures. Neutralizing antibodies are a potential therapeutic strategy for treating COVID-19. A number of neutralizing nanobodies (Nbs) were reported for their in vitro activities. However, in vivo protection of these nanobodies was not reported in animal models. In the current report, we characterized several RBD-specific Nbs isolated from a screen of an Nb library derived from an alpaca immunized with SARS-CoV-2 spike glycoprotein (S); among them, three Nbs exhibited picomolar potency against SARS-CoV-2 live virus, pseudotyped viruses, and 15 circulating SARS-CoV-2 variants. To improve the efficacy, various configurations of Nbs were engineered. Nb15-NbH-Nb15, a novel trimer constituted of three Nbs, was constructed to be bispecific for human serum albumin (HSA) and RBD of SARS-CoV-2. Nb15-NbH-Nb15 exhibited sub-ng/ml neutralization potency against the wild-type and currently circulating variants of SARS-CoV-2 with a long half-life in vivo. In addition, we showed that intranasal administration of Nb15-NbH-Nb15 provided 100% protection for both prophylactic and therapeutic purposes against SARS-CoV-2 infection in transgenic hACE2 mice. Nb15-NbH-Nb15 is a potential candidate for both prevention and treatment of SARS-CoV-2 through respiratory administration.

One sentence summary Nb15-NbH-Nb15, with a novel heterotrimeric bispecific configuration, exhibited potent and broad neutralization potency against SARS-CoV-2 in vitro and provided in vivo protection against SARS-CoV-2 infection in hACE2 transgenic mice via intranasal delivery.

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Highlights

  1. We described a novel heterotrimeric configuration of Nb-NbH-Nb (Nb15-NbH-Nb15) that exhibited improved viral inhibition and stability.

  2. Nb15-NbH-Nb15 provides ultrahigh neutralization potency against SARS-CoV-2 wild type and 18 mutant variants, including the current circulating variants of D614G and N501Y predominantly in the UK and South Africa.

  3. It is the first to demonstrate the Nbs efficacy in preventing and treating SARS-CoV-2 infection in hACE2 transgenic mice via intranasal delivery.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 09, 2021.
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A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration
Xilin Wu, Lin Cheng, Ming Fu, Bilian Huang, Linjing Zhu, Shijie Xu, Haixia Shi, Doudou Zhang, Huanyun Yuan, Waqas Nawaz, Ping Yang, Qinxue Hu, Yalan Liu, Zhiwei Wu
bioRxiv 2021.02.08.429275; doi: https://doi.org/10.1101/2021.02.08.429275
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A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration
Xilin Wu, Lin Cheng, Ming Fu, Bilian Huang, Linjing Zhu, Shijie Xu, Haixia Shi, Doudou Zhang, Huanyun Yuan, Waqas Nawaz, Ping Yang, Qinxue Hu, Yalan Liu, Zhiwei Wu
bioRxiv 2021.02.08.429275; doi: https://doi.org/10.1101/2021.02.08.429275

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