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
Affiliations
Xilin Wu
Center for Public Health Research, Medical School, Nanjing University, Nanjing, People’s Republic of China; Department of Antibody, Abrev Biotechnology Co., Ltd., Nanjing, People’s Republic of China
Lin Cheng
Institute for Hepatology, National Clinical Research Center for Infectious, Disease, Shenzhen Third People’s Hospital, Shenzhen, People’s Republic of China
Ming Fu
State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, People’s Republic of China; Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou 510623, China
Bilian Huang
Center for Public Health Research, Medical School, Nanjing University, Nanjing, People’s Republic of China
Linjing Zhu
Department of Antibody, Abrev Biotechnology Co., Ltd., Nanjing, People’s Republic of China
Shijie Xu
Center for Public Health Research, Medical School, Nanjing University, Nanjing, People’s Republic of China; Department of Antibody, Abrev Biotechnology Co., Ltd., Nanjing, People’s Republic of China
Haixia Shi
Department of Antibody, Y-clone Medical Science Co. Ltd., Suzhou, People’s Republic of China
Doudou Zhang
Department of Antibody, Abrev Biotechnology Co., Ltd., Nanjing, People’s Republic of China
Huanyun Yuan
Department of Antibody, Abrev Biotechnology Co., Ltd., Nanjing, People’s Republic of China
Waqas Nawaz
Center for Public Health Research, Medical School, Nanjing University, Nanjing, People’s Republic of China
Ping Yang
State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, People’s Republic of China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing, People’s Republic of China
Qinxue Hu
State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, People’s Republic of China; Institute for Infection and Immunity, St George’s University of London, London SW17 0RE, UK
Yalan Liu
State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, People’s Republic of China; Corresponding author
Zhiwei Wu
School of Life Sciences, Ningxia University, Yinchuan, People’s Republic of China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, People’s Republic of China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, People’s Republic of China; Corresponding author
Summary: The dramatically expanding coronavirus disease 2019 (COVID-19) needs multiple effective countermeasures. Neutralizing nanobodies (Nbs) are a potential therapeutic strategy for treating COVID-19. Here, we characterize several receptor binding domain (RBD)-specific Nbs isolated from an Nb library derived from an alpaca immunized with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S); among them, three Nbs exhibit picomolar potency against SARS-CoV-2 live virus, pseudotyped viruses, and circulating SARS-CoV-2 variants. To improve their efficacy, various configurations of Nbs are engineered. Nb15-NbH-Nb15, a trimer constituted of three Nbs, is constructed to be bispecific for human serum albumin (HSA) and RBD of SARS-CoV-2. Nb15-NbH-Nb15 exhibits single-digit ng/ml neutralization potency against the wild-type and Delta variants of SARS-CoV-2 with a long half-life in vivo. In addition, we show that intranasal administration of Nb15-NbH-Nb15 provides effective 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 the prevention and treatment of SARS-CoV-2 through respiratory administration.
