Potent prophylactic and therapeutic efficacy of recombinant human ACE2-Fc against SARS-CoV-2 infection in vivo

Cell Discovery

Jun Dai¹  Yongxia Shi¹  Jicheng Huang¹  Shuxiang Huang¹  Xiaobo Li¹  Lu Zhang¹  Weihui Shao²  Jiye Sun²  Weiming Wang²  Eric Zeng³  Yingkang Jin⁴  Guocai Zhong⁵  Yanqun Wang⁶  Fang Li⁶  Wenguang Yin⁶  Shengnan Zhang⁶  Mian Gan⁶  Peilan Wei⁶  Jingxian Zhao⁶  Zhao Chen⁶  Jing Sun⁶  Zhen Zhuang⁶  Weitao Cao⁶  Zhaoyong Zhang⁶  Nanshan Zhong⁶  Airu Zhu⁶  Jincun Zhao⁷ 

[1] Guangzhou Customs District Technology Center, Guangzhou, Guangdong, China;Nanjing GenScript Biotech Co., Ltd, NanJing, Jiangsu, China;Nanjing Legend Biotech Co., Ltd, Nanjing, Jiangsu, China;Pediatric Pulmonary Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China;Shenzhen Bay Laboratory, Shenzhen, Guangdong, China;School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, China;State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;Institute of Infectious disease, Guangzhou Eighth People’s Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;Guangzhou laboratory, Bio-island, Guangzhou, Guangdong, China;

DOI  :  10.1038/s41421-021-00302-0

来源: Springer

【 摘 要 】

The current COVID-19 pandemic, caused by SARS-CoV-2, poses a serious public health threat. Effective therapeutic and prophylactic treatments are urgently needed. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS-CoV-2, which binds to the receptor binding domain (RBD) of SARS-CoV-2 spike protein. Here, we developed recombinant human ACE2-Fc fusion protein (hACE2-Fc) and a hACE2-Fc mutant with reduced catalytic activity. hACE2-Fc and the hACE2-Fc mutant both efficiently blocked entry of SARS-CoV-2, SARS-CoV, and HCoV-NL63 into hACE2-expressing cells and inhibited SARS-CoV-2 S protein-mediated cell–cell fusion. hACE2-Fc also neutralized various SARS-CoV-2 strains with enhanced infectivity including D614G and V367F mutations, as well as the emerging SARS-CoV-2 variants, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.1 (Kappa), and B.1.617.2 (Delta), demonstrating its potent and broad-spectrum antiviral effects. In addition, hACE2-Fc proteins protected HBE from SARS-CoV-2 infection. Unlike RBD-targeting neutralizing antibodies, hACE2-Fc treatment did not induce the development of escape mutants. Furthermore, both prophylactic and therapeutic hACE2-Fc treatments effectively protected mice from SARS-CoV-2 infection, as determined by reduced viral replication, weight loss, histological changes, and inflammation in the lungs. The protection provided by hACE2 showed obvious dose-dependent efficacy in vivo. Pharmacokinetic data indicated that hACE2-Fc has a relative long half-life in vivo compared to soluble ACE2, which makes it an excellent candidate for prophylaxis and therapy for COVID-19 as well as for SARS-CoV and HCoV-NL63 infections.

【 授权许可】

CC BY