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

Abstract

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.

• Authors: Zhaoyong Zhang, Eric Zeng, Lu Zhang, Weiming Wang, Yingkang Jin, Jiye Sun, Shuxiang Huang, Wenguang Yin, Jun Dai, Zhen Zhuang, Zhao Chen, Jing Sun, Airu Zhu, Fang Li, Weitao Cao, Xiaobo Li, Yongxia Shi, Mian Gan, Shengnan Zhang, Peilan Wei, Jicheng Huang, Nanshan Zhong, Guocai Zhong, Jingxian Zhao, Yanqun Wang, Weihui Shao, Jincun Zhao
• Journal: Cell discovery (Cell Discov) Vol. 7 Issue 1 Pg. 65 (Aug 12 2021) ISSN: 2056-5968 [Print] England
• PMID: 34385423 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).