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.

Comprehensive Evaluation of ACE2-Fc Combination with Neutralization Antibody on Broad Protection against SARS-CoV-2 and Its Variants

“…This long-lasting effect was also confirmed by other scientists [3]. Further, ACE2 decoy receptor was confirmed neutralization against authentic virus [4][5][6][7][8][9] and showed promising prophylactic and therapeutic efficacy in animal models [8].…”

“…As the receptor of SARS-CoV-2, ACE2 is promising to play these roles. ACE2 decoy receptor therapies have shown broad neutralization activity against existing variants (Table 1) and demonstrated promising ability by mutated RBD binding [10] or escape assay in co-incubation of ACE2 decoy receptor [8,9] to neutralize potential variants. Table 1.…”

Killing Two Birds with One Stone by Administration of Soluble ACE2: A Promising Strategy to Treat Both Cardiovascular Diseases and SARS-CoV-2 Infection

“…It can not only block the entry of SARS-CoV-2, SARS-CoV, and HCoV-NL63 into host cells, but also neutralize various variants of SARS-CoV-2, including the D614G and V367F mutants, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.1 (Kappa), and B.1.617.2 (Delta). Most importantly, hACE2-Fc has a longer half-life in vivo than soluble ACE2 [68]. Another study demonstrated that an improved soluble ACE2, termed a "microbody", in which the ACE2 ectodomain was fused with Fc domain 3 of the immunoglobulin heavy chain, effectively inhibited the entry of SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro and in a mouse model [69].…”

“…In the study of SARS-CoV-2 infection, verified animal models are needed to fully reproduce the pathogenesis of the disease. Currently, promising animal infection models of SARS-CoV-2 have been reported, including a transgenic mouse model expressing human ACE2, Syrian hamster model, ferret model, cat model, and non-human primate model [68,[94][95][96]. The development of these animal models is crucial for vaccine evaluation and drug screening.…”

Commentary: Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells

“…The virus reduces the expression of membrane-bound ACE2 (mACE2) by internalization and shedding, resulting in the relative dominance of AT1 receptor (AT1R)/aldosterone receptor (AldR) deleterious effects over the Mas receptor (MasR)/MrgD alamandin receptor (MrgD)/angiotenin II type 2 receptor (AT2R) protective cardiovascular and anti-inflammatory actions. ACE inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARB), aldosterone receptor (AldR) blockers(Wilcox and Pitt, 2020), AT2R agonists(Tornling et al, 2021), recombinant human ACE2(Zhang et al, 2021), or kinin-kallikrein system inhibitors(Mansour et al, 2021) induce interactions with RAAS, which may render protection. Created with BioRender.com.…”