Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities

Abstract

Soluble angiotensin-converting enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses using ACE2 as their receptor. Using structure-guided approaches, we developed a series of bivalent ACE2-Fcs harboring functionally and structurally validated mutations that enhance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain recognition by up to ~12-fold and remove angiotensin enzymatic activity. The lead variant M81 potently cross-neutralized SARS-CoV-2 variants of concern (VOCs), including Omicron, at subnanomolar half-maximal inhibitory concentration and was capable of robust Fc-effector functions, including antibody-dependent cellular cytotoxicity, phagocytosis, and complement deposition. When tested in a stringent K18-hACE2 mouse model, Fc-enhanced ACE2-Fc delayed death by 3 to 5 days or effectively resolved lethal SARS-CoV-2 infection in both prophylactic and therapeutic settings via the combined effects of neutralization and Fc-effector functions. These data add to the demonstrated utility of soluble ACE2 as a valuable SARS-CoV-2 antiviral and indicate that Fc-effector functions may constitute an important component of ACE2-Fc therapeutic activity.

An ACE2 decoy can be administered by inhalation and potently targets omicron variants of SARS‐CoV ‐2

“…The engineered decoy sACE2 2 .v2.4‐IgG1 has three substitutions compared with wild‐type ACE2 that enhance affinity for S by over an order of magnitude, measured against S proteins from SARS‐CoV‐2 variants predating omicron (Chan et al , 2020, 2021; Zhang et al , 2022). Fusion to the Fc region of IgG1 increases serum stability and virus clearance (preprint: Chen et al , 2021). We recently found that intravenous (IV) administration of sACE2 2 .v2.4‐IgG1 mitigates lung vascular endothelial injury and increases survival in K18‐hACE2 transgenic mice infected with SARS‐CoV‐2 variants (Zhang et al , 2022).…”

“…There has been disagreement in the literature as to whether sACE2‐catalyzed turnover of vasoconstrictive and pro‐inflammatory peptides will confer therapeutic benefits or whether it is a safety liability. Many groups knocked out the catalytic activity when developing candidate decoy receptors, negating ill‐defined risks of adverse hypotension (preprint: Cohen‐Dvashi et al , 2020; Glasgow et al , 2020; preprint: Iwanaga et al , 2020; Lei et al , 2020; preprint: Chen et al , 2021; Higuchi et al , 2021; Sims et al , 2021; Tanaka et al , 2021). However, we show here that catalytically inactivated sACE2 2 .v2.4(NN)‐IgG1 is not as effective at prolonging the survival of hACE2 transgenic mice infected with a lethal virus dose, suggesting that the catalytic activity of ACE2 present in the decoy confers additional therapeutic benefits.…”

Multimeric ACE2-IgM fusions as broadly active antivirals that potently neutralize SARS-CoV-2 variants

“…It will be important to define suitable animal models, administration routes, and clinical scenarios where the ACE2-IgM-Fc hexamer can bring the most benefits over other ACE2fusions. Considering the importance of Fc-effector functions for the biological activity of ACE2-Fcs, it will be exciting to see how ACE2-IgM hexamers compare to ACE2-IgG-Fc constructs in terms of in vivo efficacy 24 .…”

Counter-regulatory renin-angiotensin system in hypertension: Review and update in the era of COVID-19 pandemic

“…The weekly injections of rACE2-Fc effectively lowered plasma Ang II and blood pressure, associated with meliorated albuminuria and reduced kidney and cardiac fibrosis [363] . Recently, in a stringent K18-hACE2 mouse model challenged with various SARS-CoV-2 variants, rACE2-Fc counteracts murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities with a broadly effective therapeutics capability [364] .…”