An IgM-like Inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2

Abstract

Many of the currently available COVID-19 vaccines and therapeutics are not effective against newly emerged SARS-CoV-2 variants. Here, we developed the metallo-enzyme domain of angiotensin converting enzyme 2 (ACE2)—the cellular receptor of SARS-CoV-2—into an IgM-like inhalable molecule (HH-120). HH-120 binds to the SARS-CoV-2 Spike (S) protein with exceptionally high avidity and confers potent and broad-spectrum neutralization activity against all known SARS-CoV-2 variants of concern. HH-120 was successfully developed as an inhaled formulation that achieves appropriate aerodynamic properties for respiratory system delivery, and we found that aerosol inhalation of HH-120 significantly reduced viral loads and lung pathology scores in golden Syrian hamsters infected by the SARS-CoV-2 wild-type strain and the Delta variant. Our study presents a breakthrough for the inhalation delivery of large biologics like HH-120 (molecular weight ~ 1000kDa) and demonstrates that HH-120 can serve as a highly efficacious, safe, and convenient agent against all SARS-CoV-2 variants. Finally, given the known role of ACE2 in viral reception, it is conceivable that HH-120 will be efficacious against additional emergent coronaviruses.

Nasal spray of an IgM‐like ACE2 fusion protein HH‐120 accelerates SARS‐CoV‐2 clearance: A single‐center propensity score‐matched cohort study

“…The efficacy of these ACE2‐based interventions against SARS‐CoV‐2 infection is being investigated with variable outcomes 38 . HH‐120 is a multivalent recombinant IgM‐like ACE2 with exceptionally high binding avidity for the viral spike protein (>1.0 × 10 −12 M), showing about a 100‐fold higher neutralization activity than the Fc‐tagged bivalent hACE2 (ACE2‐hIgG1) and with no infection enhancement effect, which was observed in other recombinant ACE2 proteins containing most of the collectrin domain at low concentrations 26,39 . Furthermore, unlike other ACE2 derivatives that have limited local bioavailability when administered through infusion, delivering HH‐120 directly to the upper respiratory tract has shown sufficient drug exposure to effectively contain the virus while also offering expected dose‐sparing benefits 24 .…”

“…38 HH-120 is a multivalent recombinant IgM-like ACE2 with ), showing about a 100-fold higher neutralization activity than the Fc-tagged bivalent hACE2 (ACE2-hIgG1) and with no infection enhancement effect, which was observed in other recombinant ACE2 proteins containing most of the collectrin domain at low concentrations. 26,39 Furthermore, unlike other ACE2 derivatives that have limited local bioavailability when administered through infusion, delivering HH-120 directly to the upper respiratory tract has shown sufficient drug exposure to effectively contain the virus while also offering expected dose-sparing benefits. 24 The Omicron variant mainly affects the upper respiratory tract and causes a high number of upper respiratory tract symptoms.…”

“…27 HH-120 has demonstrated potent and broad neutralizing activity against all tested SARS-CoV-2 variants in vitro, and demonstrated therapeutic effect against the ancestral strain and Delta variant in golden Syrian hamster infection models via aerosol inhalation. 26 Moreover, HH-120 works better than the monovalent ACE2 decoy in the neutralization activity of SARS-CoV-2. 26 Preclinical toxicological studies in rats and cynomolgus monkeys have demonstrated that HH-120 administration via aerosol inhalation is safe and well-tolerated, 26 Safety outcomes, including percentages of participants with AEs, treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and treatment-related adverse events (TRAEs), as well as the discontinuation of drug administration due to AEs, were evaluated in the safety population, which consisted of all participants who had received at least one dose of HH-120.…”

“…We recently reported our development of an IgM‐like oligomerized ACE2 fusion protein (named HH‐120) 26 . Each HH‐120 subunit (monomer) consists of the inactive zinc metalloenzyme extracellular domain of human ACE2 (residues 19–615) at the N‐terminus, an Fc fragment from human IgG1, and an IgM tailpiece at the C‐terminus (which enables the pentamerization and hexamerization of the fusion protein) 27 .…”

Broadly effective ACE2 decoy proteins protect mice from lethal SARS-CoV-2 infection

“…Therefore, more carefully designed studies to investigate this aspect should be warranted in the future. An ACE2-Ig product that keeps Fc effect functions has moved into clinical stage 53 (NCT05116865, NCT05659602). Safety data from these trials should be informative.…”