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

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.