ACE2-Fc fusion protein overcomes viral escape by potently neutralizing SARS-CoV-2 variants of concern

COVID-19, an infectious disease caused by the SARS-CoV-2 virus, emerged globally in early 2020 and has remained a serious public health issue. To date, although several preventative vaccines have been approved by FDA and EMA, vaccinated individuals increasingly suffer from breakthrough infections. Therapeutic antibodies may provide an alternative strategy to neutralize viral infection and treat serious cases; however, the clinical data and our experiments show that some FDA-approved monoclonal antibodies lose function against COVID-19 variants such as Omicron. Therefore, in this study, we present a novel therapeutic agent, SI–F019, an ACE2-Fc fusion protein whose neutralization efficiency is not compromised, but actually strengthened, by the mutations of dominant variants including Omicron. Comprehensive biophysical analyses revealed the mechanism of increased inhibition to be enhanced interaction of SI–F019 with all the tested spike variants, in contrast to monoclonal antibodies which tended to show weaker binding to some variants. The results imply that SI–F019 may be a broadly useful agent for treatment of COVID-19.