Abstract
Monoclonal antibodies targeting the SARS-CoV-2 spike (S) neutralize infection and are efficacious for the treatment of COVID-19. However, SARS-CoV-2 variants, notably sublineages of B.1.1.529/omicron, have emerged that escape antibodies in clinical use. As an alternative, soluble decoy receptors based on the host entry receptor ACE2 broadly bind and block S from SARS-CoV-2 variants and related betacoronaviruses. The high-affinity and catalytically active decoy sACE2 2 .v2.4-IgG1 was previously shown to be effective against SARS-CoV-2 variants when administered intravenously. Here, inhalation of aerosolized sACE2 2 .v2.4-IgG1 increased survival and ameliorated lung injury in K18-hACE2 mice inoculated with P.1/gamma virus. Loss of catalytic activity reduced the decoy’s therapeutic efficacy, which was further confirmed by intravenous administration, supporting dual mechanisms of action: direct blocking of S and turnover of ACE2 substrates associated with lung injury and inflammation. Furthermore, sACE2 2 .v2.4-IgG1 tightly binds and neutralizes BA.1, BA.2, and BA.4/BA.5 omicron and protects K18-hACE2 mice inoculated with a high dose of BA.1 omicron virus. Overall, the therapeutic potential of sACE2 2 .v2.4-IgG1 is demonstrated by the inhalation route and broad neutralization potency persists against highly divergent SARS-CoV-2 variants.
Keywords: COVID-19; SARS-CoV-2; angiotensin-converting enzyme 2; decoy; omicron; receptor.
【저자키워드】 COVID-19, SARS-CoV-2, omicron, angiotensin-converting enzyme 2, receptor., decoy, 【초록키워드】 Treatment, Inflammation, ACE2, High dose, antibody, SARS-CoV-2 variant, Infection, Lung injury, virus, SARS-CoV-2 variants, K18-hACE2 mice, receptor, mechanism, betacoronaviruses, Angiotensin-converting enzyme, administration, intravenous, Clinical use, therapeutic efficacy, therapeutic potential, increased survival, neutralization potency, entry receptor, substrate, intravenously, catalytic activity, Administered, Host, sACE2, Loss, effective, neutralize, bind, PROTECT, shown, inoculated, reduced, demonstrated, ameliorated, catalytically active, persist, the SARS-CoV-2, 【제목키워드】 ACE2, Omicron variant, target, Administered,