TY - JOUR
T1 - An ACE2 decoy can be administered by inhalation and potently targets omicron variants of SARS-CoV-2
AU - Zhang, Lianghui
AU - Narayanan, Krishna K.
AU - Cooper, Laura
AU - Chan, Kui K.
AU - Skeeters, Savanna S.
AU - Devlin, Christine A.
AU - Aguhob, Aaron
AU - Shirley, Kristie
AU - Rong, Lijun
AU - Rehman, Jalees
AU - Malik, Asrar B.
AU - Procko, Erik
N1 - Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2022/11/8
Y1 - 2022/11/8
N2 - 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 sACE22.v2.4-IgG1 was previously shown to be effective against SARS-CoV-2 variants when administered intravenously. Here, inhalation of aerosolized sACE22.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, sACE22.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 sACE22.v2.4-IgG1 is demonstrated by the inhalation route and broad neutralization potency persists against highly divergent SARS-CoV-2 variants.
AB - 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 sACE22.v2.4-IgG1 was previously shown to be effective against SARS-CoV-2 variants when administered intravenously. Here, inhalation of aerosolized sACE22.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, sACE22.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 sACE22.v2.4-IgG1 is demonstrated by the inhalation route and broad neutralization potency persists against highly divergent SARS-CoV-2 variants.
KW - COVID-19
KW - SARS-CoV-2
KW - angiotensin-converting enzyme 2
KW - decoy
KW - omicron
KW - receptor
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U2 - 10.15252/emmm.202216109
DO - 10.15252/emmm.202216109
M3 - Article
C2 - 36094679
AN - SCOPUS:85138670317
SN - 1757-4676
VL - 14
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 11
M1 - e16109
ER -