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 - This work was supported in part by NIH grants R43-AI162329 to EP and KKC; R01HL157489 to LZ; R01-HL162308 to ABM and JR. The following reagents were obtained through BEI Resources: isolate hCoV-19/Japan/TY7-503/2021 (P.1; NR-54982), isolate 2019n-CoV/USA-WA1/2020 (original; NR-52281), and isolate hCoV-19/USA/MD-HP20874/2021 (BA.1; NR-56461). Flow cytometry services were used at the Roy J. Carver Biotechnology Center, University of Illinois.
This work was supported in part by NIH grants R43‐AI162329 to EP and KKC; R01HL157489 to LZ; R01‐HL162308 to ABM and JR. The following reagents were obtained through BEI Resources: isolate hCoV‐19/Japan/TY7‐503/2021 (P.1; NR‐54982), isolate 2019n‐CoV/USA‐WA1/2020 (original; NR‐52281), and isolate hCoV‐19/USA/MD‐HP20874/2021 (BA.1; NR‐56461). Flow cytometry services were used at the Roy J. Carver Biotechnology Center, University of Illinois.
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
UR - http://www.scopus.com/inward/record.url?scp=85138670317&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85138670317&partnerID=8YFLogxK
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 -