TY - JOUR
T1 - Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities
AU - Chen, Yaozong
AU - Sun, Lulu
AU - Ullah, Irfan
AU - Beaudoin-Bussières, Guillaume
AU - Anand, Sai Priya
AU - Hederman, Andrew P.
AU - Tolbert, William D.
AU - Sherburn, Rebekah
AU - Nguyen, Dung N.
AU - Marchitto, Lorie
AU - Ding, Shilei
AU - Wu, Di
AU - Luo, Yuhong
AU - Gottumukkala, Suneetha
AU - Moran, Sean
AU - Kumar, Priti
AU - Piszczek, Grzegorz
AU - Mothes, Walther
AU - Ackerman, Margaret E.
AU - Finzi, Andrés
AU - Uchil, Pradeep D.
AU - Gonzalez, Frank J.
AU - Pazgier, Marzena
N1 - Funding Information:
We thank J. S. McLellan from University of Texas, Austin for sharing the expression plasmids of SARS-CoV-2 S-2P, S-6P, SARS-CoV-1 RBD-Fc, and monomeric ACE2. We thank BEI Resources for sharing the SARS-CoV-2–related reagents, including pseudo-typed lentiviral kits (NR-53816 and NR-53817), recombinant SB.1.1.7 (NR-55311), SB.1.351 (NR-55311), SB.1526 (NR-55438), SP.1 (NR-55307), etc. We thank K. Pratt and P. Vir from the Department of Medicine, USUHS for providing laboratory resources and technical support to this project. We thank A. Malloy and Z. Lu from the Department of Pediatric, USUHS for sharing the hACE2-expressing HEK293T cell line. We thank R. Petrovich and N. P. Martin from NIEHS for sharing the SP.1 plasmid for PsV production. The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Uniformed Services University, the U.S. Army, the Department of Defense, the National Institutes of Health, Department of Health and Human Services, or the U.S. government, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This work was supported by USU, Bethesda, MD intramural funds to M.P.; in part by funding to F.J.G. from the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research; and in part by NIH grant R01AI163395 to W.M. This work was also supported by Canadian Institutes of Health Research (CIHR) operating Pandemic and Health Emergencies Research grant #177958 and an Exceptional Fund COVID-19 from the Canada Foundation for Innovation (CFI) #41027 to A.F. A.F. is the recipient of Canada Research Chair on Retroviral Entry no. RCHS0235 950-232424. G.B.-B. is a recipient of the FRQS Ph.D. fellowship, and S.P.A. is a recipient of the CIHR Ph.D. fellowship. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health, National Institute of General Medical Sciences.
Publisher Copyright:
Copyright © 2022 The Authors
PY - 2022/7
Y1 - 2022/7
N2 - Soluble angiotensin-converting enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses using ACE2 as their receptor. Using structure-guided approaches, we developed a series of bivalent ACE2-Fcs harboring functionally and structurally validated mutations that enhance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain recognition by up to ~12-fold and remove angiotensin enzymatic activity. The lead variant M81 potently cross-neutralized SARS-CoV-2 variants of concern (VOCs), including Omicron, at subnanomolar half-maximal inhibitory concentration and was capable of robust Fc-effector functions, including antibody-dependent cellular cytotoxicity, phagocytosis, and complement deposition. When tested in a stringent K18-hACE2 mouse model, Fc-enhanced ACE2-Fc delayed death by 3 to 5 days or effectively resolved lethal SARS-CoV-2 infection in both prophylactic and therapeutic settings via the combined effects of neutralization and Fc-effector functions. These data add to the demonstrated utility of soluble ACE2 as a valuable SARS-CoV-2 antiviral and indicate that Fc-effector functions may constitute an important component of ACE2-Fc therapeutic activity.
AB - Soluble angiotensin-converting enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses using ACE2 as their receptor. Using structure-guided approaches, we developed a series of bivalent ACE2-Fcs harboring functionally and structurally validated mutations that enhance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain recognition by up to ~12-fold and remove angiotensin enzymatic activity. The lead variant M81 potently cross-neutralized SARS-CoV-2 variants of concern (VOCs), including Omicron, at subnanomolar half-maximal inhibitory concentration and was capable of robust Fc-effector functions, including antibody-dependent cellular cytotoxicity, phagocytosis, and complement deposition. When tested in a stringent K18-hACE2 mouse model, Fc-enhanced ACE2-Fc delayed death by 3 to 5 days or effectively resolved lethal SARS-CoV-2 infection in both prophylactic and therapeutic settings via the combined effects of neutralization and Fc-effector functions. These data add to the demonstrated utility of soluble ACE2 as a valuable SARS-CoV-2 antiviral and indicate that Fc-effector functions may constitute an important component of ACE2-Fc therapeutic activity.
UR - http://www.scopus.com/inward/record.url?scp=85134428421&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abn4188
DO - 10.1126/sciadv.abn4188
M3 - Article
C2 - 35857504
AN - SCOPUS:85134428421
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 28
M1 - eabn4188
ER -