期刊
SCIENCE ADVANCES
卷 8, 期 28, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abn4188
关键词
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资金
- USU, Bethesda, MD
- National Institutes of Health, National Cancer Institute, Center for Cancer Research
- NIH [R01AI163395]
- Canadian Institutes of Health Research (CIHR) operating Pandemic and Health Emergencies Research grant [177958]
- Canada Foundation for Innovation (CFI) [41027]
- FRQS Ph.D. fellowship
- U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences
- Canada Research Chair on Retroviral Entry [RCHS0235 950-232424]
- CIHR Ph.D. fellowship
Researchers developed a bivalent ACE2-Fc with enhanced recognition of SARS-CoV-2 and improved antibody effector functions. In mouse models, this ACE2-Fc delayed death and effectively treated lethal SARS-CoV-2 infection through neutralization and effector functions.
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 similar 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.
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