Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities

Yaozong Chen, Lulu Sun, Irfan Ullah, Guillaume Beaudoin-Bussières, Sai Priya Anand, Andrew P. Hederman, William D. Tolbert, Rebekah Sherburn, Dung N. Nguyen, Lorie Marchitto, Shilei Ding, Di Wu, Yuhong Luo, Suneetha Gottumukkala, Sean Moran, Priti Kumar, Grzegorz Piszczek, Walther Mothes, Margaret E. Ackerman, Andrés FinziPradeep D. Uchil, Frank J. Gonzalez, Marzena Pazgier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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.

Original languageEnglish
Article numbereabn4188
JournalScience Advances
Volume8
Issue number28
DOIs
StatePublished - Jul 2022
Externally publishedYes

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