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

• DOI: 10.1126/sciadv.abn4188
• Publication Date: 2022-07-13T17:58:47Z
• Authors: Yaozong Chen; Lulu Sun; Irfan Ullah; Guillaume Beaudoi...; Sai Priya Anand; Andrew P. Hederman; William D. Tolbert; Rebekah Sherburn; Dung N. Nguyen; Lorie Marchitto; Shilei Ding; Di Wu; Yuhong Luo; Suneetha Gottumuk...; Sean Moran; Priti Kumar; Grzegorz Piszczek; Walther Mothes; Margaret E. Ackerman; Andrés Finzi; Pradeep D. Uchil; Frank J. Gonzalez; Marzena Pazgier
• Keywords: Angiotensin-converting enzyme 2; Coronavirus

Soluble angiotensin-converting enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range coronaviruses using ACE2 as their receptor. Using structure-guided approaches, we developed series bivalent ACE2-Fcs harboring functionally and structurally validated mutations that enhance severe acute respiratory syndrome coronavirus (SARS-CoV-2) receptor binding domain recognition by up to ~12-fold remove angiotensin enzymatic activity. The lead variant M81 potently cross-neutralized SARS-CoV-2 variants concern (VOCs), including Omicron, at subnanomolar half-maximal inhibitory concentration was robust Fc-effector functions, antibody-dependent cellular cytotoxicity, phagocytosis, complement deposition. When tested in stringent K18-hACE2 mouse model, Fc-enhanced ACE2-Fc delayed death 3 5 days or effectively resolved lethal infection both prophylactic therapeutic settings via the combined effects neutralization functions. These data add demonstrated utility soluble valuable indicate functions may constitute important component