tetano
Editor, Senior Moderator
Sci Adv
. 2022 Jul 15;8(28):eabn4188.
doi: 10.1126/sciadv.abn4188. Epub 2022 Jul 13.
Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities
Yaozong Chen[SUP] 1 [/SUP], Lulu Sun[SUP] 2 [/SUP], Irfan Ullah[SUP] 3 [/SUP], Guillaume Beaudoin-Bussières[SUP] 4 5 [/SUP], Sai Priya Anand[SUP] 4 6 [/SUP], Andrew P Hederman[SUP] 7 [/SUP], William D Tolbert[SUP] 1 [/SUP], Rebekah Sherburn[SUP] 1 [/SUP], Dung N Nguyen[SUP] 1 [/SUP], Lorie Marchitto[SUP] 4 5 [/SUP], Shilei Ding[SUP] 4 [/SUP], Di Wu[SUP] 8 [/SUP], Yuhong Luo[SUP] 2 [/SUP], Suneetha Gottumukkala[SUP] 1 [/SUP], Sean Moran[SUP] 9 [/SUP], Priti Kumar[SUP] 3 [/SUP], Grzegorz Piszczek[SUP] 8 [/SUP], Walther Mothes[SUP] 10 [/SUP], Margaret E Ackerman[SUP] 7 [/SUP], Andrés Finzi[SUP] 4 5 6 [/SUP], Pradeep D Uchil[SUP] 10 [/SUP], Frank J Gonzalez[SUP] 2 [/SUP], Marzena Pazgier[SUP] 1 [/SUP]
Affiliations
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.
. 2022 Jul 15;8(28):eabn4188.
doi: 10.1126/sciadv.abn4188. Epub 2022 Jul 13.
Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities
Yaozong Chen[SUP] 1 [/SUP], Lulu Sun[SUP] 2 [/SUP], Irfan Ullah[SUP] 3 [/SUP], Guillaume Beaudoin-Bussières[SUP] 4 5 [/SUP], Sai Priya Anand[SUP] 4 6 [/SUP], Andrew P Hederman[SUP] 7 [/SUP], William D Tolbert[SUP] 1 [/SUP], Rebekah Sherburn[SUP] 1 [/SUP], Dung N Nguyen[SUP] 1 [/SUP], Lorie Marchitto[SUP] 4 5 [/SUP], Shilei Ding[SUP] 4 [/SUP], Di Wu[SUP] 8 [/SUP], Yuhong Luo[SUP] 2 [/SUP], Suneetha Gottumukkala[SUP] 1 [/SUP], Sean Moran[SUP] 9 [/SUP], Priti Kumar[SUP] 3 [/SUP], Grzegorz Piszczek[SUP] 8 [/SUP], Walther Mothes[SUP] 10 [/SUP], Margaret E Ackerman[SUP] 7 [/SUP], Andrés Finzi[SUP] 4 5 6 [/SUP], Pradeep D Uchil[SUP] 10 [/SUP], Frank J Gonzalez[SUP] 2 [/SUP], Marzena Pazgier[SUP] 1 [/SUP]
Affiliations
- PMID: 35857504
- DOI: 10.1126/sciadv.abn4188
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.