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Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities
Soluble Angiotensin-Converting Enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses utilizing ACE2 as their receptor. Here, using structure-guided approaches, we developed divalent ACE2 molecules by grafting the extracellular ACE2-domain onto a human...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629194/ https://www.ncbi.nlm.nih.gov/pubmed/34845451 http://dx.doi.org/10.1101/2021.11.24.469776 |
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author | Chen, Yaozong Sun, Lulu Ullah, Irfan Beaudoin-Bussières, Guillaume Anand, Sai Priya Hederman, Andrew P. Tolbert, William D. Sherburn, Rebekah Nguyen, Dung N. Marchitto, Lorie Ding, Shilei Wu, Di Luo, Yuhong Gottumukkala, Suneetha Moran, Sean Kumar, Priti Piszczek, Grzegorz Mothes, Walther Ackerman, Margaret E. Finzi, Andrés Uchil, Pradeep D. Gonzalez, Frank J. Pazgier, Marzena |
author_facet | Chen, Yaozong Sun, Lulu Ullah, Irfan Beaudoin-Bussières, Guillaume Anand, Sai Priya Hederman, Andrew P. Tolbert, William D. Sherburn, Rebekah Nguyen, Dung N. Marchitto, Lorie Ding, Shilei Wu, Di Luo, Yuhong Gottumukkala, Suneetha Moran, Sean Kumar, Priti Piszczek, Grzegorz Mothes, Walther Ackerman, Margaret E. Finzi, Andrés Uchil, Pradeep D. Gonzalez, Frank J. Pazgier, Marzena |
author_sort | Chen, Yaozong |
collection | PubMed |
description | Soluble Angiotensin-Converting Enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses utilizing ACE2 as their receptor. Here, using structure-guided approaches, we developed divalent ACE2 molecules by grafting the extracellular ACE2-domain onto a human IgG1 or IgG3 (ACE2-Fc). These ACE2-Fcs harbor structurally validated mutations that enhance spike (S) binding and remove angiotensin enzymatic activity. The lead variant bound tightly to S, mediated in vitro neutralization of SARS-CoV-2 variants of concern (VOCs) with sub-nanomolar IC(50) 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, it delayed death or effectively resolved lethal SARS-CoV-2 infection in a prophylactic or therapeutic setting utilizing the combined effect of neutralization and Fc-effector functions. These data confirm the utility of ACE2-Fcs as valuable agents in preventing and eliminating SARS-CoV-2 infection and demonstrate that ACE2-Fc therapeutic activity require Fc-effector functions. |
format | Online Article Text |
id | pubmed-8629194 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-86291942021-11-30 Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities Chen, Yaozong Sun, Lulu Ullah, Irfan Beaudoin-Bussières, Guillaume Anand, Sai Priya Hederman, Andrew P. Tolbert, William D. Sherburn, Rebekah Nguyen, Dung N. Marchitto, Lorie Ding, Shilei Wu, Di Luo, Yuhong Gottumukkala, Suneetha Moran, Sean Kumar, Priti Piszczek, Grzegorz Mothes, Walther Ackerman, Margaret E. Finzi, Andrés Uchil, Pradeep D. Gonzalez, Frank J. Pazgier, Marzena bioRxiv Article Soluble Angiotensin-Converting Enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses utilizing ACE2 as their receptor. Here, using structure-guided approaches, we developed divalent ACE2 molecules by grafting the extracellular ACE2-domain onto a human IgG1 or IgG3 (ACE2-Fc). These ACE2-Fcs harbor structurally validated mutations that enhance spike (S) binding and remove angiotensin enzymatic activity. The lead variant bound tightly to S, mediated in vitro neutralization of SARS-CoV-2 variants of concern (VOCs) with sub-nanomolar IC(50) 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, it delayed death or effectively resolved lethal SARS-CoV-2 infection in a prophylactic or therapeutic setting utilizing the combined effect of neutralization and Fc-effector functions. These data confirm the utility of ACE2-Fcs as valuable agents in preventing and eliminating SARS-CoV-2 infection and demonstrate that ACE2-Fc therapeutic activity require Fc-effector functions. Cold Spring Harbor Laboratory 2021-11-24 /pmc/articles/PMC8629194/ /pubmed/34845451 http://dx.doi.org/10.1101/2021.11.24.469776 Text en https://creativecommons.org/licenses/by-nc/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Chen, Yaozong Sun, Lulu Ullah, Irfan Beaudoin-Bussières, Guillaume Anand, Sai Priya Hederman, Andrew P. Tolbert, William D. Sherburn, Rebekah Nguyen, Dung N. Marchitto, Lorie Ding, Shilei Wu, Di Luo, Yuhong Gottumukkala, Suneetha Moran, Sean Kumar, Priti Piszczek, Grzegorz Mothes, Walther Ackerman, Margaret E. Finzi, Andrés Uchil, Pradeep D. Gonzalez, Frank J. Pazgier, Marzena Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities |
title | Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities |
title_full | Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities |
title_fullStr | Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities |
title_full_unstemmed | Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities |
title_short | Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities |
title_sort | engineered ace2-fc counters murine lethal sars-cov-2 infection through direct neutralization and fc-effector activities |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629194/ https://www.ncbi.nlm.nih.gov/pubmed/34845451 http://dx.doi.org/10.1101/2021.11.24.469776 |
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