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Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic protection

Emma S. Winkler, Pavlo Gilchuk, Jinsheng Yu, Adam L. Bailey, Rita E. Chen, Seth J. Zost, Hyesun Jang, Ying Huang, James D. Allen, James Brett Case, Rachel E. Sutton, Robert H. Carnahan, Tamarand L. Darling, View ORCID ProfileAdrianus C. M. Boon, Matthias Mack, Richard D. Head, View ORCID ProfileTed M. Ross, View ORCID ProfileJames E. Crowe Jr., View ORCID ProfileMichael S. Diamond
doi: https://doi.org/10.1101/2020.12.28.424554
Emma S. Winkler
1Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
2Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Pavlo Gilchuk
3Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Jinsheng Yu
4Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Adam L. Bailey
2Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Rita E. Chen
1Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
2Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Seth J. Zost
3Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Hyesun Jang
5Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA
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Ying Huang
5Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA
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James D. Allen
5Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA
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James Brett Case
1Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Rachel E. Sutton
3Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Robert H. Carnahan
3Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA
6Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
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Tamarand L. Darling
1Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Adrianus C. M. Boon
1Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
2Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
7Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA
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Matthias Mack
8Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
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Richard D. Head
4Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Ted M. Ross
5Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA
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James E. Crowe Jr.
3Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA
5Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA
9Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • For correspondence: james.crowe@vumc.org diamond@wusm.wustl.edu
Michael S. Diamond
1Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
2Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
7Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA
10The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
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  • For correspondence: james.crowe@vumc.org diamond@wusm.wustl.edu
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SUMMARY

SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes for therapeutic efficacy. Thus, potently neutralizing mAbs require Fc effector functions for maximal therapeutic benefit during therapy to modulate protective immune responses and mitigate lung disease.

Competing Interest Statement

M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. J.E.C. has served as a consultant for Eli Lilly and Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from AstraZeneca and IDBiologics. Vanderbilt University has applied for patents related to antibodies described in this paper. The Boon laboratory has received unrelated funding support in sponsored research agreements from AI Therapeutics, GreenLight Biosciences, AbbVie, and Nano Targeting & Therapy Biopharma.

Footnotes

  • ↵¶ Lead Contact: Michael S. Diamond, M.D., Ph.D.,

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic protection
Emma S. Winkler, Pavlo Gilchuk, Jinsheng Yu, Adam L. Bailey, Rita E. Chen, Seth J. Zost, Hyesun Jang, Ying Huang, James D. Allen, James Brett Case, Rachel E. Sutton, Robert H. Carnahan, Tamarand L. Darling, Adrianus C. M. Boon, Matthias Mack, Richard D. Head, Ted M. Ross, James E. Crowe Jr., Michael S. Diamond
bioRxiv 2020.12.28.424554; doi: https://doi.org/10.1101/2020.12.28.424554
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Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic protection
Emma S. Winkler, Pavlo Gilchuk, Jinsheng Yu, Adam L. Bailey, Rita E. Chen, Seth J. Zost, Hyesun Jang, Ying Huang, James D. Allen, James Brett Case, Rachel E. Sutton, Robert H. Carnahan, Tamarand L. Darling, Adrianus C. M. Boon, Matthias Mack, Richard D. Head, Ted M. Ross, James E. Crowe Jr., Michael S. Diamond
bioRxiv 2020.12.28.424554; doi: https://doi.org/10.1101/2020.12.28.424554

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