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An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19

View ORCID ProfileC. Garrett Rappazzo, View ORCID ProfileLongping V. Tse, Chengzi I. Kaku, View ORCID ProfileDaniel Wrapp, Mrunal Sakharkar, View ORCID ProfileDeli Huang, Laura M. Deveau, Thomas J. Yockachonis, View ORCID ProfileAndrew S. Herbert, View ORCID ProfileMichael B. Battles, Cecilia M. O’Brien, View ORCID ProfileMichael E. Brown, James C. Geoghegan, Jonathan Belk, View ORCID ProfileLinghang Peng, View ORCID ProfileLinlin Yang, View ORCID ProfileTrevor D. Scobey, View ORCID ProfileDennis R. Burton, View ORCID ProfileDavid Nemazee, View ORCID ProfileJohn M. Dye, View ORCID ProfileJames E. Voss, View ORCID ProfileBronwyn M. Gunn, View ORCID ProfileJason S. McLellan, View ORCID ProfileRalph S. Baric, View ORCID ProfileLisa E. Gralinski, View ORCID ProfileLaura M. Walker
doi: https://doi.org/10.1101/2020.11.17.385500
C. Garrett Rappazzo
1Adimab LLC, Lebanon, NH 03766, USA
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Longping V. Tse
2Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Chengzi I. Kaku
1Adimab LLC, Lebanon, NH 03766, USA
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Daniel Wrapp
3Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
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Mrunal Sakharkar
1Adimab LLC, Lebanon, NH 03766, USA
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Deli Huang
4Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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Laura M. Deveau
1Adimab LLC, Lebanon, NH 03766, USA
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Thomas J. Yockachonis
5Paul G. Allen School of Global Animal Health, Washington State University, Pullman, WA 99164, USA
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Andrew S. Herbert
6U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
7The Geneva Foundation, 917 Pacific Avenue, Tacoma, WA 98402, USA
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Michael B. Battles
1Adimab LLC, Lebanon, NH 03766, USA
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Cecilia M. O’Brien
6U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
7The Geneva Foundation, 917 Pacific Avenue, Tacoma, WA 98402, USA
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Michael E. Brown
1Adimab LLC, Lebanon, NH 03766, USA
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James C. Geoghegan
1Adimab LLC, Lebanon, NH 03766, USA
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Jonathan Belk
1Adimab LLC, Lebanon, NH 03766, USA
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Linghang Peng
4Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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Linlin Yang
4Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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Trevor D. Scobey
2Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Dennis R. Burton
4Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
8IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA
9Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
10Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA 02139, USA
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David Nemazee
4Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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John M. Dye
6U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
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James E. Voss
4Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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Bronwyn M. Gunn
5Paul G. Allen School of Global Animal Health, Washington State University, Pullman, WA 99164, USA
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Jason S. McLellan
3Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
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Ralph S. Baric
2Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
11Departments of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • For correspondence: rbaric@email.unc.edu lgralins@email.unc.edu laura.walker@adimab.com
Lisa E. Gralinski
2Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • ORCID record for Lisa E. Gralinski
  • For correspondence: rbaric@email.unc.edu lgralins@email.unc.edu laura.walker@adimab.com
Laura M. Walker
1Adimab LLC, Lebanon, NH 03766, USA
12Adagio Therapeutics, Inc., Waltham, MA 02451, USA
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  • For correspondence: rbaric@email.unc.edu lgralins@email.unc.edu laura.walker@adimab.com
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Abstract

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. Here, we employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with remarkable potency. Structural and biochemical studies demonstrate that ADG-2 employs a unique angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In murine models of SARS-CoV and SARS-CoV-2 infection, passive transfer of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate for the treatment and prevention of SARS-CoV-2 and future emerging SARS-like CoVs.

Competing Interest Statement

C.G.R, C.I.K, M.S., L.M.D., M.B.B., M.E.B., J.C.G., and L.M.W. are employees of Adimab, LLC and may hold shares in Adimab, LLC. L.M.W. is an employee of Adagio Therapeutics Inc. and holds shares in Adagio Therapeutics Inc. D.R.B. is on the SAB of Adimab, LLC and Adagio Therapeutics Inc. and holds shares in Adimab, LLC.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19
C. Garrett Rappazzo, Longping V. Tse, Chengzi I. Kaku, Daniel Wrapp, Mrunal Sakharkar, Deli Huang, Laura M. Deveau, Thomas J. Yockachonis, Andrew S. Herbert, Michael B. Battles, Cecilia M. O’Brien, Michael E. Brown, James C. Geoghegan, Jonathan Belk, Linghang Peng, Linlin Yang, Trevor D. Scobey, Dennis R. Burton, David Nemazee, John M. Dye, James E. Voss, Bronwyn M. Gunn, Jason S. McLellan, Ralph S. Baric, Lisa E. Gralinski, Laura M. Walker
bioRxiv 2020.11.17.385500; doi: https://doi.org/10.1101/2020.11.17.385500
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An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19
C. Garrett Rappazzo, Longping V. Tse, Chengzi I. Kaku, Daniel Wrapp, Mrunal Sakharkar, Deli Huang, Laura M. Deveau, Thomas J. Yockachonis, Andrew S. Herbert, Michael B. Battles, Cecilia M. O’Brien, Michael E. Brown, James C. Geoghegan, Jonathan Belk, Linghang Peng, Linlin Yang, Trevor D. Scobey, Dennis R. Burton, David Nemazee, John M. Dye, James E. Voss, Bronwyn M. Gunn, Jason S. McLellan, Ralph S. Baric, Lisa E. Gralinski, Laura M. Walker
bioRxiv 2020.11.17.385500; doi: https://doi.org/10.1101/2020.11.17.385500

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