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Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants

Hyeseon Cho, Kristina Kay Gonzales-Wartz, Deli Huang, View ORCID ProfileMeng Yuan, Mary Peterson, Janie Liang, Nathan Beutler, Jonathan L. Torres, Yu Cong, Elena Postnikova, Sandhya Bangaru, Chloe Adrienna Talana, Wei Shi, Eun Sung Yang, Yi Zhang, Kwanyee Leung, Lingshu Wang, Linghang Peng, Jeff Skinner, Shanping Li, View ORCID ProfileNicholas C. Wu, Hejun Liu, Cherrelle Dacon, Thomas Moyer, Melanie Cohen, Ming Zhao, F. Eun-Hyung Lee, Rona S. Weinberg, Iyadh Douagi, Robin Gross, Connie Schmaljohn, Amarendra Pegu, John R. Mascola, View ORCID ProfileMichael Holbrook, View ORCID ProfileDavid Nemazee, Thomas F. Rogers, View ORCID ProfileAndrew B. Ward, Ian A. Wilson, Peter D. Crompton, View ORCID ProfileJoshua Tan
doi: https://doi.org/10.1101/2021.04.01.437942
Hyeseon Cho
1Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
12The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA
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Kristina Kay Gonzales-Wartz
2Antibody Biology Unit, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
12The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA
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Deli Huang
3Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
12The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA
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Meng Yuan
4Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
12The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA
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Mary Peterson
1Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
12The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA
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Janie Liang
5Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA
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Nathan Beutler
3Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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Jonathan L. Torres
4Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
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Yu Cong
5Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA
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Elena Postnikova
5Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA
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Sandhya Bangaru
4Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
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Chloe Adrienna Talana
6Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Wei Shi
6Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Eun Sung Yang
6Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Yi Zhang
6Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Kwanyee Leung
6Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Lingshu Wang
6Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Linghang Peng
3Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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Jeff Skinner
1Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
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Shanping Li
1Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
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Nicholas C. Wu
4Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
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  • ORCID record for Nicholas C. Wu
Hejun Liu
4Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
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Cherrelle Dacon
2Antibody Biology Unit, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
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Thomas Moyer
7Flow Cytometry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Melanie Cohen
7Flow Cytometry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Ming Zhao
8Protein Chemistry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
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F. Eun-Hyung Lee
9Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Emory University, Atlanta, GA 30322, USA
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Rona S. Weinberg
10New York Blood Center, Lindsley F. Kimball Research Institute, New York, NY 10065, USA.
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Iyadh Douagi
7Flow Cytometry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Robin Gross
6Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Connie Schmaljohn
5Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA
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Amarendra Pegu
6Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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John R. Mascola
6Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Michael Holbrook
5Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA
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David Nemazee
3Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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Thomas F. Rogers
3Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
11Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA
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Andrew B. Ward
4Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
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Ian A. Wilson
4Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
12The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA
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Peter D. Crompton
1Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
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  • For correspondence: pcrompton@niaid.nih.gov tanj4@nih.gov
Joshua Tan
2Antibody Biology Unit, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
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  • For correspondence: pcrompton@niaid.nih.gov tanj4@nih.gov
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Abstract

The emergence of SARS-CoV-2 variants that threaten the efficacy of existing vaccines and therapeutic antibodies underscores the urgent need for new antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells of COVID-19 patients. The three most potent antibodies targeted distinct regions of the RBD, and all three neutralized the SARS-CoV-2 variants B.1.1.7 and B.1.351. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the ACE2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five ultrapotent bispecific antibodies that inhibit authentic SARS-CoV-2 infection at concentrations of <1 ng/mL. Through a novel mode of action three bispecific antibodies cross-linked adjacent spike proteins using dual NTD/RBD specificities. One bispecific antibody was >100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, six of nine bispecific antibodies neutralized B.1.1.7, B.1.351 and the wild-type virus with comparable potency, despite partial or complete loss of activity of at least one parent monoclonal antibody against B.1.351. Furthermore, a bispecific antibody that neutralized B.1.351 protected against SARS-CoV-2 expressing the crucial E484K mutation in the hamster model. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.

Competing Interest Statement

A patent application has been submitted on the antibodies described in this manuscript. R.G., J.L., and M.R.H. performed this work as employees of Laulima Government Solutions, LLC while E.P performed this work as an employee of Tunnell Government Services. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services (DHHS) or of the institutions and companies affiliated with the authors. All other authors declare no competing interests.

Footnotes

  • ↵14 These authors jointly supervised the work

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants
Hyeseon Cho, Kristina Kay Gonzales-Wartz, Deli Huang, Meng Yuan, Mary Peterson, Janie Liang, Nathan Beutler, Jonathan L. Torres, Yu Cong, Elena Postnikova, Sandhya Bangaru, Chloe Adrienna Talana, Wei Shi, Eun Sung Yang, Yi Zhang, Kwanyee Leung, Lingshu Wang, Linghang Peng, Jeff Skinner, Shanping Li, Nicholas C. Wu, Hejun Liu, Cherrelle Dacon, Thomas Moyer, Melanie Cohen, Ming Zhao, F. Eun-Hyung Lee, Rona S. Weinberg, Iyadh Douagi, Robin Gross, Connie Schmaljohn, Amarendra Pegu, John R. Mascola, Michael Holbrook, David Nemazee, Thomas F. Rogers, Andrew B. Ward, Ian A. Wilson, Peter D. Crompton, Joshua Tan
bioRxiv 2021.04.01.437942; doi: https://doi.org/10.1101/2021.04.01.437942
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Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants
Hyeseon Cho, Kristina Kay Gonzales-Wartz, Deli Huang, Meng Yuan, Mary Peterson, Janie Liang, Nathan Beutler, Jonathan L. Torres, Yu Cong, Elena Postnikova, Sandhya Bangaru, Chloe Adrienna Talana, Wei Shi, Eun Sung Yang, Yi Zhang, Kwanyee Leung, Lingshu Wang, Linghang Peng, Jeff Skinner, Shanping Li, Nicholas C. Wu, Hejun Liu, Cherrelle Dacon, Thomas Moyer, Melanie Cohen, Ming Zhao, F. Eun-Hyung Lee, Rona S. Weinberg, Iyadh Douagi, Robin Gross, Connie Schmaljohn, Amarendra Pegu, John R. Mascola, Michael Holbrook, David Nemazee, Thomas F. Rogers, Andrew B. Ward, Ian A. Wilson, Peter D. Crompton, Joshua Tan
bioRxiv 2021.04.01.437942; doi: https://doi.org/10.1101/2021.04.01.437942

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