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Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations

Shane Miersch, Zhijie Li, Reza Saberianfar, Mart Ustav, James Brett Case, Levi Blazer, Chao Chen, Wei Ye, Alevtina Pavlenco, Maryna Gorelik, Julia Garcia Perez, Suryasree Subramania, Serena Singh, Lynda Ploder, Safder Ganaie, Rita E. Chen, Daisy W. Leung, Pier Paolo Pandolfi, View ORCID ProfileGiuseppe Novelli, Giulia Matusali, Francesca Colavita, Maria R. Capobianchi, Suresh Jain, J.B. Gupta, Gaya K. Amarasinghe, Michael S. Diamond, James Rini, Sachdev S. Sidhu
doi: https://doi.org/10.1101/2020.10.31.362848
Shane Miersch
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Zhijie Li
2Department of Molecular Genetics, University of Toronto, Toronto, Canada
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Reza Saberianfar
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Mart Ustav
3Icosagen, Ōssu, Estonia
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James Brett Case
4Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Levi Blazer
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Chao Chen
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Wei Ye
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Alevtina Pavlenco
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Maryna Gorelik
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Julia Garcia Perez
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Suryasree Subramania
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Serena Singh
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Lynda Ploder
1The Donnelly Centre, University of Toronto, Toronto, Canada
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Safder Ganaie
4Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Rita E. Chen
4Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
12Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Daisy W. Leung
4Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Pier Paolo Pandolfi
5Renown Institute for Cancer, Nevada System of Higher Education, Reno, NV, USA
6Department of Molecular Biotechnologies & Health Sciences, Molecular Biotechnology Center, University of Turin, Italy
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Giuseppe Novelli
7Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133, Rome, Italy
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  • ORCID record for Giuseppe Novelli
Giulia Matusali
8Laboratory of Virology, National Institute for Infectious Diseases “L. Spallanzani” IRCCS, Rome, Italy
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Francesca Colavita
8Laboratory of Virology, National Institute for Infectious Diseases “L. Spallanzani” IRCCS, Rome, Italy
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Maria R. Capobianchi
8Laboratory of Virology, National Institute for Infectious Diseases “L. Spallanzani” IRCCS, Rome, Italy
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Suresh Jain
9Virna Therapeutics, West Roxbury, MA, USA
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J.B. Gupta
9Virna Therapeutics, West Roxbury, MA, USA
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Gaya K. Amarasinghe
12Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Michael S. Diamond
4Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
11Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA
12Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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James Rini
2Department of Molecular Genetics, University of Toronto, Toronto, Canada
10Department of Biochemistry, University of Toronto, Toronto, Canada
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  • For correspondence: james.rini@utoronto.ca sachdev.sidhu@utoronto.ca
Sachdev S. Sidhu
1The Donnelly Centre, University of Toronto, Toronto, Canada
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  • For correspondence: james.rini@utoronto.ca sachdev.sidhu@utoronto.ca
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SUMMARY

Neutralizing antibodies (nAbs) hold promise as effective therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and its tetravalent versions can block entry with a potency that exceeds the bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, observations consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show much increased tolerance to potential virus escape mutants. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for developing potent antiviral therapies against COVID-19 and related viral threats, and our strategy can be readily applied to any antibody drug currently in development.

Competing Interest Statement

MSD 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. SSS, SJ, SM, MU, JBG and PPP are shareholders in Virna Therapeutics.

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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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Posted December 21, 2020.
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Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations
Shane Miersch, Zhijie Li, Reza Saberianfar, Mart Ustav, James Brett Case, Levi Blazer, Chao Chen, Wei Ye, Alevtina Pavlenco, Maryna Gorelik, Julia Garcia Perez, Suryasree Subramania, Serena Singh, Lynda Ploder, Safder Ganaie, Rita E. Chen, Daisy W. Leung, Pier Paolo Pandolfi, Giuseppe Novelli, Giulia Matusali, Francesca Colavita, Maria R. Capobianchi, Suresh Jain, J.B. Gupta, Gaya K. Amarasinghe, Michael S. Diamond, James Rini, Sachdev S. Sidhu
bioRxiv 2020.10.31.362848; doi: https://doi.org/10.1101/2020.10.31.362848
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Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations
Shane Miersch, Zhijie Li, Reza Saberianfar, Mart Ustav, James Brett Case, Levi Blazer, Chao Chen, Wei Ye, Alevtina Pavlenco, Maryna Gorelik, Julia Garcia Perez, Suryasree Subramania, Serena Singh, Lynda Ploder, Safder Ganaie, Rita E. Chen, Daisy W. Leung, Pier Paolo Pandolfi, Giuseppe Novelli, Giulia Matusali, Francesca Colavita, Maria R. Capobianchi, Suresh Jain, J.B. Gupta, Gaya K. Amarasinghe, Michael S. Diamond, James Rini, Sachdev S. Sidhu
bioRxiv 2020.10.31.362848; doi: https://doi.org/10.1101/2020.10.31.362848

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