Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape

Fred D. Mast; Peter C. Fridy; Natalia E. Ketaren; Junjie Wang; Erica Y. Jacobs; Jean Paul Olivier; Tanmoy Sanyal; Kelly R. Molloy; Fabian Schmidt; Magdalena Rutkowska; Yiska Weisblum; Lucille M. Rich; Elizabeth R. Vanderwall; Nicholas Dambrauskas; Vladimir Vigdorovich; Sarah Keegan; Jacob B. Jiler; Milana E. Stein; Paul Dominic B. Olinares; Louis Herlands; Theodora Hatziioannou; D. Noah Sather; Jason S. Debley; David Fenyö; Andrej Sali; Paul D. Bieniasz; John D. Aitchison; Brian T. Chait; Michael P. Rout

doi:10.7554/eLife.73027

Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape

Fred D. Mast, Peter C. Fridy, Natalia E. Ketaren, Junjie Wang, Erica Y. Jacobs, Jean Paul Olivier, Tanmoy Sanyal, Kelly R. Molloy, Fabian Schmidt, Magdalena Rutkowska, Yiska Weisblum, Lucille M. Rich, Elizabeth R. Vanderwall, Nicholas Dambrauskas, Vladimir Vigdorovich, Sarah Keegan, Jacob B. Jiler, Milana E. Stein, Paul Dominic B. Olinares, Louis HerlandsTheodora Hatziioannou, D. Noah Sather, Jason S. Debley, David Fenyö, Andrej Sali, Paul D. Bieniasz, John D. Aitchison, Brian T. Chait, Michael P. Rout

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

The emergence of SARS-CoV-2 variants threatens current vaccines and therapeutic antibodies and urgently demands powerful new therapeutics that can resist viral escape. We therefore generated a large nanobody repertoire to saturate the distinct and highly conserved available epitope space of SARS-CoV-2 spike, including the S1 receptor binding domain, N-terminal domain, and the S2 subunit, to identify new nanobody binding sites that may reflect novel mechanisms of viral neutralization. Structural mapping and functional assays show that indeed these highly stable monovalent nanobodies potently inhibit SARS-CoV-2 infection, display numerous neutralization mechanisms, are effective against emerging variants of concern, and are resistant to mutational escape. Rational combinations of these nanobodies that bind to distinct sites within and between spike subunits exhibit extraordinary synergy and suggest multiple tailored therapeutic and prophy-lactic strategies.

Original language	English (US)
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.73027
State	Published - Dec 1 2021
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Medicine
General Immunology and Microbiology
General Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.73027

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Mast, F. D., Fridy, P. C., Ketaren, N. E., Wang, J., Jacobs, E. Y., Olivier, J. P., Sanyal, T., Molloy, K. R., Schmidt, F., Rutkowska, M., Weisblum, Y., Rich, L. M., Vanderwall, E. R., Dambrauskas, N., Vigdorovich, V., Keegan, S., Jiler, J. B., Stein, M. E., Olinares, P. D. B., ... Rout, M. P. (2021). Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape. eLife, 10. https://doi.org/10.7554/eLife.73027

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abstract = "The emergence of SARS-CoV-2 variants threatens current vaccines and therapeutic antibodies and urgently demands powerful new therapeutics that can resist viral escape. We therefore generated a large nanobody repertoire to saturate the distinct and highly conserved available epitope space of SARS-CoV-2 spike, including the S1 receptor binding domain, N-terminal domain, and the S2 subunit, to identify new nanobody binding sites that may reflect novel mechanisms of viral neutralization. Structural mapping and functional assays show that indeed these highly stable monovalent nanobodies potently inhibit SARS-CoV-2 infection, display numerous neutralization mechanisms, are effective against emerging variants of concern, and are resistant to mutational escape. Rational combinations of these nanobodies that bind to distinct sites within and between spike subunits exhibit extraordinary synergy and suggest multiple tailored therapeutic and prophy-lactic strategies.",

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Mast, FD, Fridy, PC, Ketaren, NE, Wang, J, Jacobs, EY, Olivier, JP, Sanyal, T, Molloy, KR, Schmidt, F, Rutkowska, M, Weisblum, Y, Rich, LM, Vanderwall, ER, Dambrauskas, N, Vigdorovich, V, Keegan, S, Jiler, JB, Stein, ME, Olinares, PDB, Herlands, L, Hatziioannou, T, Sather, DN, Debley, JS, Fenyö, D, Sali, A, Bieniasz, PD, Aitchison, JD, Chait, BT & Rout, MP 2021, 'Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape', eLife, vol. 10. https://doi.org/10.7554/eLife.73027

TY - JOUR

T1 - Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape

AU - Mast, Fred D.

AU - Fridy, Peter C.

AU - Ketaren, Natalia E.

AU - Wang, Junjie

AU - Jacobs, Erica Y.

AU - Olivier, Jean Paul

AU - Sanyal, Tanmoy

AU - Molloy, Kelly R.

AU - Schmidt, Fabian

AU - Rutkowska, Magdalena

AU - Weisblum, Yiska

AU - Rich, Lucille M.

AU - Vanderwall, Elizabeth R.

AU - Dambrauskas, Nicholas

AU - Vigdorovich, Vladimir

AU - Keegan, Sarah

AU - Jiler, Jacob B.

AU - Stein, Milana E.

AU - Olinares, Paul Dominic B.

AU - Herlands, Louis

AU - Hatziioannou, Theodora

AU - Sather, D. Noah

AU - Debley, Jason S.

AU - Fenyö, David

AU - Sali, Andrej

AU - Bieniasz, Paul D.

AU - Aitchison, John D.

AU - Chait, Brian T.

AU - Rout, Michael P.

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PY - 2021/12/1

Y1 - 2021/12/1

N2 - The emergence of SARS-CoV-2 variants threatens current vaccines and therapeutic antibodies and urgently demands powerful new therapeutics that can resist viral escape. We therefore generated a large nanobody repertoire to saturate the distinct and highly conserved available epitope space of SARS-CoV-2 spike, including the S1 receptor binding domain, N-terminal domain, and the S2 subunit, to identify new nanobody binding sites that may reflect novel mechanisms of viral neutralization. Structural mapping and functional assays show that indeed these highly stable monovalent nanobodies potently inhibit SARS-CoV-2 infection, display numerous neutralization mechanisms, are effective against emerging variants of concern, and are resistant to mutational escape. Rational combinations of these nanobodies that bind to distinct sites within and between spike subunits exhibit extraordinary synergy and suggest multiple tailored therapeutic and prophy-lactic strategies.

AB - The emergence of SARS-CoV-2 variants threatens current vaccines and therapeutic antibodies and urgently demands powerful new therapeutics that can resist viral escape. We therefore generated a large nanobody repertoire to saturate the distinct and highly conserved available epitope space of SARS-CoV-2 spike, including the S1 receptor binding domain, N-terminal domain, and the S2 subunit, to identify new nanobody binding sites that may reflect novel mechanisms of viral neutralization. Structural mapping and functional assays show that indeed these highly stable monovalent nanobodies potently inhibit SARS-CoV-2 infection, display numerous neutralization mechanisms, are effective against emerging variants of concern, and are resistant to mutational escape. Rational combinations of these nanobodies that bind to distinct sites within and between spike subunits exhibit extraordinary synergy and suggest multiple tailored therapeutic and prophy-lactic strategies.

UR - https://elifesciences.org/articles/73027

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U2 - 10.7554/eLife.73027

DO - 10.7554/eLife.73027

M3 - Article

SN - 2050-084X

VL - 10

JO - eLife

JF - eLife

ER -

Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape

Abstract

ASJC Scopus subject areas

UN SDGs

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