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^*

^*Corresponding author for this work

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

45 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
Article number	e73027
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.73027
State	Published - Dec 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
‍© Mast et al.

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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, Article e73027. https://doi.org/10.7554/eLife.73027

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

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.",

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

note = "Publisher Copyright: ‍{\textcopyright} Mast et al.",

year = "2021",

month = dec,

doi = "10.7554/eLife.73027",

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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, e73027. https://doi.org/10.7554/eLife.73027

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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.

PY - 2021/12

Y1 - 2021/12

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.

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C2 - 34874007

AN - SCOPUS:85122147822

SN - 2050-084X

VL - 10

JO - eLife

JF - eLife

M1 - e73027

ER -

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

Abstract

Bibliographical note

UN SDGs

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