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Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance

The ongoing COVID‐19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS‐CoV‐2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering w...

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Autores principales: Walter, Justin D, Scherer, Melanie, Hutter, Cedric A J, Garaeva, Alisa A, Zimmermann, Iwan, Wyss, Marianne, Rheinberger, Jan, Ruedin, Yelena, Earp, Jennifer C, Egloff, Pascal, Sorgenfrei, Michèle, Hürlimann, Lea M, Gonda, Imre, Meier, Gianmarco, Remm, Sille, Thavarasah, Sujani, van Geest, Geert, Bruggmann, Rémy, Zimmer, Gert, Slotboom, Dirk J, Paulino, Cristina, Plattet, Philippe, Seeger, Markus A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982573/
https://www.ncbi.nlm.nih.gov/pubmed/35253970
http://dx.doi.org/10.15252/embr.202154199
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author Walter, Justin D
Scherer, Melanie
Hutter, Cedric A J
Garaeva, Alisa A
Zimmermann, Iwan
Wyss, Marianne
Rheinberger, Jan
Ruedin, Yelena
Earp, Jennifer C
Egloff, Pascal
Sorgenfrei, Michèle
Hürlimann, Lea M
Gonda, Imre
Meier, Gianmarco
Remm, Sille
Thavarasah, Sujani
van Geest, Geert
Bruggmann, Rémy
Zimmer, Gert
Slotboom, Dirk J
Paulino, Cristina
Plattet, Philippe
Seeger, Markus A
author_facet Walter, Justin D
Scherer, Melanie
Hutter, Cedric A J
Garaeva, Alisa A
Zimmermann, Iwan
Wyss, Marianne
Rheinberger, Jan
Ruedin, Yelena
Earp, Jennifer C
Egloff, Pascal
Sorgenfrei, Michèle
Hürlimann, Lea M
Gonda, Imre
Meier, Gianmarco
Remm, Sille
Thavarasah, Sujani
van Geest, Geert
Bruggmann, Rémy
Zimmer, Gert
Slotboom, Dirk J
Paulino, Cristina
Plattet, Philippe
Seeger, Markus A
author_sort Walter, Justin D
collection PubMed
description The ongoing COVID‐19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS‐CoV‐2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo‐EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri‐bispecific fusion constructs that exhibit up to 100‐ and 1,000‐fold increase in neutralization potency, respectively. Cryo‐EM of the sybody‐spike complex additionally reveals a novel up‐out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS‐CoV‐2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS‐CoV‐2 escape mutants.
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spelling pubmed-89825732022-04-15 Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance Walter, Justin D Scherer, Melanie Hutter, Cedric A J Garaeva, Alisa A Zimmermann, Iwan Wyss, Marianne Rheinberger, Jan Ruedin, Yelena Earp, Jennifer C Egloff, Pascal Sorgenfrei, Michèle Hürlimann, Lea M Gonda, Imre Meier, Gianmarco Remm, Sille Thavarasah, Sujani van Geest, Geert Bruggmann, Rémy Zimmer, Gert Slotboom, Dirk J Paulino, Cristina Plattet, Philippe Seeger, Markus A EMBO Rep Articles The ongoing COVID‐19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS‐CoV‐2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo‐EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri‐bispecific fusion constructs that exhibit up to 100‐ and 1,000‐fold increase in neutralization potency, respectively. Cryo‐EM of the sybody‐spike complex additionally reveals a novel up‐out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS‐CoV‐2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS‐CoV‐2 escape mutants. John Wiley and Sons Inc. 2022-03-07 /pmc/articles/PMC8982573/ /pubmed/35253970 http://dx.doi.org/10.15252/embr.202154199 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Walter, Justin D
Scherer, Melanie
Hutter, Cedric A J
Garaeva, Alisa A
Zimmermann, Iwan
Wyss, Marianne
Rheinberger, Jan
Ruedin, Yelena
Earp, Jennifer C
Egloff, Pascal
Sorgenfrei, Michèle
Hürlimann, Lea M
Gonda, Imre
Meier, Gianmarco
Remm, Sille
Thavarasah, Sujani
van Geest, Geert
Bruggmann, Rémy
Zimmer, Gert
Slotboom, Dirk J
Paulino, Cristina
Plattet, Philippe
Seeger, Markus A
Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance
title Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance
title_full Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance
title_fullStr Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance
title_full_unstemmed Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance
title_short Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance
title_sort biparatopic sybodies neutralize sars‐cov‐2 variants of concern and mitigate drug resistance
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982573/
https://www.ncbi.nlm.nih.gov/pubmed/35253970
http://dx.doi.org/10.15252/embr.202154199
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