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Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift

Here, we report the molecular engineering of nanobodies that bind with picomolar affinity to both SARS-CoV-1 and SARS-CoV-2 receptor-binding domains (RBD) and are highly neutralizing. We applied deep mutational engineering to VHH72, a nanobody initially specific for SARS-CoV-1 RBD with little cross-...

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Autores principales: Laroche, Adrien, Orsini Delgado, Maria Lucia, Chalopin, Benjamin, Cuniasse, Philippe, Dubois, Steven, Sierocki, Raphaël, Gallais, Fabrice, Debroas, Stéphanie, Bellanger, Laurent, Simon, Stéphanie, Maillère, Bernard, Nozach, Hervé
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9132424/
https://www.ncbi.nlm.nih.gov/pubmed/35593235
http://dx.doi.org/10.1080/19420862.2022.2076775
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author Laroche, Adrien
Orsini Delgado, Maria Lucia
Chalopin, Benjamin
Cuniasse, Philippe
Dubois, Steven
Sierocki, Raphaël
Gallais, Fabrice
Debroas, Stéphanie
Bellanger, Laurent
Simon, Stéphanie
Maillère, Bernard
Nozach, Hervé
author_facet Laroche, Adrien
Orsini Delgado, Maria Lucia
Chalopin, Benjamin
Cuniasse, Philippe
Dubois, Steven
Sierocki, Raphaël
Gallais, Fabrice
Debroas, Stéphanie
Bellanger, Laurent
Simon, Stéphanie
Maillère, Bernard
Nozach, Hervé
author_sort Laroche, Adrien
collection PubMed
description Here, we report the molecular engineering of nanobodies that bind with picomolar affinity to both SARS-CoV-1 and SARS-CoV-2 receptor-binding domains (RBD) and are highly neutralizing. We applied deep mutational engineering to VHH72, a nanobody initially specific for SARS-CoV-1 RBD with little cross-reactivity to SARS-CoV-2 antigen. We first identified all the individual VHH substitutions that increase binding to SARS-CoV-2 RBD and then screened highly focused combinatorial libraries to isolate engineered nanobodies with improved properties. The corresponding VHH-Fc molecules show high affinities for SARS-CoV-2 antigens from various emerging variants and SARS-CoV-1, block the interaction between ACE2 and RBD, and neutralize the virus with high efficiency. Its rare specificity across sarbecovirus relies on its peculiar epitope outside the immunodominant regions. The engineered nanobodies share a common motif of three amino acids, which contribute to the broad specificity of recognition. Our results show that deep mutational engineering is a very powerful method, especially to rapidly adapt existing antibodies to new variants of pathogens.
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spelling pubmed-91324242022-05-26 Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift Laroche, Adrien Orsini Delgado, Maria Lucia Chalopin, Benjamin Cuniasse, Philippe Dubois, Steven Sierocki, Raphaël Gallais, Fabrice Debroas, Stéphanie Bellanger, Laurent Simon, Stéphanie Maillère, Bernard Nozach, Hervé MAbs Reports Here, we report the molecular engineering of nanobodies that bind with picomolar affinity to both SARS-CoV-1 and SARS-CoV-2 receptor-binding domains (RBD) and are highly neutralizing. We applied deep mutational engineering to VHH72, a nanobody initially specific for SARS-CoV-1 RBD with little cross-reactivity to SARS-CoV-2 antigen. We first identified all the individual VHH substitutions that increase binding to SARS-CoV-2 RBD and then screened highly focused combinatorial libraries to isolate engineered nanobodies with improved properties. The corresponding VHH-Fc molecules show high affinities for SARS-CoV-2 antigens from various emerging variants and SARS-CoV-1, block the interaction between ACE2 and RBD, and neutralize the virus with high efficiency. Its rare specificity across sarbecovirus relies on its peculiar epitope outside the immunodominant regions. The engineered nanobodies share a common motif of three amino acids, which contribute to the broad specificity of recognition. Our results show that deep mutational engineering is a very powerful method, especially to rapidly adapt existing antibodies to new variants of pathogens. Taylor & Francis 2022-05-20 /pmc/articles/PMC9132424/ /pubmed/35593235 http://dx.doi.org/10.1080/19420862.2022.2076775 Text en © 2022 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Reports
Laroche, Adrien
Orsini Delgado, Maria Lucia
Chalopin, Benjamin
Cuniasse, Philippe
Dubois, Steven
Sierocki, Raphaël
Gallais, Fabrice
Debroas, Stéphanie
Bellanger, Laurent
Simon, Stéphanie
Maillère, Bernard
Nozach, Hervé
Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift
title Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift
title_full Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift
title_fullStr Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift
title_full_unstemmed Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift
title_short Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift
title_sort deep mutational engineering of broadly-neutralizing nanobodies accommodating sars-cov-1 and 2 antigenic drift
topic Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9132424/
https://www.ncbi.nlm.nih.gov/pubmed/35593235
http://dx.doi.org/10.1080/19420862.2022.2076775
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