Cargando…

Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD

Mutations in the spike protein of SARS-CoV-2 can lead to evasion from neutralizing antibodies and affect the efficacy of passive and active immunization strategies. Immunization of mice harboring an entire set of human immunoglobulin variable region gene segments allowed to identify nine neutralizin...

Descripción completa

Detalles Bibliográficos
Autores principales: Peter, Antonia Sophia, Grüner, Eva, Socher, Eileen, Fraedrich, Kirsten, Richel, Elie, Mueller-Schmucker, Sandra, Cordsmeier, Arne, Ensser, Armin, Sticht, Heinrich, Überla, Klaus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9332373/
https://www.ncbi.nlm.nih.gov/pubmed/35897753
http://dx.doi.org/10.3390/ijms23158177
_version_ 1784758630793347072
author Peter, Antonia Sophia
Grüner, Eva
Socher, Eileen
Fraedrich, Kirsten
Richel, Elie
Mueller-Schmucker, Sandra
Cordsmeier, Arne
Ensser, Armin
Sticht, Heinrich
Überla, Klaus
author_facet Peter, Antonia Sophia
Grüner, Eva
Socher, Eileen
Fraedrich, Kirsten
Richel, Elie
Mueller-Schmucker, Sandra
Cordsmeier, Arne
Ensser, Armin
Sticht, Heinrich
Überla, Klaus
author_sort Peter, Antonia Sophia
collection PubMed
description Mutations in the spike protein of SARS-CoV-2 can lead to evasion from neutralizing antibodies and affect the efficacy of passive and active immunization strategies. Immunization of mice harboring an entire set of human immunoglobulin variable region gene segments allowed to identify nine neutralizing monoclonal antibodies, which either belong to a cluster of clonally related RBD or NTD binding antibodies. To better understand the genetic barrier to emergence of SARS-CoV-2 variants resistant to these antibodies, escape mutants were selected in cell culture to one antibody from each cluster and a combination of the two antibodies. Three independently derived escape mutants to the RBD antibody harbored mutations in the RBD at the position T478 or S477. These mutations impaired the binding of the RBD antibodies to the spike protein and conferred resistance in a pseudotype neutralization assay. Although the binding of the NTD cluster antibodies were not affected by the RBD mutations, the RBD mutations also reduced the neutralization efficacy of the NTD cluster antibodies. The mutations found in the escape variants to the NTD antibody conferred resistance to the NTD, but not to the RBD cluster antibodies. A variant resistant to both antibodies was more difficult to select and only emerged after longer passages and higher inoculation volumes. VOC carrying the same mutations as the ones identified in the escape variants were also resistant to neutralization. This study further underlines the rapid emergence of escape mutants to neutralizing monoclonal antibodies in cell culture and indicates the need for thorough investigation of escape mutations to select the most potent combination of monoclonal antibodies for clinical use.
format Online
Article
Text
id pubmed-9332373
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-93323732022-07-29 Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD Peter, Antonia Sophia Grüner, Eva Socher, Eileen Fraedrich, Kirsten Richel, Elie Mueller-Schmucker, Sandra Cordsmeier, Arne Ensser, Armin Sticht, Heinrich Überla, Klaus Int J Mol Sci Article Mutations in the spike protein of SARS-CoV-2 can lead to evasion from neutralizing antibodies and affect the efficacy of passive and active immunization strategies. Immunization of mice harboring an entire set of human immunoglobulin variable region gene segments allowed to identify nine neutralizing monoclonal antibodies, which either belong to a cluster of clonally related RBD or NTD binding antibodies. To better understand the genetic barrier to emergence of SARS-CoV-2 variants resistant to these antibodies, escape mutants were selected in cell culture to one antibody from each cluster and a combination of the two antibodies. Three independently derived escape mutants to the RBD antibody harbored mutations in the RBD at the position T478 or S477. These mutations impaired the binding of the RBD antibodies to the spike protein and conferred resistance in a pseudotype neutralization assay. Although the binding of the NTD cluster antibodies were not affected by the RBD mutations, the RBD mutations also reduced the neutralization efficacy of the NTD cluster antibodies. The mutations found in the escape variants to the NTD antibody conferred resistance to the NTD, but not to the RBD cluster antibodies. A variant resistant to both antibodies was more difficult to select and only emerged after longer passages and higher inoculation volumes. VOC carrying the same mutations as the ones identified in the escape variants were also resistant to neutralization. This study further underlines the rapid emergence of escape mutants to neutralizing monoclonal antibodies in cell culture and indicates the need for thorough investigation of escape mutations to select the most potent combination of monoclonal antibodies for clinical use. MDPI 2022-07-25 /pmc/articles/PMC9332373/ /pubmed/35897753 http://dx.doi.org/10.3390/ijms23158177 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Peter, Antonia Sophia
Grüner, Eva
Socher, Eileen
Fraedrich, Kirsten
Richel, Elie
Mueller-Schmucker, Sandra
Cordsmeier, Arne
Ensser, Armin
Sticht, Heinrich
Überla, Klaus
Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD
title Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD
title_full Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD
title_fullStr Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD
title_full_unstemmed Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD
title_short Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD
title_sort characterization of sars-cov-2 escape mutants to a pair of neutralizing antibodies targeting the rbd and the ntd
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9332373/
https://www.ncbi.nlm.nih.gov/pubmed/35897753
http://dx.doi.org/10.3390/ijms23158177
work_keys_str_mv AT peterantoniasophia characterizationofsarscov2escapemutantstoapairofneutralizingantibodiestargetingtherbdandthentd
AT grunereva characterizationofsarscov2escapemutantstoapairofneutralizingantibodiestargetingtherbdandthentd
AT sochereileen characterizationofsarscov2escapemutantstoapairofneutralizingantibodiestargetingtherbdandthentd
AT fraedrichkirsten characterizationofsarscov2escapemutantstoapairofneutralizingantibodiestargetingtherbdandthentd
AT richelelie characterizationofsarscov2escapemutantstoapairofneutralizingantibodiestargetingtherbdandthentd
AT muellerschmuckersandra characterizationofsarscov2escapemutantstoapairofneutralizingantibodiestargetingtherbdandthentd
AT cordsmeierarne characterizationofsarscov2escapemutantstoapairofneutralizingantibodiestargetingtherbdandthentd
AT ensserarmin characterizationofsarscov2escapemutantstoapairofneutralizingantibodiestargetingtherbdandthentd
AT stichtheinrich characterizationofsarscov2escapemutantstoapairofneutralizingantibodiestargetingtherbdandthentd
AT uberlaklaus characterizationofsarscov2escapemutantstoapairofneutralizingantibodiestargetingtherbdandthentd