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Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2

Neutralization assays are experimental surrogates for the effectiveness of infection- or vaccine-elicited polyclonal antibodies and therapeutic monoclonal antibodies targeting SARS-CoV-2. However, the measured neutralization can depend on details of the experimental assay. Here we systematically ass...

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Autores principales: Farrell, Ariana Ghez, Dadonaite, Bernadeta, Greaney, Allison J., Eguia, Rachel, Loes, Andrea N., Franko, Nicholas M., Logue, Jennifer, Carreño, Juan Manuel, Abbad, Anass, Chu, Helen Y., Matreyek, Kenneth A., Bloom, Jesse D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9460967/
https://www.ncbi.nlm.nih.gov/pubmed/36093349
http://dx.doi.org/10.1101/2022.08.29.505713
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author Farrell, Ariana Ghez
Dadonaite, Bernadeta
Greaney, Allison J.
Eguia, Rachel
Loes, Andrea N.
Franko, Nicholas M.
Logue, Jennifer
Carreño, Juan Manuel
Abbad, Anass
Chu, Helen Y.
Matreyek, Kenneth A.
Bloom, Jesse D.
author_facet Farrell, Ariana Ghez
Dadonaite, Bernadeta
Greaney, Allison J.
Eguia, Rachel
Loes, Andrea N.
Franko, Nicholas M.
Logue, Jennifer
Carreño, Juan Manuel
Abbad, Anass
Chu, Helen Y.
Matreyek, Kenneth A.
Bloom, Jesse D.
author_sort Farrell, Ariana Ghez
collection PubMed
description Neutralization assays are experimental surrogates for the effectiveness of infection- or vaccine-elicited polyclonal antibodies and therapeutic monoclonal antibodies targeting SARS-CoV-2. However, the measured neutralization can depend on details of the experimental assay. Here we systematically assess how ACE2 expression in target cells affects neutralization by antibodies to different spike epitopes in lentivirus pseudovirus neutralization assays. For high ACE2-expressing target cells, receptor binding domain (RBD) antibodies account for nearly all neutralizing activity in polyclonal human sera. But for lower ACE2-expressing target cells, antibodies targeting regions outside the RBD make a larger (although still modest) contribution to serum neutralization. These serum-level results are mirrored for monoclonal antibodies: N-terminal domain (NTD) antibodies and RBD antibodies that do not compete for ACE2 binding incompletely neutralize on high ACE2-expressing target cells, but completely neutralize on cells with lower ACE2 expression. Our results show that ACE2 expression level in the target cells is an important experimental variable, and that high ACE2 expression emphasizes the role of a subset of RBD-directed antibodies.
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spelling pubmed-94609672022-09-10 Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2 Farrell, Ariana Ghez Dadonaite, Bernadeta Greaney, Allison J. Eguia, Rachel Loes, Andrea N. Franko, Nicholas M. Logue, Jennifer Carreño, Juan Manuel Abbad, Anass Chu, Helen Y. Matreyek, Kenneth A. Bloom, Jesse D. bioRxiv Article Neutralization assays are experimental surrogates for the effectiveness of infection- or vaccine-elicited polyclonal antibodies and therapeutic monoclonal antibodies targeting SARS-CoV-2. However, the measured neutralization can depend on details of the experimental assay. Here we systematically assess how ACE2 expression in target cells affects neutralization by antibodies to different spike epitopes in lentivirus pseudovirus neutralization assays. For high ACE2-expressing target cells, receptor binding domain (RBD) antibodies account for nearly all neutralizing activity in polyclonal human sera. But for lower ACE2-expressing target cells, antibodies targeting regions outside the RBD make a larger (although still modest) contribution to serum neutralization. These serum-level results are mirrored for monoclonal antibodies: N-terminal domain (NTD) antibodies and RBD antibodies that do not compete for ACE2 binding incompletely neutralize on high ACE2-expressing target cells, but completely neutralize on cells with lower ACE2 expression. Our results show that ACE2 expression level in the target cells is an important experimental variable, and that high ACE2 expression emphasizes the role of a subset of RBD-directed antibodies. Cold Spring Harbor Laboratory 2022-08-30 /pmc/articles/PMC9460967/ /pubmed/36093349 http://dx.doi.org/10.1101/2022.08.29.505713 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Farrell, Ariana Ghez
Dadonaite, Bernadeta
Greaney, Allison J.
Eguia, Rachel
Loes, Andrea N.
Franko, Nicholas M.
Logue, Jennifer
Carreño, Juan Manuel
Abbad, Anass
Chu, Helen Y.
Matreyek, Kenneth A.
Bloom, Jesse D.
Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2
title Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2
title_full Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2
title_fullStr Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2
title_full_unstemmed Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2
title_short Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2
title_sort receptor binding domain (rbd) antibodies contribute more to sars-cov-2 neutralization when target cells express high levels of ace2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9460967/
https://www.ncbi.nlm.nih.gov/pubmed/36093349
http://dx.doi.org/10.1101/2022.08.29.505713
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