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Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1

In this largest to-date genetic analysis of anti-drug antibody (ADA) response to a therapeutic monoclonal antibody (MAb), genome-wide association was performed for five measures of ADA status among 8844 individuals randomized to bococizumab, which targets PCSK9 for LDL-C lowering and cardiovascular...

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Autores principales: Chasman, Daniel I., Hyde, Craig L., Giulianini, Franco, Danning, Rebecca D., Wang, Ellen Q., Hickling, Timothy, Ridker, Paul M, Loomis, A. Katrina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917227/
https://www.ncbi.nlm.nih.gov/pubmed/35277540
http://dx.doi.org/10.1038/s41598-022-07997-5
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author Chasman, Daniel I.
Hyde, Craig L.
Giulianini, Franco
Danning, Rebecca D.
Wang, Ellen Q.
Hickling, Timothy
Ridker, Paul M
Loomis, A. Katrina
author_facet Chasman, Daniel I.
Hyde, Craig L.
Giulianini, Franco
Danning, Rebecca D.
Wang, Ellen Q.
Hickling, Timothy
Ridker, Paul M
Loomis, A. Katrina
author_sort Chasman, Daniel I.
collection PubMed
description In this largest to-date genetic analysis of anti-drug antibody (ADA) response to a therapeutic monoclonal antibody (MAb), genome-wide association was performed for five measures of ADA status among 8844 individuals randomized to bococizumab, which targets PCSK9 for LDL-C lowering and cardiovascular protection. Index associations prioritized specific amino acid substitutions at the DRB1 and DQB1 MHC class II genes rather than canonical haplotypes. Two clusters of missense variants at DRB1 were associated with general ADA measures (residues 9, 11, 13; and 96, 112, 120, 180) and a third cluster of missense variants in DQB1 was associated with ADA measures including neutralizing antibody (NAb) titers (residues 66, 67, 71, 74, 75). The structural disposition of the missense substitutions implicates peptide antigen binding and CD4 effector function, mechanisms that are potentially generalizable to other therapeutic mAbs. Clinicaltrials.gov: NCT01968954, NCT01968967, NCT01968980, NCT01975376, NCT01975389, NCT02100514.
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spelling pubmed-89172272022-03-16 Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1 Chasman, Daniel I. Hyde, Craig L. Giulianini, Franco Danning, Rebecca D. Wang, Ellen Q. Hickling, Timothy Ridker, Paul M Loomis, A. Katrina Sci Rep Article In this largest to-date genetic analysis of anti-drug antibody (ADA) response to a therapeutic monoclonal antibody (MAb), genome-wide association was performed for five measures of ADA status among 8844 individuals randomized to bococizumab, which targets PCSK9 for LDL-C lowering and cardiovascular protection. Index associations prioritized specific amino acid substitutions at the DRB1 and DQB1 MHC class II genes rather than canonical haplotypes. Two clusters of missense variants at DRB1 were associated with general ADA measures (residues 9, 11, 13; and 96, 112, 120, 180) and a third cluster of missense variants in DQB1 was associated with ADA measures including neutralizing antibody (NAb) titers (residues 66, 67, 71, 74, 75). The structural disposition of the missense substitutions implicates peptide antigen binding and CD4 effector function, mechanisms that are potentially generalizable to other therapeutic mAbs. Clinicaltrials.gov: NCT01968954, NCT01968967, NCT01968980, NCT01975376, NCT01975389, NCT02100514. Nature Publishing Group UK 2022-03-11 /pmc/articles/PMC8917227/ /pubmed/35277540 http://dx.doi.org/10.1038/s41598-022-07997-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Chasman, Daniel I.
Hyde, Craig L.
Giulianini, Franco
Danning, Rebecca D.
Wang, Ellen Q.
Hickling, Timothy
Ridker, Paul M
Loomis, A. Katrina
Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1
title Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1
title_full Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1
title_fullStr Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1
title_full_unstemmed Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1
title_short Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1
title_sort genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in hla drb1 and dqb1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917227/
https://www.ncbi.nlm.nih.gov/pubmed/35277540
http://dx.doi.org/10.1038/s41598-022-07997-5
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