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HLAII peptide presentation of infliximab increases when complexed with TNF

CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides de...

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Autores principales: Casasola-LaMacchia, Andrea, Seward, Robert Joseph, Tourdot, Sophie, Willetts, Matthew, Kruppa, Gary, Agostino, Michael J., Bergeron, Gabrielle, Ahyi-Amendah, Nathalie, Ciarla, Andrew, Lu, Zhaojiang, Kim, Hai-Young, Hickling, Timothy P., Neubert, Hendrik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513746/
https://www.ncbi.nlm.nih.gov/pubmed/36177046
http://dx.doi.org/10.3389/fimmu.2022.932252
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author Casasola-LaMacchia, Andrea
Seward, Robert Joseph
Tourdot, Sophie
Willetts, Matthew
Kruppa, Gary
Agostino, Michael J.
Bergeron, Gabrielle
Ahyi-Amendah, Nathalie
Ciarla, Andrew
Lu, Zhaojiang
Kim, Hai-Young
Hickling, Timothy P.
Neubert, Hendrik
author_facet Casasola-LaMacchia, Andrea
Seward, Robert Joseph
Tourdot, Sophie
Willetts, Matthew
Kruppa, Gary
Agostino, Michael J.
Bergeron, Gabrielle
Ahyi-Amendah, Nathalie
Ciarla, Andrew
Lu, Zhaojiang
Kim, Hai-Young
Hickling, Timothy P.
Neubert, Hendrik
author_sort Casasola-LaMacchia, Andrea
collection PubMed
description CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides derived from biotherapeutics is a crucial part of immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous CD4+ T-cell epitopes have been identified by HLAII immunopeptidomics in antibody-based biotherapeutics using either their native or aggregated form. Antibody-target immune complexes have been detected in patients with ADA and are thought to play a role in ADA development by enhancing the presentation of CD4+ T-cell epitopes at the surface of antigen presenting cells (APCs). The aim of this study was to investigate the effect of biotherapeutic antibody-target immune complexes on the HLAII peptide presentation of biotherapeutics in human primary monocyte-derived dendritic cells (DCs). The trimeric tumor necrosis factor (TNF) and its biotherapeutic antagonists infliximab (INFL), adalimumab (ADAL), and a single armed Fab’ were used as a model system. The HLAII immunopeptidome of DCs loaded with antagonists or their immune complexes with TNF was analyzed by trapped ion mobility time-of-flight mass spectrometry (timsTOF MS) leading to the identification of ~ 12,000 unique HLAII-associated peptides per preparation. Anti-TNF sequences were detected at a median of 0.3% of the total immunopeptidome, against a majority background of peptides from endogenous and media-derived proteins. TNF antagonist presentation spanned the variable and constant regions in a widespread manner in both light and heavy chains, consistent with previously discovered HLAII peptides. This investigation extends the collection of observed HLAII peptides from anti-TNF biotherapeutics to include sequences that at least partially span the complementary determining regions (CDRs), such as the LCDR1 for both INFL and ADAL. Although antagonist presentation varied significantly across donors, peptides from both bivalent antagonists INFL and ADAL were more highly presented relative to the Fab’. While TNF immune complexes did not alter overall HLAII presentation, a moderate increase in presentation of a subset of peptide clusters was observed in the case of INFL-TNF, which included HCDR2, HCDR3 and LCDR2 sequences.
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spelling pubmed-95137462022-09-28 HLAII peptide presentation of infliximab increases when complexed with TNF Casasola-LaMacchia, Andrea Seward, Robert Joseph Tourdot, Sophie Willetts, Matthew Kruppa, Gary Agostino, Michael J. Bergeron, Gabrielle Ahyi-Amendah, Nathalie Ciarla, Andrew Lu, Zhaojiang Kim, Hai-Young Hickling, Timothy P. Neubert, Hendrik Front Immunol Immunology CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides derived from biotherapeutics is a crucial part of immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous CD4+ T-cell epitopes have been identified by HLAII immunopeptidomics in antibody-based biotherapeutics using either their native or aggregated form. Antibody-target immune complexes have been detected in patients with ADA and are thought to play a role in ADA development by enhancing the presentation of CD4+ T-cell epitopes at the surface of antigen presenting cells (APCs). The aim of this study was to investigate the effect of biotherapeutic antibody-target immune complexes on the HLAII peptide presentation of biotherapeutics in human primary monocyte-derived dendritic cells (DCs). The trimeric tumor necrosis factor (TNF) and its biotherapeutic antagonists infliximab (INFL), adalimumab (ADAL), and a single armed Fab’ were used as a model system. The HLAII immunopeptidome of DCs loaded with antagonists or their immune complexes with TNF was analyzed by trapped ion mobility time-of-flight mass spectrometry (timsTOF MS) leading to the identification of ~ 12,000 unique HLAII-associated peptides per preparation. Anti-TNF sequences were detected at a median of 0.3% of the total immunopeptidome, against a majority background of peptides from endogenous and media-derived proteins. TNF antagonist presentation spanned the variable and constant regions in a widespread manner in both light and heavy chains, consistent with previously discovered HLAII peptides. This investigation extends the collection of observed HLAII peptides from anti-TNF biotherapeutics to include sequences that at least partially span the complementary determining regions (CDRs), such as the LCDR1 for both INFL and ADAL. Although antagonist presentation varied significantly across donors, peptides from both bivalent antagonists INFL and ADAL were more highly presented relative to the Fab’. While TNF immune complexes did not alter overall HLAII presentation, a moderate increase in presentation of a subset of peptide clusters was observed in the case of INFL-TNF, which included HCDR2, HCDR3 and LCDR2 sequences. Frontiers Media S.A. 2022-09-13 /pmc/articles/PMC9513746/ /pubmed/36177046 http://dx.doi.org/10.3389/fimmu.2022.932252 Text en Copyright © 2022 Casasola-LaMacchia, Seward, Tourdot, Willetts, Kruppa, Agostino, Bergeron, Ahyi-Amendah, Ciarla, Lu, Kim, Hickling and Neubert https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Casasola-LaMacchia, Andrea
Seward, Robert Joseph
Tourdot, Sophie
Willetts, Matthew
Kruppa, Gary
Agostino, Michael J.
Bergeron, Gabrielle
Ahyi-Amendah, Nathalie
Ciarla, Andrew
Lu, Zhaojiang
Kim, Hai-Young
Hickling, Timothy P.
Neubert, Hendrik
HLAII peptide presentation of infliximab increases when complexed with TNF
title HLAII peptide presentation of infliximab increases when complexed with TNF
title_full HLAII peptide presentation of infliximab increases when complexed with TNF
title_fullStr HLAII peptide presentation of infliximab increases when complexed with TNF
title_full_unstemmed HLAII peptide presentation of infliximab increases when complexed with TNF
title_short HLAII peptide presentation of infliximab increases when complexed with TNF
title_sort hlaii peptide presentation of infliximab increases when complexed with tnf
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513746/
https://www.ncbi.nlm.nih.gov/pubmed/36177046
http://dx.doi.org/10.3389/fimmu.2022.932252
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