Pegylation Reduces the Uptake of Certolizumab Pegol by Dendritic Cells and Epitope Presentation to T-Cells
Pegylation of biopharmaceuticals is the most common strategy to increase their half-life in the blood and is associated with a reduced immunogenicity. As antigen presentation is a primary event in the activation of CD4 T-cells and initiation of Anti-Drug Antibody (ADA) response, we investigated the...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.808606/full |
| _version_ | 1798031853479788544 |
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| author | Marie de Bourayne Sylvain Meunier Samuel Bitoun Evelyne Correia Xavier Mariette Hervé Nozach Bernard Maillère |
| author_facet | Marie de Bourayne Sylvain Meunier Samuel Bitoun Evelyne Correia Xavier Mariette Hervé Nozach Bernard Maillère |
| author_sort | Marie de Bourayne |
| collection | DOAJ |
| description | Pegylation of biopharmaceuticals is the most common strategy to increase their half-life in the blood and is associated with a reduced immunogenicity. As antigen presentation is a primary event in the activation of CD4 T-cells and initiation of Anti-Drug Antibody (ADA) response, we investigated the role of the PEG molecule on the T-cell reactivity of certolizumab pegol (CZP), a pegylated anti-TNFα Fab. We generated T-cell lines raised against CZP and its non-pegylated form (CZNP) and demonstrated CZP primed few T-cells in comparison to CZNP. CZP-primed lines from 3 donors responded to a total of 5 epitopes, while CZNP-primed lines from 3 donors responded to a total of 7 epitopes, 4 epitopes were recognized by both CZP- and CZNP-primed lines. In line with this difference of T-cell reactivity, CZP is less internalized by the dendritic cells than CZNP. In vitro digestion assay of CZP by Cathepsin B showed a rapid removal of the PEG moiety, suggesting a limited influence of PEG on CZP proteolysis. We therefore demonstrate that pegylation diminishes antigen capture by dendritic cells, peptide presentation to T-cells and T-cell priming. This mechanism might reduce immunogenicity and contribute to the long half-life of CZP and possibly of other pegylated molecules. |
| first_indexed | 2024-04-11T20:03:12Z |
| format | Article |
| id | doaj.art-1691747e1b1a4fa5b04d3fbcc5117f00 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T20:03:12Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1691747e1b1a4fa5b04d3fbcc5117f002022-12-22T04:05:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-02-011310.3389/fimmu.2022.808606808606Pegylation Reduces the Uptake of Certolizumab Pegol by Dendritic Cells and Epitope Presentation to T-CellsMarie de Bourayne0Sylvain Meunier1Samuel Bitoun2Evelyne Correia3Xavier Mariette4Hervé Nozach5Bernard Maillère6Université de Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, FranceUniversité de Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, FranceUniversité Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Department of Rheumatology, INSERM UMR1184, Le Kremlin Bicêtre, FranceUniversité de Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, FranceUniversité Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Department of Rheumatology, INSERM UMR1184, Le Kremlin Bicêtre, FranceUniversité de Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, FranceUniversité de Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, FrancePegylation of biopharmaceuticals is the most common strategy to increase their half-life in the blood and is associated with a reduced immunogenicity. As antigen presentation is a primary event in the activation of CD4 T-cells and initiation of Anti-Drug Antibody (ADA) response, we investigated the role of the PEG molecule on the T-cell reactivity of certolizumab pegol (CZP), a pegylated anti-TNFα Fab. We generated T-cell lines raised against CZP and its non-pegylated form (CZNP) and demonstrated CZP primed few T-cells in comparison to CZNP. CZP-primed lines from 3 donors responded to a total of 5 epitopes, while CZNP-primed lines from 3 donors responded to a total of 7 epitopes, 4 epitopes were recognized by both CZP- and CZNP-primed lines. In line with this difference of T-cell reactivity, CZP is less internalized by the dendritic cells than CZNP. In vitro digestion assay of CZP by Cathepsin B showed a rapid removal of the PEG moiety, suggesting a limited influence of PEG on CZP proteolysis. We therefore demonstrate that pegylation diminishes antigen capture by dendritic cells, peptide presentation to T-cells and T-cell priming. This mechanism might reduce immunogenicity and contribute to the long half-life of CZP and possibly of other pegylated molecules.https://www.frontiersin.org/articles/10.3389/fimmu.2022.808606/fullcertolizumab pegolimmunogenicityPEGylationCD4 T-cell responseT-cell epitope |
| spellingShingle | Marie de Bourayne Sylvain Meunier Samuel Bitoun Evelyne Correia Xavier Mariette Hervé Nozach Bernard Maillère Pegylation Reduces the Uptake of Certolizumab Pegol by Dendritic Cells and Epitope Presentation to T-Cells Frontiers in Immunology certolizumab pegol immunogenicity PEGylation CD4 T-cell response T-cell epitope |
| title | Pegylation Reduces the Uptake of Certolizumab Pegol by Dendritic Cells and Epitope Presentation to T-Cells |
| title_full | Pegylation Reduces the Uptake of Certolizumab Pegol by Dendritic Cells and Epitope Presentation to T-Cells |
| title_fullStr | Pegylation Reduces the Uptake of Certolizumab Pegol by Dendritic Cells and Epitope Presentation to T-Cells |
| title_full_unstemmed | Pegylation Reduces the Uptake of Certolizumab Pegol by Dendritic Cells and Epitope Presentation to T-Cells |
| title_short | Pegylation Reduces the Uptake of Certolizumab Pegol by Dendritic Cells and Epitope Presentation to T-Cells |
| title_sort | pegylation reduces the uptake of certolizumab pegol by dendritic cells and epitope presentation to t cells |
| topic | certolizumab pegol immunogenicity PEGylation CD4 T-cell response T-cell epitope |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.808606/full |
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