Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics
Immunogenicity, defined as the ability to provoke an immune response, can be either wanted (i.e., vaccines) or unwanted. The latter refers to an immune response to protein or peptide therapeutics, characterized by the production of anti-drug antibodies, which may affect the efficacy and/or the safet...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/12/2672 |
| _version_ | 1797455730376179712 |
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| author | Michel Siegel Guido Steiner Linnea C. Franssen Francesca Carratu James Herron Katharina Hartman Cary M. Looney Axel Ducret Katharine Bray-French Olivier Rohr Timothy P. Hickling Noel Smith Céline Marban-Doran |
| author_facet | Michel Siegel Guido Steiner Linnea C. Franssen Francesca Carratu James Herron Katharina Hartman Cary M. Looney Axel Ducret Katharine Bray-French Olivier Rohr Timothy P. Hickling Noel Smith Céline Marban-Doran |
| author_sort | Michel Siegel |
| collection | DOAJ |
| description | Immunogenicity, defined as the ability to provoke an immune response, can be either wanted (i.e., vaccines) or unwanted. The latter refers to an immune response to protein or peptide therapeutics, characterized by the production of anti-drug antibodies, which may affect the efficacy and/or the safety profiles of these drugs. Consequently, evaluation of the risk of immunogenicity early in the development of biotherapeutics is of critical importance for defining their efficacy and safety profiles. Here, we describe and validate a fit-for-purpose FluoroSpot-based in vitro assay for the evaluation of drug-specific T cell responses. A panel of 24 biotherapeutics with a wide range of clinical anti-drug antibody response rates were tested in this assay. We demonstrated that using suitable cutoffs and donor cohort sizes, this assay could identify most of the compounds with high clinical immunogenicity rates (71% and 78% for sensitivity and specificity, respectively) while we characterized the main sources of assay variability. Overall, these data indicate that the dendritic cell and CD4+ T cell restimulation assay published herein could be a valuable tool to assess the risk of drug-specific T cell responses and contribute to the selection of clinical candidates in early development. |
| first_indexed | 2024-03-09T15:58:32Z |
| format | Article |
| id | doaj.art-9163ac23f8bd4fae95f0bd210a951c5c |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T15:58:32Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-9163ac23f8bd4fae95f0bd210a951c5c2023-11-24T17:20:01ZengMDPI AGPharmaceutics1999-49232022-12-011412267210.3390/pharmaceutics14122672Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of BiotherapeuticsMichel Siegel0Guido Steiner1Linnea C. Franssen2Francesca Carratu3James Herron4Katharina Hartman5Cary M. Looney6Axel Ducret7Katharine Bray-French8Olivier Rohr9Timothy P. Hickling10Noel Smith11Céline Marban-Doran12Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4070 Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4070 Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4070 Basel, SwitzerlandLonza Biologics, Chesterford Research Park, Saffron Walden CB10 1XL, UKLonza Biologics, Chesterford Research Park, Saffron Walden CB10 1XL, UKRoche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4070 Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4070 Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4070 Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4070 Basel, SwitzerlandUR 7292, IUT Louis Pasteur, Université de Strasbourg, 67300 Schiltigheim, FranceRoche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4070 Basel, SwitzerlandLonza Biologics, Chesterford Research Park, Saffron Walden CB10 1XL, UKRoche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4070 Basel, SwitzerlandImmunogenicity, defined as the ability to provoke an immune response, can be either wanted (i.e., vaccines) or unwanted. The latter refers to an immune response to protein or peptide therapeutics, characterized by the production of anti-drug antibodies, which may affect the efficacy and/or the safety profiles of these drugs. Consequently, evaluation of the risk of immunogenicity early in the development of biotherapeutics is of critical importance for defining their efficacy and safety profiles. Here, we describe and validate a fit-for-purpose FluoroSpot-based in vitro assay for the evaluation of drug-specific T cell responses. A panel of 24 biotherapeutics with a wide range of clinical anti-drug antibody response rates were tested in this assay. We demonstrated that using suitable cutoffs and donor cohort sizes, this assay could identify most of the compounds with high clinical immunogenicity rates (71% and 78% for sensitivity and specificity, respectively) while we characterized the main sources of assay variability. Overall, these data indicate that the dendritic cell and CD4+ T cell restimulation assay published herein could be a valuable tool to assess the risk of drug-specific T cell responses and contribute to the selection of clinical candidates in early development.https://www.mdpi.com/1999-4923/14/12/2672immunogenicityimmunomodulationbiotherapeuticsin vitro T cell assayassay validation |
| spellingShingle | Michel Siegel Guido Steiner Linnea C. Franssen Francesca Carratu James Herron Katharina Hartman Cary M. Looney Axel Ducret Katharine Bray-French Olivier Rohr Timothy P. Hickling Noel Smith Céline Marban-Doran Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics Pharmaceutics immunogenicity immunomodulation biotherapeutics in vitro T cell assay assay validation |
| title | Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics |
| title_full | Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics |
| title_fullStr | Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics |
| title_full_unstemmed | Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics |
| title_short | Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics |
| title_sort | validation of a dendritic cell and cd4 t cell restimulation assay contributing to the immunogenicity risk evaluation of biotherapeutics |
| topic | immunogenicity immunomodulation biotherapeutics in vitro T cell assay assay validation |
| url | https://www.mdpi.com/1999-4923/14/12/2672 |
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