The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling
Therapeutic protein products (TPP) have been widely used to treat a variety of human diseases, including cancer, hemophilia, and autoimmune diseases. However, TPP can induce unwanted immune responses that can impact both drug efficacy and patient safety. The presence of aggregates is of particular c...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2015/401956 |
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| author | Liusong Yin Xiaoying Chen Abhinav Tiwari Paolo Vicini Timothy P. Hickling |
| author_facet | Liusong Yin Xiaoying Chen Abhinav Tiwari Paolo Vicini Timothy P. Hickling |
| author_sort | Liusong Yin |
| collection | DOAJ |
| description | Therapeutic protein products (TPP) have been widely used to treat a variety of human diseases, including cancer, hemophilia, and autoimmune diseases. However, TPP can induce unwanted immune responses that can impact both drug efficacy and patient safety. The presence of aggregates is of particular concern as they have been implicated in inducing both T cell-independent and T cell-dependent immune responses. We used mathematical modeling to evaluate several mechanisms through which aggregates of TPP could contribute to the development of immunogenicity. Modeling interactions between aggregates and B cell receptors demonstrated that aggregates are unlikely to induce T cell-independent immune responses by cross-linking B cell receptors because the amount of signal transducing complex that can form under physiologically relevant conditions is limited. We systematically evaluate the role of aggregates in inducing T cell-dependent immune responses using a recently developed multiscale mechanistic mathematical model. Our analysis indicates that aggregates could contribute to T cell-dependent immune response by inducing high affinity epitopes which may not be present in the nonaggregated TPP and/or by enhancing danger signals to break tolerance. In summary, our computational analysis is suggestive of novel insights into the mechanisms underlying aggregate-induced immunogenicity, which could be used to develop mitigation strategies. |
| format | Article |
| id | doaj-art-712edb5d7fca413e97691682b1cbf003 |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-712edb5d7fca413e97691682b1cbf0032025-02-03T01:04:51ZengWileyJournal of Immunology Research2314-88612314-71562015-01-01201510.1155/2015/401956401956The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical ModelingLiusong Yin0Xiaoying Chen1Abhinav Tiwari2Paolo Vicini3Timothy P. Hickling4Pharmacokinetics, Dynamics and Metabolism-New Biological Entities, Pfizer, Andover, MA 01810, USAPharmacokinetics, Dynamics and Metabolism-New Biological Entities, Pfizer, Cambridge, MA 02138, USAPharmacokinetics, Dynamics and Metabolism-New Biological Entities, Pfizer, Cambridge, MA 02138, USAPharmacokinetics, Dynamics and Metabolism-New Biological Entities, Pfizer, San Diego, CA 92121, USAPharmacokinetics, Dynamics and Metabolism-New Biological Entities, Pfizer, Andover, MA 01810, USATherapeutic protein products (TPP) have been widely used to treat a variety of human diseases, including cancer, hemophilia, and autoimmune diseases. However, TPP can induce unwanted immune responses that can impact both drug efficacy and patient safety. The presence of aggregates is of particular concern as they have been implicated in inducing both T cell-independent and T cell-dependent immune responses. We used mathematical modeling to evaluate several mechanisms through which aggregates of TPP could contribute to the development of immunogenicity. Modeling interactions between aggregates and B cell receptors demonstrated that aggregates are unlikely to induce T cell-independent immune responses by cross-linking B cell receptors because the amount of signal transducing complex that can form under physiologically relevant conditions is limited. We systematically evaluate the role of aggregates in inducing T cell-dependent immune responses using a recently developed multiscale mechanistic mathematical model. Our analysis indicates that aggregates could contribute to T cell-dependent immune response by inducing high affinity epitopes which may not be present in the nonaggregated TPP and/or by enhancing danger signals to break tolerance. In summary, our computational analysis is suggestive of novel insights into the mechanisms underlying aggregate-induced immunogenicity, which could be used to develop mitigation strategies.http://dx.doi.org/10.1155/2015/401956 |
| spellingShingle | Liusong Yin Xiaoying Chen Abhinav Tiwari Paolo Vicini Timothy P. Hickling The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling Journal of Immunology Research |
| title | The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling |
| title_full | The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling |
| title_fullStr | The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling |
| title_full_unstemmed | The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling |
| title_short | The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling |
| title_sort | role of aggregates of therapeutic protein products in immunogenicity an evaluation by mathematical modeling |
| url | http://dx.doi.org/10.1155/2015/401956 |
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