Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies.
The antiglobulin (anti-Ig) response to therapeutic monoclonal antibodies (mAbs) poses a significant obstacle to their routine application in man. Whilst humanization has lessened the problem, repeated courses of humanized mAbs still sensitise some patients. Previous work suggested that unresponsiven...
| Main Authors: | , |
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| Format: | Journal article |
| Language: | English |
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1994
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| _version_ | 1826258600636448768 |
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| author | Isaacs, J Waldmann, H |
| author_facet | Isaacs, J Waldmann, H |
| author_sort | Isaacs, J |
| collection | OXFORD |
| description | The antiglobulin (anti-Ig) response to therapeutic monoclonal antibodies (mAbs) poses a significant obstacle to their routine application in man. Whilst humanization has lessened the problem, repeated courses of humanized mAbs still sensitise some patients. Previous work suggested that unresponsiveness to cell-binding (therapeutic) mAbs could not be achieved due to an unexpected immunogenicity of their idiotypes (ids). The current work examines this phenomenon in more detail using CBA/Ca mice receiving rat antimouse CD8 mAbs as a model system. It is shown that the anti-Ig response is dependent on CD4+ T-cells. Furthermore, for at least some mAbs, most helper epitopes appear to reside within the mAb c-region. Consequently, when tolerance is induced to c-region (isotype), the anti-id response is extremely weak (induced helplessness). For one (weakly immunogenic) CD8 mAb concomitant administration of a CD4 mAb was sufficient to induce tolerance, whereas for another (more immunogenic) CD8 mAb, tolerance could only be achieved by prior concomitant exposure to both a CD4 mAb and an isotype-matched non-cell-binding mAb. The general applicability of these results is discussed and extrapolated to the clinical situation. Non-cell-binding variants of therapeutic mAbs could be usefully exploited to generate therapeutic unresponsiveness to any clinically useful mAb. |
| first_indexed | 2024-03-06T18:36:32Z |
| format | Journal article |
| id | oxford-uuid:0b715a62-dd7d-4905-9351-b4dbe7a22c19 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:36:32Z |
| publishDate | 1994 |
| record_format | dspace |
| spelling | oxford-uuid:0b715a62-dd7d-4905-9351-b4dbe7a22c192022-03-26T09:29:23ZHelplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0b715a62-dd7d-4905-9351-b4dbe7a22c19EnglishSymplectic Elements at Oxford1994Isaacs, JWaldmann, HThe antiglobulin (anti-Ig) response to therapeutic monoclonal antibodies (mAbs) poses a significant obstacle to their routine application in man. Whilst humanization has lessened the problem, repeated courses of humanized mAbs still sensitise some patients. Previous work suggested that unresponsiveness to cell-binding (therapeutic) mAbs could not be achieved due to an unexpected immunogenicity of their idiotypes (ids). The current work examines this phenomenon in more detail using CBA/Ca mice receiving rat antimouse CD8 mAbs as a model system. It is shown that the anti-Ig response is dependent on CD4+ T-cells. Furthermore, for at least some mAbs, most helper epitopes appear to reside within the mAb c-region. Consequently, when tolerance is induced to c-region (isotype), the anti-id response is extremely weak (induced helplessness). For one (weakly immunogenic) CD8 mAb concomitant administration of a CD4 mAb was sufficient to induce tolerance, whereas for another (more immunogenic) CD8 mAb, tolerance could only be achieved by prior concomitant exposure to both a CD4 mAb and an isotype-matched non-cell-binding mAb. The general applicability of these results is discussed and extrapolated to the clinical situation. Non-cell-binding variants of therapeutic mAbs could be usefully exploited to generate therapeutic unresponsiveness to any clinically useful mAb. |
| spellingShingle | Isaacs, J Waldmann, H Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies. |
| title | Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies. |
| title_full | Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies. |
| title_fullStr | Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies. |
| title_full_unstemmed | Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies. |
| title_short | Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies. |
| title_sort | helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies |
| work_keys_str_mv | AT isaacsj helplessnessasastrategyforavoidingantiglobulinresponsestotherapeuticmonoclonalantibodies AT waldmannh helplessnessasastrategyforavoidingantiglobulinresponsestotherapeuticmonoclonalantibodies |