The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics
Specificity profiling is a requirement for monoclonal antibodies (mAbs) and antibody-directed biotherapeutics such as CAR-T cells prior to initiating human trials. However, traditional approaches to assess the specificity of mAbs, primarily tissue cross-reactivity studies, have been unreliable, lead...
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| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2393785 |
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| author | Diana M. Norden Carmen T. Navia Jonathan T. Sullivan Benjamin J. Doranz |
| author_facet | Diana M. Norden Carmen T. Navia Jonathan T. Sullivan Benjamin J. Doranz |
| author_sort | Diana M. Norden |
| collection | DOAJ |
| description | Specificity profiling is a requirement for monoclonal antibodies (mAbs) and antibody-directed biotherapeutics such as CAR-T cells prior to initiating human trials. However, traditional approaches to assess the specificity of mAbs, primarily tissue cross-reactivity studies, have been unreliable, leading to off-target binding going undetected. Here, we review the emergence of cell-based protein arrays as an alternative and improved assessment of mAb specificity. Cell-based protein arrays assess binding across the full human membrane proteome, ~6,000 membrane proteins each individually expressed in their native structural configuration within live or unfixed cells. Our own profiling indicates a surprisingly high off-target rate across the industry, with 33% of lead candidates displaying off-target binding. Moreover, about 20% of therapeutic mAbs in clinical development and currently on the market display off-target binding. Case studies and off-target rates at different phases of biotherapeutic drug approval suggest that off-target binding is likely a major cause of adverse events and drug attrition. |
| format | Article |
| id | doaj-art-e71bd051d23e4748a5db97586af61d16 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-e71bd051d23e4748a5db97586af61d162025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2393785The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeuticsDiana M. Norden0Carmen T. Navia1Jonathan T. Sullivan2Benjamin J. Doranz3Integral Molecular, Philadelphia, PA, USAIntegral Molecular, Philadelphia, PA, USAIntegral Molecular, Philadelphia, PA, USAIntegral Molecular, Philadelphia, PA, USASpecificity profiling is a requirement for monoclonal antibodies (mAbs) and antibody-directed biotherapeutics such as CAR-T cells prior to initiating human trials. However, traditional approaches to assess the specificity of mAbs, primarily tissue cross-reactivity studies, have been unreliable, leading to off-target binding going undetected. Here, we review the emergence of cell-based protein arrays as an alternative and improved assessment of mAb specificity. Cell-based protein arrays assess binding across the full human membrane proteome, ~6,000 membrane proteins each individually expressed in their native structural configuration within live or unfixed cells. Our own profiling indicates a surprisingly high off-target rate across the industry, with 33% of lead candidates displaying off-target binding. Moreover, about 20% of therapeutic mAbs in clinical development and currently on the market display off-target binding. Case studies and off-target rates at different phases of biotherapeutic drug approval suggest that off-target binding is likely a major cause of adverse events and drug attrition.https://www.tandfonline.com/doi/10.1080/19420862.2024.2393785Antibodycell-based protein arraycross-reactivitymembrane proteome arrayoff-target bindingpolyspecificity |
| spellingShingle | Diana M. Norden Carmen T. Navia Jonathan T. Sullivan Benjamin J. Doranz The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics mAbs Antibody cell-based protein array cross-reactivity membrane proteome array off-target binding polyspecificity |
| title | The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics |
| title_full | The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics |
| title_fullStr | The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics |
| title_full_unstemmed | The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics |
| title_short | The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics |
| title_sort | emergence of cell based protein arrays to test for polyspecific off target binding of antibody therapeutics |
| topic | Antibody cell-based protein array cross-reactivity membrane proteome array off-target binding polyspecificity |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2393785 |
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