Maximizing activity and selectivity of antibody-mediated effector functions using antibody mixtures
Fc-mediated effector functions are key for conferring potent antibody-mediated killing of cancer cells. However, it is difficult to achieve highly selective targeting of cancer cells while minimizing toxicity on healthy tissue because of the expression of most receptors, albeit at lower levels, on n...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2025-12-01
|
| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2025.2480666 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849769241844121600 |
|---|---|
| author | Tiexin Wang Alec A. Desai Greg M. Thurber Peter M. Tessier |
| author_facet | Tiexin Wang Alec A. Desai Greg M. Thurber Peter M. Tessier |
| author_sort | Tiexin Wang |
| collection | DOAJ |
| description | Fc-mediated effector functions are key for conferring potent antibody-mediated killing of cancer cells. However, it is difficult to achieve highly selective targeting of cancer cells while minimizing toxicity on healthy tissue because of the expression of most receptors, albeit at lower levels, on non-cancer cells. Previous attempts to increase the selectivity of antibody-mediated effector functions have sought to reduce binding affinity and/or increase avidity, which typically results in modest improvements in selectivity. To overcome this limitation, we report the use of mixtures of antibody variants that achieve high selectivity based on receptor level while maintaining high activity for cells with high receptor levels. We have studied mixtures of two variants of an anti-HER2 antibody (trastuzumab), one that is affinity-reduced and effector-competent and a second high-affinity variant that is effectorless. Notably, we observe that the high-affinity, effectorless antibody reduces effector function for cells with low receptor levels, including reduced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), while the high-avidity, effector-competent antibody mediates significant effector function for cells with high receptor levels. Moreover, replacing the effector-competent Fc region of the affinity-reduced antibody with high-affinity Fc domains that enhance effector function drives high activity while maintaining high selectivity for the antibody mixtures. These findings outline a general strategy for maximizing the therapeutic window by selectively targeting cancer cells based on receptor levels that could be applied to a wide range of applications involving antibody-mediated synapse formation, including antibody-drug conjugates and bispecific antibodies, such as T cell engagers. |
| format | Article |
| id | doaj-art-edf1bb3ebfc44ac4a189d9ffa8088022 |
| institution | DOAJ |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-edf1bb3ebfc44ac4a189d9ffa80880222025-08-20T03:03:29ZengTaylor & Francis GroupmAbs1942-08621942-08702025-12-0117110.1080/19420862.2025.2480666Maximizing activity and selectivity of antibody-mediated effector functions using antibody mixturesTiexin Wang0Alec A. Desai1Greg M. Thurber2Peter M. Tessier3Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USADepartment of Chemical Engineering, University of Michigan, Ann Arbor, MI, USADepartment of Chemical Engineering, University of Michigan, Ann Arbor, MI, USADepartment of Chemical Engineering, University of Michigan, Ann Arbor, MI, USAFc-mediated effector functions are key for conferring potent antibody-mediated killing of cancer cells. However, it is difficult to achieve highly selective targeting of cancer cells while minimizing toxicity on healthy tissue because of the expression of most receptors, albeit at lower levels, on non-cancer cells. Previous attempts to increase the selectivity of antibody-mediated effector functions have sought to reduce binding affinity and/or increase avidity, which typically results in modest improvements in selectivity. To overcome this limitation, we report the use of mixtures of antibody variants that achieve high selectivity based on receptor level while maintaining high activity for cells with high receptor levels. We have studied mixtures of two variants of an anti-HER2 antibody (trastuzumab), one that is affinity-reduced and effector-competent and a second high-affinity variant that is effectorless. Notably, we observe that the high-affinity, effectorless antibody reduces effector function for cells with low receptor levels, including reduced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), while the high-avidity, effector-competent antibody mediates significant effector function for cells with high receptor levels. Moreover, replacing the effector-competent Fc region of the affinity-reduced antibody with high-affinity Fc domains that enhance effector function drives high activity while maintaining high selectivity for the antibody mixtures. These findings outline a general strategy for maximizing the therapeutic window by selectively targeting cancer cells based on receptor levels that could be applied to a wide range of applications involving antibody-mediated synapse formation, including antibody-drug conjugates and bispecific antibodies, such as T cell engagers.https://www.tandfonline.com/doi/10.1080/19420862.2025.2480666AvidityADCCADCPcancerHER2mAb |
| spellingShingle | Tiexin Wang Alec A. Desai Greg M. Thurber Peter M. Tessier Maximizing activity and selectivity of antibody-mediated effector functions using antibody mixtures mAbs Avidity ADCC ADCP cancer HER2 mAb |
| title | Maximizing activity and selectivity of antibody-mediated effector functions using antibody mixtures |
| title_full | Maximizing activity and selectivity of antibody-mediated effector functions using antibody mixtures |
| title_fullStr | Maximizing activity and selectivity of antibody-mediated effector functions using antibody mixtures |
| title_full_unstemmed | Maximizing activity and selectivity of antibody-mediated effector functions using antibody mixtures |
| title_short | Maximizing activity and selectivity of antibody-mediated effector functions using antibody mixtures |
| title_sort | maximizing activity and selectivity of antibody mediated effector functions using antibody mixtures |
| topic | Avidity ADCC ADCP cancer HER2 mAb |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2025.2480666 |
| work_keys_str_mv | AT tiexinwang maximizingactivityandselectivityofantibodymediatedeffectorfunctionsusingantibodymixtures AT alecadesai maximizingactivityandselectivityofantibodymediatedeffectorfunctionsusingantibodymixtures AT gregmthurber maximizingactivityandselectivityofantibodymediatedeffectorfunctionsusingantibodymixtures AT petermtessier maximizingactivityandselectivityofantibodymediatedeffectorfunctionsusingantibodymixtures |