A novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy
ABSTRACTEpithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays several roles in cancer biology. EpCAM is an attractive therapeutic target because of its expression in most solid tumors. However, targeting EpCAM has been challenging because it is also highly expressed in...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2322562 |
| _version_ | 1797271886860648448 |
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| author | Gerhard Frey Ana Paula G. Cugnetti Haizhen Liu Charles Xing Christina Wheeler Hwai Wen Chang William J. Boyle Jay M. Short |
| author_facet | Gerhard Frey Ana Paula G. Cugnetti Haizhen Liu Charles Xing Christina Wheeler Hwai Wen Chang William J. Boyle Jay M. Short |
| author_sort | Gerhard Frey |
| collection | DOAJ |
| description | ABSTRACTEpithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays several roles in cancer biology. EpCAM is an attractive therapeutic target because of its expression in most solid tumors. However, targeting EpCAM has been challenging because it is also highly expressed in normal epithelial tissues. Initial attempts to develop EpCAM-specific T-cell engagers were unsuccessful due to severe cytokine release effects, as well as serious on-target, off-tumor drug-related toxicities. We developed novel, conditionally active biological (CAB) bispecific antibodies that bind to both EpCAM and CD3 in an acidic tumor microenvironment. In healthy tissues, binding to EpCAM and CD3 is greatly reduced by a novel, dual CAB selection, where each binding domain is independently blocked by the presence of physiological chemicals known as Protein-associated Chemical Switches (PaCS). The CAB anti-EpCAM T-cell engagers displayed the anticipated bispecific binding properties and mediated the potent lysis of EpCAM-positive cancer cell lines through the recruitment of T cells in the tumor microenvironment. Xenograft studies showed that the efficacy of CAB bispecific antibodies is similar to that of a non-CAB anti-EpCAM bispecific antibody, but they have markedly reduced toxicity in non-human primates, indicating an unprecedentedly widened therapeutic index of over 100-fold. These preclinical results indicate that the dual CAB bispecific antibody is potentially both a powerful and safe therapeutic platform and a promising T cell-engaging treatment for patients with EpCAM-expressing tumors. |
| first_indexed | 2024-03-07T14:15:41Z |
| format | Article |
| id | doaj.art-7fc31e7a3b674b338e4ac1b2672d0edf |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-03-07T14:15:41Z |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-7fc31e7a3b674b338e4ac1b2672d0edf2024-03-06T12:18:47ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2322562A novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapyGerhard Frey0Ana Paula G. Cugnetti1Haizhen Liu2Charles Xing3Christina Wheeler4Hwai Wen Chang5William J. Boyle6Jay M. Short7Research & Development, BioAtla Inc, San Diego, CA, USAResearch & Development, BioAtla Inc, San Diego, CA, USAResearch & Development, BioAtla Inc, San Diego, CA, USAResearch & Development, BioAtla Inc, San Diego, CA, USAResearch & Development, BioAtla Inc, San Diego, CA, USAResearch & Development, BioAtla Inc, San Diego, CA, USAResearch & Development, BioAtla Inc, San Diego, CA, USAResearch & Development, BioAtla Inc, San Diego, CA, USAABSTRACTEpithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays several roles in cancer biology. EpCAM is an attractive therapeutic target because of its expression in most solid tumors. However, targeting EpCAM has been challenging because it is also highly expressed in normal epithelial tissues. Initial attempts to develop EpCAM-specific T-cell engagers were unsuccessful due to severe cytokine release effects, as well as serious on-target, off-tumor drug-related toxicities. We developed novel, conditionally active biological (CAB) bispecific antibodies that bind to both EpCAM and CD3 in an acidic tumor microenvironment. In healthy tissues, binding to EpCAM and CD3 is greatly reduced by a novel, dual CAB selection, where each binding domain is independently blocked by the presence of physiological chemicals known as Protein-associated Chemical Switches (PaCS). The CAB anti-EpCAM T-cell engagers displayed the anticipated bispecific binding properties and mediated the potent lysis of EpCAM-positive cancer cell lines through the recruitment of T cells in the tumor microenvironment. Xenograft studies showed that the efficacy of CAB bispecific antibodies is similar to that of a non-CAB anti-EpCAM bispecific antibody, but they have markedly reduced toxicity in non-human primates, indicating an unprecedentedly widened therapeutic index of over 100-fold. These preclinical results indicate that the dual CAB bispecific antibody is potentially both a powerful and safe therapeutic platform and a promising T cell-engaging treatment for patients with EpCAM-expressing tumors.https://www.tandfonline.com/doi/10.1080/19420862.2024.2322562Antibody engineeringbispecific antibodyconditionally activeEpCAMprotein engineeringT-cell engager |
| spellingShingle | Gerhard Frey Ana Paula G. Cugnetti Haizhen Liu Charles Xing Christina Wheeler Hwai Wen Chang William J. Boyle Jay M. Short A novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy mAbs Antibody engineering bispecific antibody conditionally active EpCAM protein engineering T-cell engager |
| title | A novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy |
| title_full | A novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy |
| title_fullStr | A novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy |
| title_full_unstemmed | A novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy |
| title_short | A novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy |
| title_sort | novel conditional active biologic anti epcam x anti cd3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy |
| topic | Antibody engineering bispecific antibody conditionally active EpCAM protein engineering T-cell engager |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2322562 |
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