A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificity
P-cadherin (pCAD) and LI-cadherin (CDH17) are cell-surface proteins belonging to the cadherin superfamily that are both highly expressed in colorectal cancer. This co-expression profile presents a novel and attractive opportunity for a dual targeting approach using an antibody–drug conjugate (ADC)....
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| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2441411 |
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| author | Alyssa Synan Nila C. Wu Roberto Velazquez Thomas Gesner Claude Logel Kathrin Mueller Andrew Green Patrizia Barzaghi-Rinaudo Quincey Simmons Samuele Mercan Xingyi Shi Xun Li Vivek Sagar Joshua Korn Margaret McLaughlin William R. Tschantz Dominik Hainzl Anthony Malamas Thomas Huber Regis Cebe Kathleen T. Xie Joseph A. D’Alessio |
| author_facet | Alyssa Synan Nila C. Wu Roberto Velazquez Thomas Gesner Claude Logel Kathrin Mueller Andrew Green Patrizia Barzaghi-Rinaudo Quincey Simmons Samuele Mercan Xingyi Shi Xun Li Vivek Sagar Joshua Korn Margaret McLaughlin William R. Tschantz Dominik Hainzl Anthony Malamas Thomas Huber Regis Cebe Kathleen T. Xie Joseph A. D’Alessio |
| author_sort | Alyssa Synan |
| collection | DOAJ |
| description | P-cadherin (pCAD) and LI-cadherin (CDH17) are cell-surface proteins belonging to the cadherin superfamily that are both highly expressed in colorectal cancer. This co-expression profile presents a novel and attractive opportunity for a dual targeting approach using an antibody–drug conjugate (ADC). In this study, we used a unique avidity-driven in vitro screening approach to generate pCAD x CDH17 bispecific antibodies that selectively target cells expressing both antigens over cells expressing only pCAD or only CDH17. Based on in vitro binding and inhibition of cell proliferation results, we selected a lead bispecific antibody to link to the cytotoxic payload monomethyl auristatin E (MMAE) to generate a pCAD x CDH17 bispecific MMAE ADC. In in vivo dual flank mouse models, we demonstrated antitumor activity of the bispecific ADC in tumors expressing both antigens but not in tumors expressing only pCAD or only CDH17. Overall, the preclinical data presented here support the proof-of-concept bispecific antibody discovery approach, demonstrating a rational design for screening antibodies by prioritizing cross-arm avid IgGs to target dual-positive cells. |
| format | Article |
| id | doaj-art-3186d56ae3cc475d857627344d571aa3 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-3186d56ae3cc475d857627344d571aa32025-01-07T04:23:57ZengTaylor & Francis GroupmAbs1942-08621942-08702025-12-0117110.1080/19420862.2024.2441411A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificityAlyssa Synan0Nila C. Wu1Roberto Velazquez2Thomas Gesner3Claude Logel4Kathrin Mueller5Andrew Green6Patrizia Barzaghi-Rinaudo7Quincey Simmons8Samuele Mercan9Xingyi Shi10Xun Li11Vivek Sagar12Joshua Korn13Margaret McLaughlin14William R. Tschantz15Dominik Hainzl16Anthony Malamas17Thomas Huber18Regis Cebe19Kathleen T. Xie20Joseph A. D’Alessio21Department of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Basel, SwitzerlandDepartment of Oncology, Novartis Biomedical Research, Basel, SwitzerlandDepartment of Oncology, Novartis Biomedical Research, Basel, SwitzerlandDepartment of Oncology, Novartis Biomedical Research, Basel, SwitzerlandDepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Basel, SwitzerlandDepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USANavigate BioPharma Services Inc., A Novartis Subsidiary, Carlsbad, CA, USADepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Basel, SwitzerlandDepartment of Oncology, Novartis Biomedical Research, Basel, SwitzerlandDepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USADepartment of Oncology, Novartis Biomedical Research, Cambridge, MA, USAP-cadherin (pCAD) and LI-cadherin (CDH17) are cell-surface proteins belonging to the cadherin superfamily that are both highly expressed in colorectal cancer. This co-expression profile presents a novel and attractive opportunity for a dual targeting approach using an antibody–drug conjugate (ADC). In this study, we used a unique avidity-driven in vitro screening approach to generate pCAD x CDH17 bispecific antibodies that selectively target cells expressing both antigens over cells expressing only pCAD or only CDH17. Based on in vitro binding and inhibition of cell proliferation results, we selected a lead bispecific antibody to link to the cytotoxic payload monomethyl auristatin E (MMAE) to generate a pCAD x CDH17 bispecific MMAE ADC. In in vivo dual flank mouse models, we demonstrated antitumor activity of the bispecific ADC in tumors expressing both antigens but not in tumors expressing only pCAD or only CDH17. Overall, the preclinical data presented here support the proof-of-concept bispecific antibody discovery approach, demonstrating a rational design for screening antibodies by prioritizing cross-arm avid IgGs to target dual-positive cells.https://www.tandfonline.com/doi/10.1080/19420862.2024.2441411Antibody–drug conjugateaviditybispecific antibodyCDH17colorectal cancerdual targeting |
| spellingShingle | Alyssa Synan Nila C. Wu Roberto Velazquez Thomas Gesner Claude Logel Kathrin Mueller Andrew Green Patrizia Barzaghi-Rinaudo Quincey Simmons Samuele Mercan Xingyi Shi Xun Li Vivek Sagar Joshua Korn Margaret McLaughlin William R. Tschantz Dominik Hainzl Anthony Malamas Thomas Huber Regis Cebe Kathleen T. Xie Joseph A. D’Alessio A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificity mAbs Antibody–drug conjugate avidity bispecific antibody CDH17 colorectal cancer dual targeting |
| title | A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificity |
| title_full | A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificity |
| title_fullStr | A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificity |
| title_full_unstemmed | A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificity |
| title_short | A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificity |
| title_sort | bispecific antibody drug conjugate targeting pcad and cdh17 has antitumor activity and improved tumor specificity |
| topic | Antibody–drug conjugate avidity bispecific antibody CDH17 colorectal cancer dual targeting |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2441411 |
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