Abstract P4-07-26: Development of CDCP1-targeting antibody-drug conjugate for Triple negative and metastatic breast cancer

Abstract Introduction: CUB-domain containing- protein 1 (CDCP1) is a transmembrane receptor involved in the progression of several cancers. Recent studies demonstrate that CDCP1 is a rational target for the development of innovative targeted therapies for cancer including theranostics agents and antibody-drug conjugates. Objective/Methods: To determine the therapeutic potential of CDCP1 in breast cancer, we investigated its expression in multiple cohorts of breast cancer tissues by immunohistochemistry, as well as in various preclinical models including cell lines, primary cells and patient-derived xenografts using flow cytometry, western blot and immunofluorescence staining. Then, we evaluated the capacity of the CDCP1-targeting chimeric antibody ch10D7 to specifically accumulate in breast cancer lesions in in vivo preclinical models including patient-derived xenografts and breast cancer metastasis models. Finally, we determined the efficacy of the ch10D7-MMAE antibody-drug conjugate to kill breast cancer cells in vitro and breast tumours ex-vivo and in vivo. Results: The CDCP1 receptor is expressed at targetable level in a significant proportion of breast cancer cases with high/intermediate expression detected in ~30% of localized ER-positive cases, ~50% of metastatic ER-positive cases and >70% of Triple negative or HER2-positive cases. Similar proportion of expression was detected in cellular models. We demonstrated that ch10D7 antibody labelled with the radionucleotide Zircodium-89 specifically accumulates in breast cancer lesions in vivo allowing the detection of mammary-fat pad implanted patient-derived xenografts and of breast cancer metastasis by PET/CT imaging. Finally, we confirmed that the ch10D7-MMAE antibody-drug conjugate is very efficient at inducing cell death in vitro as well as controlling primary tumour and metastatic tumour burden in pre-clinical models, conferring a significant survival advantage compared to classical therapy. Conclusion: Our work demonstrates that CDCP1 is a potential target to detect and limit the progression of breast tumours and that biomolecules specifically recognising this receptor are promising agents which could improve survival of patients. Citation Format: Madeline Gough, Tashbib Khan, Kayden Kwah, Yaowu He, Gishan Ratnayake, Christopher Pyke, Cameron Snell, John Hooper, Thomas Kryza. Development of CDCP1-targeting antibody-drug conjugate for Triple negative and metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-26.