Anti-CDCP1 immuno-conjugates for detection and inhibition of ovarian cancer
| Autor: | Paul J. Conroy, Kamil A. Sokolowski, Simon Puttick, S. John Weroha, Thomas Kryza, James C. Whisstock, Brittney S. Harrington, Samantha J. Stehbens, Paul Haluska, T. Cuda, Rohan Lourie, Sarah Reed, Brian W.C. Tse, Buddhika J. Arachchige, Lewis Perrin, Yaowu He, Tashbib Khan, Katherine K. Robbins, Ruby H. P. Law, Carlos Salomon, Pamela M. Pollock, John D. Hooper |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Immunoconjugates CDCP1 Transplantation Heterologous Medicine (miscellaneous) Flow cytometry Metastasis Mice 03 medical and health sciences 0302 clinical medicine Western blot Antigens Neoplasm Cell Movement In vivo antibody Cell Line Tumor medicine Animals Pharmacology Toxicology and Pharmaceutics (miscellaneous) Ovarian Neoplasms Radioisotopes biology medicine.diagnostic_test Chemistry Cell Membrane Membrane Proteins Cancer Cell migration Surface Plasmon Resonance medicine.disease 3. Good health ovarian cancer src-Family Kinases 030104 developmental biology Positron-Emission Tomography 030220 oncology & carcinogenesis Models Animal biology.protein Cancer research immuno-conjugate Female Zirconium Antibody Ovarian cancer Cell Adhesion Molecules Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | CUB-domain containing protein 1 (CDCP1) is a cancer associated cell surface protein that amplifies pro-tumorigenic signalling by other receptors including EGFR and HER2. Its potential as a cancer target is supported by studies showing that anti-CDCP1 antibodies inhibit cell migration and survival in vitro, and tumor growth and metastasis in vivo. Here we characterize two anti-CDCP1 antibodies, focusing on immuno-conjugates of one of these as a tool to detect and inhibit ovarian cancer. Methods: A panel of ovarian cancer cell lines was examined for cell surface expression of CDCP1 and loss of expression induced by anti-CDCP1 antibodies 10D7 and 41-2 using flow cytometry and Western blot analysis. Surface plasmon resonance analysis and examination of truncation mutants was used to analyse the binding properties of the antibodies for CDCP1. Live-cell spinning-disk confocal microscopy of GFP-tagged CDCP1 was used to track internalization and intracellular trafficking of CDCP1/antibody complexes. In vivo, zirconium 89-labelled 10D7 was detected by positron-emission tomography imaging, of an ovarian cancer patient-derived xenograft grown intraperitoneally in mice. The efficacy of cytotoxin-conjugated 10D7 was examined against ovarian cancer cells in vitro and in vivo. Results: Our data indicate that each antibody binds with high affinity to the extracellular domain of CDCP1 causing rapid internalization of the receptor/antibody complex and degradation of CDCP1 via processes mediated by the kinase Src. Highlighting the potential clinical utility of CDCP1, positron-emission tomography imaging, using zirconium 89-labelled 10D7, was able to detect subcutaneous and intraperitoneal xenograft ovarian cancers in mice, including small (diameter |
| Databáze: | OpenAIRE |
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