EpCAM-selective elimination of carcinoma cells by a novel MAP-based cytolytic fusion protein
Autor: | Rainer Fischer, Manal Amoury, Wijnand Helfrich, Theo Thepen, Michael Huhn, Judith Niesen, Stefan Barth, Dmitrij Hristodorov, Anh-Tuan Pham, Nina Berges, Katharina Arens, Stefano Di Fiore, Radoslav Mladenov, Lea Hein |
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Přispěvatelé: | Targeted Gynaecologic Oncology (TARGON), Translational Immunology Groningen (TRIGR), Publica |
Jazyk: | angličtina |
Rok vydání: | 2014 |
Předmět: |
Cancer Research
EP-CAM medicine.medical_treatment Cell Apoptosis chemistry.chemical_compound Mice Cancer immunotherapy Tubulin Neoplasms PSEUDOMONAS EXOTOXIN ADHESION MOLECULE IN-VIVO Mice Inbred BALB C Cell adhesion molecule Epithelial cell adhesion molecule respiratory system Epithelial Cell Adhesion Molecule medicine.anatomical_structure Oncology Female Immunotherapy VASCULAR LEAK SYNDROME Protein Binding CANCER-THERAPY TUMOR-MODEL Recombinant Fusion Proteins Mice Nude tau Proteins chemical and pharmacologic phenomena Biology Inhibitory Concentration 50 Open Reading Frames Antigen In vivo Antigens Neoplasm Cell Line Tumor medicine Animals Humans BREAST-CANCER Cell Proliferation Cell growth Carcinoma Fusion protein Molecular biology HEK293 Cells IMMUNOTOXIN TREATMENT chemistry Cell Adhesion Molecules HUMAN MONOCLONAL-ANTIBODY Neoplasm Transplantation |
Zdroj: | Molecular cancer therapeutics, 13(9), 2194-2202. AMER ASSOC CANCER RESEARCH |
ISSN: | 1535-7163 |
Popis: | In normal epithelia, the epithelial cell adhesion molecule (EpCAM) expression is relatively low and only present at the basolateral cell surface. In contrast, EpCAM is aberrantly overexpressed in various human carcinomas. Therefore, EpCAM is considered to be a highly promising target for antibody-based cancer immunotherapy. Here, we present a new and fully human cytolytic fusion protein (CFP), designated “anti–EpCAM(scFv)-MAP,” that is comprised of an EpCAM-specific antibody fragment (scFv) genetically fused to the microtubule-associated protein tau (MAP). Anti–EpCAM(scFv)-MAP shows potent EpCAM-restricted proapoptotic activity toward rapidly proliferating carcinoma cells. In vitro assays confirmed that treatment with anti–EpCAM(scFv)-MAP resulted in the colocalization and stabilization of microtubules, suggesting that this could be the potential mode of action. Dose-finding experiments indicated that anti–EpCAM(scFv)-MAP is well tolerated in mice. Using noninvasive far-red in vivo imaging in a tumor xenograft mouse model, we further demonstrated that anti–EpCAM(scFv)-MAP inhibited tumor growth in vivo. In conclusion, our data suggest that anti–EpCAM(scFv)-MAP may be of therapeutic value for the targeted elimination of EpCAM+ carcinomas. Mol Cancer Ther; 13(9); 2194–202. ©2014 AACR. |
Databáze: | OpenAIRE |
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