title: EpCAM-selective elimination of carcinoma cells by a novel MAP-based cytolytic fusion protein.
abstract: 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.
authors: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen, Germany.
authors: Dmitrij
authors: D
authors: Hristodorov
authors: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen, Germany.
authors: Manal
authors: M
authors: Amoury
authors: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen, Germany.
authors: Radoslav
authors: R
authors: Mladenov
authors: Pharmedartis GmbH, Aachen, Germany.
authors: Judith
authors: J
authors: Niesen
authors: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen, Germany.
authors: Katharina
authors: K
authors: Arens
authors: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen, Germany.
authors: Nina
authors: N
authors: Berges
authors: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen, Germany.
authors: Lea
authors: L
authors: Hein
authors: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany.
authors: Stefano
authors: S
authors: Di Fiore
authors: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen, Germany.
authors: Anh-Tuan
authors: AT
authors: Pham
authors: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen, Germany.
authors: Michael
authors: M
authors: Huhn
authors: Laboratory for Translational Surgical Oncology, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors: Wijnand
authors: W
authors: Helfrich
authors: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany. Institute of Molecular Biotechnology (Biology VII), RWTH Aachen University, Aachen, Germany.
authors: Rainer
authors: R
authors: Fischer
authors: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany.
authors: Theo
authors: T
authors: Thepen
authors: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen, Germany. Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany. stefan.barth@ime.fraunhofer.de.
authors: Stefan
authors: S
authors: Barth
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry*; D017209:Apoptosis; D002277:Carcinoma / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D016366:Open Reading Frames; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D014404:Tubulin / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C054369:MAPT protein, human; D011993:Recombinant Fusion Proteins; D014404:Tubulin; D016875:tau Proteins