title: A bispecific EpCAM/CD133-targeted toxin is effective against carcinoma.
abstract: The discovery of chemoresistant cancer stem cells (CSCs) in carcinomas has created the need for therapies that specifically target these subpopulations of cells. Here, we characterized a bispecific targeted toxin that is composed of two antibody fragments and a catalytic protein toxin allowing it to bind two CSC markers on the same cell killing this resistant subpopulation. CD133 is a well-known CSC marker and has been successfully targeted and caused regression of head and neck squamous cell carcinoma (HNSCC) in vivo. To enable it to bind a broader range of CSCs, an anti-epithelial cell adhesion molecule (EpCAM) scFv was added to create dEpCAMCD133KDEL, a deimmunized bispecific targeted toxin on a single amino acid chain. This bispecific potently inhibited protein translation and proliferation in vitro in three different types of carcinoma. Furthermore, in a CSC spheroid model dEpCAMCD133KDEL eliminated Mary-X spheroids, an inflammatory breast carcinoma. Finally, this bispecific also caused tumor regression in an in vivo model of HNSCC. This represents the first bispecific CSC-targeted toxin and warrants further development as a possible therapy for carcinoma.
authors.affiliation: Department of Pharmacology, University of Minnesota, 210 Delaware Street Southeast, Minneapolis, MN, 55455, USA.
authors.forename: Nate N
authors.initials: NN
authors.lastname: Waldron
authors.forename: Sanford H
authors.initials: SH
authors.lastname: Barsky
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Dougherty
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Vallera
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D018938:Caco-2 Cells; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D049109:Cell Proliferation; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins / Q000276:immunology*; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000276:immunology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D014162:Transfection
chemical_list: D000071916:AC133 Antigen; D018033:Antibodies, Bispecific; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins; D000922:Immunotoxins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse
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