title: The novel immunotoxin HM1.24-ETA' induces apoptosis in multiple myeloma cells.
abstract: Despite new treatment modalities, the clinical outcome in a substantial number of patients with multiple myeloma (MM) has yet to be improved. Antibody-based targeted therapies for myeloma patients could make use of the HM1.24 antigen (CD317), a surface molecule overexpressed on malignant plasma cells and efficiently internalized. Here, a novel immunotoxin, HM1.24-ETA', is described. HM1.24-ETA' was generated by genetic fusion of a CD317-specific single-chain Fv (scFv) antibody and a truncated variant of Pseudomonas aeruginosa exotoxin A (ETA'). HM1.24-ETA' inhibited growth of interleukin 6 (IL-6)-dependent and -independent myeloma cell lines. Half-maximal growth inhibition was observed at concentrations as low as 0.3 nM. Target cell killing occurred via induction of apoptosis and was unaffected in co-culture experiments with bone marrow stromal cells. HM1.24-ETA' efficiently triggered apoptosis of freshly isolated/cryopreserved cells of patients with plasma cell leukemia and MM and was active in a preclinical severe combined immunodeficiency (SCID) mouse xenograft model. Importantly, HM1.24-ETA' was not cytotoxic against CD317-positive cells from healthy tissue (monocytes, human umbilical vein endothelial cells). These results indicate that CD317 may represent a promising target structure for specific and efficient immunotoxin therapy for patients with plasma cell tumors.
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Staudinger
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Glorius
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Burger
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kellner
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Klausz
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Günther
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Repp
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gramatzki
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Peipp
mesh_terms: D036002:ADP Ribose Transferases / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001427:Bacterial Toxins / Q000737:chemistry / Q000494:pharmacology*; D000939:Epitopes; D005098:Exotoxins / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D019169:Jurkat Cells; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D037521:Virulence Factors / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D036002:ADP Ribose Transferases; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D001427:Bacterial Toxins; D000939:Epitopes; D005098:Exotoxins; D058851:GPI-Linked Proteins; D000922:Immunotoxins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2