title: α-Radioimmunotherapy with ²¹³Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma.
abstract: In spite of development of molecular therapeutics, multiple myeloma (MM) is fatal in most cases. CD38 is a promising target for selective treatment of MM. We tested radioimmunoconjugates consisting of the α-emitter ²¹³Bi coupled to an anti-CD38 MAb in preclinical treatment of MM. Efficacy of ²¹³Bi-anti-CD38-MAb was assayed towards different MM cell lines with regard to induction of DNA double-strand breaks, induction of apoptosis and initiation of cell cycle arrest. Moreover, mice bearing luciferase-expressing MM xenografts were treated with ²¹³Bi-anti-CD38-MAb. Therapeutic efficacy was monitored by bioluminescence imaging, overall survival and histology. ²¹³Bi-anti-CD38-MAb treatment induced DNA damage which did not result in activation of the G2 DNA-damage-response checkpoint, but instead in mitotic arrest and subsequent mitotic catastrophe. The anti-tumor effect of ²¹³Bi-anti-CD38-MAb correlated with the expression level of CD38 in each MM cell line. In myeloma xenografts, treatment with ²¹³Bi-anti-CD38-MAb suppressed tumor growth via induction of apoptosis in tumor tissue and significantly prolonged survival compared to controls. The major organ systems did not show any signs of ²¹³Bi-induced toxicity. Preclinical treatment of MM with ²¹³Bi-anti-CD38-MAb turned out as an effective therapeutic option.
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Teiluf
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.|Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Seidl
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Blechert
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.|Department of Nuclear Medicine, Universitätsklinikum Bonn, Bonn, Germany.
authors.forename: Florian C
authors.initials: FC
authors.lastname: Gaertner
authors.affiliation: Institute of Radiobiology, German Armed Forces, Munich, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Gilbertz
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Fernandez
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Bassermann
authors.affiliation: MorphoSys AG, Martinsried/Planegg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Endell
authors.affiliation: MorphoSys AG, Martinsried/Planegg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Boxhammer
authors.affiliation: MorphoSys AG, Martinsried/Planegg, Germany.
authors.forename: Stephane
authors.initials: S
authors.lastname: Leclair
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.|Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Vallon
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.affiliation: European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.|Department of Nuclear Medicine, Universitätsklinikum Bonn, Bonn, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Essler
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D000512:Alpha Particles / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology / Q000528:radiation effects; D001729:Bismuth / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000276:immunology / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology* / Q000532:radiotherapy*; D016499:Radioimmunotherapy; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D001729:Bismuth
keywords: OPM2 cells; anti-CD38-MAb; multiple myeloma xenograft model; radioimmunotherapy; α-emitter 213Bi