α-Radioimmunotherapy with ²¹³Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma

• Published in: Oncotarget 2015-03, Vol.6 (7), p.4692-4703
• Main Authors: Teiluf, Katharina, Seidl, Christof, Blechert, Birgit, Gaertner, Florian C, Gilbertz, Klaus-Peter, Fernandez, Vanesa, Bassermann, Florian, Endell, Jan, Boxhammer, Rainer, Leclair, Stephane, Vallon, Mario, Aichler, Michaela, Feuchtinger, Annette, Bruchertseifer, Frank, Morgenstern, Alfred, Essler, Markus
• Format: Article
• Language: English
• Subjects: ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - immunology; Alpha Particles - therapeutic use; Animals; Antibodies, Monoclonal - pharmacology; Apoptosis - immunology; Apoptosis - radiation effects; Bismuth - pharmacology; Blotting, Western; Cell Cycle - immunology; Cell Cycle - radiation effects; Cell Proliferation - radiation effects; DNA Breaks, Double-Stranded; Flow Cytometry; Humans; Immunoconjugates - pharmacology; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - immunology; Mice; Mice, SCID; Multiple Myeloma - immunology; Multiple Myeloma - radiotherapy; Radioimmunotherapy; Research Paper; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.2986

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.