Work

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

Year: 2014

Type: article

Abstract: // Katharina Teiluf 1,* , Christof Seidl 1,2,* , Birgit Blechert 1 , Florian C. Gaertner 1,3 , Klaus-Peter Gilbertz 4 , Vanesa Fernandez 5 , Florian Bassermann 5 , Jan Endell 6 , Rainer Boxhammer 6 , Stephane Leclair 6 , Mario Vallon 1,7 , Michaela Aichler 8 , Annette Feuchtinger 8 , Frank Bruchertseifer 9 , Alfred Morgenstern 9 and Markus Essler 1,3 1 Department of Nuclear Medicine, Technische Universität München, Munich, Germany 2 Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany 3 Department of Nuclear Medicine, Universitätsklinikum Bonn, Bonn, Germany 4 Institute of Radiobiology, German Armed Forces, Munich, Germany 5 III. Medical Department, Technische Universität München, Munich, Germany 6 MorphoSys AG, Martinsried/Planegg, Germany 7 Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA 8 Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany 9 European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany * These authors contributed equally to this work Correspondence to: Christof Seidl, email: // Keywords : anti-CD38-MAb, α-emitter 213 Bi, OPM2 cells, radioimmunotherapy, cell death Received : October 20, 2014 Accepted : December 09, 2014 Published : December 10, 2014 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 213 Bi coupled to an anti-CD38 MAb in preclinical treatment of MM. Efficacy of 213 Bi-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 213 Bi-anti-CD38-MAb. Therapeutic efficacy was monitored by bioluminescence imaging, overall survival and histology. 213 Bi-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 213 Bi-anti-CD38-MAb correlated with the expression level of CD38 in each MM cell line. In myeloma xenografts, treatment with 213 Bi-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 213 Bi-induced toxicity. Preclinical treatment of MM with 213 Bi-anti-CD38-MAb turned out as an effective therapeutic option.

Source: Oncotarget

DOI: 10.18632/oncotarget.2986