Α-RADIOIMMUNOTHERAPY WITH 213-BI-ANTI-CD38 IMMUNOCONJUGATES IS EFFECTIVE IN A MOUSE MODEL OF HUMAN MULTIPLE MYELOMA
Katharina Teiluf, Christof Seidl, Birgit Blechert, Florian C. Gaertner, Klaus-Peter Gilbertz, Vanesa Fernandez, Florian Bassermann, Jan Endell, Rainer Boxhammer, Stephane Leclair, Mario Vallon, Michaela Aichler, Annette Feuchtinger, Frank Bruchertseifer, Alfred Morgenstern and Markus Essler. (09-02-2015).Oncotarget, Advance Publications 2014, 2014
Research Area B
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.