Die Alpha-Emitter Radioimmuntherapie des multiplen Myeloms mit 213Bi-CHX-A“-DTPA-anti-CD38 Immunkonjugaten zeigt eine hohe Effizienz im präklinischen Xenograft-Modell

Trotz jüngster Fortschritte in der Behandlung des multiplen Myeloms mit Bortezomib oder Lenalidomid ist diese Tumorerkrankung unheilbar. Ein Zielmolekül für einen neuen Therapieansatz ist das Glykoprotein CD38, das von Myelomzellen meist überexprimiert wird. Es wurden die therapeutische Effizienz von 213Bi-anti-CD38 Immunkonjugaten im Mausmodell und die zugrundeliegenden molekularen Mechanismen untersucht.JRC.E.5-Nuclear chemistr

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

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