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.
Highlights
Multiple myeloma (MM) is a hematological malignancy characterized by infiltration of the bone marrow by malignant plasma cells
C) Weights of tumor tissue two weeks after the final treatment cycle in mice treated with PBS and 213Bi-anti-CD38-MAb
Treatment of nude mice bearing human B-lymphoma xenografts with the α-emitter 227Th coupled to the anti-CD20 antibody rituximab was significantly more efficient than with the β-emitter 90Y (90Y-tiuxetan-ibritumomab) [29]. 213Bilintuzumab targeting CD33 has been successfully applied in clinical trials with patients suffering from acute myeloid leukemia [30, 31]
Summary
Multiple myeloma (MM) is a hematological malignancy characterized by infiltration of the bone marrow by malignant plasma cells. Additional application of new therapeutic agents such as the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has further increased progressionfree survival and contributed to improvement in overall www.impactjournals.com/oncotarget survival [4]. Despite these proceedings, MM remains an incurable disease as most patients relapse due to multidrug resistance. Compounds targeting cytokines or accessory cells in the bone-marrow microenvironment have shown promising results [8] Another successful approach is the application of therapeutic monoclonal antibodies targeting MM [9]. The anti-CS1 MAb elotuzumab triggered tumor regression in preclinical models of MM and showed promising response rates in patients with relapsed or refractory MM after combined administration of elotuzumab, lenalidomide and dexamethasone [10, 11]
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