Abstract
Multiple myeloma (MM) is a plasma cell cancer and represents the second most frequent hematologic malignancy. Despite new treatments and protocols, including high-dose chemotherapy associated with autologous stem cell transplantation, the prognosis of MM patients is still poor. α-radioimmunotherapy (α-RIT) represents an attractive treatment strategy because of the high-linear-energy transfer and short pathlength of α-radiation in tissues, resulting in high tumor cell killing and low toxicity to surrounding tissues. In this study, we investigated the potential of α-RIT with 212Pb-daratumumab (anti-hCD38), in both in vitro and in vivo models, as well as an antimouse CD38 antibody using in vivo models. Methods: Inhibition of cell proliferation after incubation of the RPMI8226 cell line with an increasing activity (0.185–3.7 kBq/mL) of 212Pb-isotypic control or 212Pb-daratumumab was evaluated. Biodistribution was performed in vivo by SPECT/CT imaging and after death. Dose-range–finding and acute toxicity studies were conducted. Because daratumumab does not bind the murine CD38, biodistribution and dose-range finding were also determined using an antimurine CD38 antibody. To evaluate the in vivo efficacy of 212Pb-daratumumab, mice were engrafted subcutaneously with 5 × 106 RPMI8226 cells. Mice were treated 13 d after engraftment with an intravenous injection of 212Pb-daratumumab or control solution. Therapeutic efficacy was monitored by tumor volume measurements and overall survival. Results: Significant inhibition of proliferation of the human myeloma RPMI8226 cell line was observed after 3 d of incubation with 212Pb-daratumumab, compared with 212Pb-isotypic control or cold antibodies. Biodistribution studies showed a specific tumoral accumulation of daratumumab. No toxicity was observed with 212Pb-daratumumab up to 370 kBq because of lack of cross-reactivity. Nevertheless, acute toxicity experiments with 212Pb-anti-mCD38 established a toxic activity of 277.5 kBq. To remain within realistically safe treatment activities for efficacy studies, mice were treated with 185 kBq or 277.5 kBq of 212Pb-daratumumab. Marked tumor growth inhibition compared with controls was observed, with a median survival of 55 d for 277.5 kBq of 212Pb-daratumumab instead of 11 d for phosphate-buffered saline. Conclusion: These results showed 212Pb-daratumumab to have efficacy in xenografted mice, with significant tumor regression and increased survival. This study highlights the potency of α-RIT in MM treatment.
Highlights
Multiple myeloma (MM) features monoclonal proliferation of plasma cells in bone marrow
The efficacy of radioimmunotherapy (RIT) in the treatment of non-Hodgkin lymphoma is well established, with there being 2 marketed anti-CD20 monoclonal antibodies (mAbs) coupled with b-emitters: 90Y-ibritumomab tiuxetan (Zevalin; Acrotech Biopharma, LLC) and 131I-tositumomab (Bexxar; GlaxoSmithKline) [2]
Considering that 212Pb-daratumumab does not cross-react with the murine CD38, biodistribution and toxicity studies were performed with an antimurine CD38 mAb
Summary
Multiple myeloma (MM) features monoclonal proliferation of plasma cells in bone marrow. Many advances have been made in MM therapy, and the median life expectancy of patients has almost doubled This improvement was mostly due to the development of proteasome inhibitors, immunomodulatory drugs, histone deacetylase blockers, and, more recently, monoclonal antibodies (mAbs) (daratumumab and elotuzumab) [1]. A-particles produce clustered DNA doublestrand breaks and highly reactive hydroxyl radicals when hitting biologic tissues Their short path range leads to a high-linearenergy transfer of approximately 50–230 keV/mm, compared with 0.1–1.0 keV/mm for b-emitters, making a-emitters 100-fold more cytotoxic. We have developed a targeted a-therapy in which the daratumumab antibody is coupled to the a-particle–emitting radioisotope 212Pb. The goal of this study was to investigate the potential of 212Pbdaratumumab in the treatment of plasma cell malignancies. The therapeutic efficacy of this treatment was assessed in vitro and in vivo on a subcutaneous xenograft model
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