²¹³Bi Radioimmunotherapy with an Anti-mCD138 Monoclonal Antibody in a Murine Model of Multiple Myeloma

Abstract

New multiple myeloma (MM) treatments-such as high-dose melphalan therapy plus autologous stem cell transplantation or regimens incorporating bortezomide, thalidomide, and lenalidomidesubstantially increase the rate of complete response that is associated with longer patient survival. Thus, maintaining the complete response status by improving the minimal residual disease after induction therapy is a key goal for MM management. Here, we address the question of radioimmunotherapy efficacy in MM minimal residual disease treatment in mice with a low tumor burden. a-emitters are particularly well adapted to this approach because the short range of a-particles enables localized irradiation of tumor cells within the bone marrow and a cytotoxic effect on isolated cells due to the high LET (linear energy transfer) of a-particles. The CD138 antigen was used as a target because of its strong expression on myeloma cells in 100% of patients. Method: Intravenous injection of 10 6 5T33 mouse myeloma cells into the Syngeneic mouse strain C57BL/KaLwRij resulted in a rapid invasion of the marrow and limb paralysis, as illustrated by bioluminescence imaging with luciferase-transfected 5T33 cells. Radioimmunotherapy was performed 10 d after 5T33 cell engraftment with an intravenous injection of an antimouse CD138 antibody radiolabeled with 213 Bi at activities of 1.85, 3.7, 7.4, and 11.1 MBq. A blood cell count was performed weekly to monitor hematologic toxicity. The levels of blood Flt3 ligand were also measured to evaluate the radioimmunotherapy-related myelotoxicity. Disease progression was monitored by titrating the monoclonal IgG2b antibody produced by 5T33 cells. Results: The groups treated with 3.7 and 7.4 MBq exhibited a median survival greater than 300 and 227 d, respectively, compared with 45.5 d in the control untreated group. The highest activity (11.1 MBq) showed short-term toxicity whereas the lowest activity (1.85 MBq) gave results similar to those of the controls. With activities of 3.7 and 7.4 MBq, mice exhibited a transient hematologic toxicity whereas only temporary and moderate myelotoxicity was observed with 7.4 MBq. Conclusion: This study demonstrates promising therapeutic efficacy of 213 Bi-labeled antimCD138 for the treatment of residual disease in the case of MM, with only moderate and transient toxicity.

Radioimmunoconjugates for the Treatment of Cancer

“…30 Recently, RIT using an anti-mouse CD138 MAb labeled with escalated activities of 213 Bi was assessed in a syngeneic MM mouse model. 31 Alpha-RIT performed 10 days after engraftment increased survival, with only moderate and transient hematological toxicity. Alpha-RIT also has been tested in 18 patients with AML using a humanized antibody specific for a human myelogenous leukemia antigen (CD33) labeled with 213 Bi.…”

“…Preclinical and clinical pilot studies reported promising data in acute leukemia and multiple myeloma. [27][28][29][30][31][32][33][34][35] For example, acute lymphoblastic leukemia (ALL) expressing CD22 may be a good target for RIT using radiolabeled epratuzumab. Recently, a case of molecular remission was reported in a patient with Philadelphiapositive B-cell ALL in third relapse, treated by fractionated 90 Y-epratuzumab.…”

Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma

“…Radio-conjugated CD20 antibodies show additional toxicity in phase I when added to mel200 for conditioning ( 90 Y-ibritumomab) (Dispenzieri et al, 2011), and limited efficacy when used as a single agent ( 131 I-tositumomab), which may relate to low CD20 expression on myeloma cells, with higher response rates correlating with expression of CD20 (Lebovic et al, 2012). Radioconjugate antibodies against CD38 and CD138 have been studied in animal models, but clinical trials are awaited (Green et al, 2013;Chérel et al, 2013). Tomotherapy (radiotherapy delivered from many emitters arranged radially to focus treatment, analogous to computed tomography scans) has hitherto only been studied in leukaemias and lymphomas (Pica et al, 2011), but studies in myeloma are underway.…”

Nuclear medicine imaging of multiple myeloma, particularly in the relapsed setting

“…Alpha-radio-immunotherapy treatment using a [213Bi]-labelled anti-mouse CD138 antibody has been performed in mouse models, showing promising results. Mice treated with [213Bi]-CD138 had a longer median survival than the control group [40]. …”