title: 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 lenalidomide--substantially 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. α-emitters are particularly well adapted to this approach because the short range of α-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 α-particles. The CD138 antigen was used as a target because of its strong expression on myeloma cells in 100% of patients.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  This study demonstrates promising therapeutic efficacy of (213)Bi-labeled anti-mCD138 for the treatment of residual disease in the case of MM, with only moderate and transient toxicity.
authors.affiliation: Nantes-Angers Cancer Research Center CRCNA, University of Nantes, INSERM UMR892, CNRS UMR6299, Nantes, France. Michel.Cherel@univ-nantes.fr
authors.forename: Michel
authors.initials: M
authors.lastname: Chérel
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gouard
authors.forename: Joëlle
authors.initials: J
authors.lastname: Gaschet
authors.forename: Catherine
authors.initials: C
authors.lastname: Saï-Maurel
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: Mickael
authors.initials: M
authors.lastname: Bourgeois
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gestin
authors.forename: Françoise Kraeber
authors.initials: FK
authors.lastname: Bodéré
authors.forename: Jacques
authors.initials: J
authors.lastname: Barbet
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.forename: François
authors.initials: F
authors.lastname: Davodeau
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001729:Bismuth / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000175:diagnosis / Q000276:immunology* / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D015996:Survival Rate; D053668:Syndecan-1 / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D011868:Radioisotopes; D019275:Radiopharmaceuticals; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D001729:Bismuth
keywords: 213Bi; 5T33; CD138; multiple myeloma; oncology; radioimmunotherapy; α-particle