title: Comparison of the biologic effects of MA5 and B-B4 monoclonal antibody labeled with iodine-131 and bismuth-213 on multiple myeloma.
abstract: BACKGROUND
  Using a specific monoclonal antibody (MAb), B-B4, coupled to bismuth-213 ((213)Bi) by a chelating agent (CITC-DTPA), the feasibility of alpha-radioimmunotherapy (RIT) for multiple myeloma (MM) has been demonstrated previously.
  
  
  METHODS
  In this study, the two MAbs tested, MA5 and B-B4, target the epithelial antigens Muc-1 and syndecan-1, respectively, which are both expressed by MM cell lines. Antibody characterization was evaluated by flow cytometric analysis of normal and tumoral hematopoeitic cells of MM patients as well as immunohistochemical tests of normal, nonhematopoetic tissues. Radiobiologic effects were evaluated for (213)Bi- and iodine-131 ((131)I)--labeled antibodies. We assessed in vitro mortality (thymidine incorporation, MTT, and clonogenic assays) and cell cycle modifications with propidium iodide staining. These tests were performed on MM cell lines until 120 hours postirradiation at several time points, using radiolabeled antibody concentrations ranging from 0.5 to 20 nM and specific activities ranging from 240 to 1200 MBq/mg of MAb.
  
  
  RESULTS
  MA5 stained all MM cells in only 50% of patients, whereas B-B4 recognized all MM cells in all patients. B-B4 principally showed hepatic, pulmonary, and duodenal staining, whereas MA5 marked renal and pulmonary tissues. RIT with (213)Bi-B-B4 induced specific mortality and G(2)/M phase cell cycle arrest, which depended on the concentrations and specific activity. For (213)Bi-MA5, this arrest appeared at concentrations above 10 nM, an amount fivefold higher than that required with B-B4. This difference was also found in thymidine incorporation assays. Furthermore, with (213)Bi-B-B4, the arrest at the G(2)/M phase appeared quickly, within 24 hours after irradiation, and affected up to 60% of the cells (for 20 nM of (213)Bi-B-B4 at 1,200 MBq/mg). Conversly, (131)I-B-B4 had a very limited effect on cell mortality and did not induce any cell cycle arrest.
  
  
  CONCLUSIONS
  The results of this study show that B-B4 might be the more effective therapeutic antibody and suggest that alpha-RIT might be more suitable than beta-RIT for treating single-cell tumor models. Thus, these findings set the stage for the beginning of clinical trials using alpha-emitter--radiolabeled B-B4, with special attention paid to hepatic, pulmonary, and intestinal side effects.
authors.affiliation: INSERM U463, Institut de Biologie, Nantes, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Supiot
authors.forename: Alain
authors.initials: A
authors.lastname: Faivre-Chauvet
authors.forename: Olivier
authors.initials: O
authors.lastname: Couturier
authors.forename: Marie Françoise
authors.initials: MF
authors.lastname: Heymann
authors.forename: Nelly
authors.initials: N
authors.lastname: Robillard
authors.forename: Françoise
authors.initials: F
authors.lastname: Kraeber-Bodéré
authors.forename: Laurence
authors.initials: L
authors.lastname: Morandeau
authors.forename: Marc Andrè
authors.initials: MA
authors.lastname: Mahé
authors.forename: Michel
authors.initials: M
authors.lastname: Chérel
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001729:Bismuth / Q000737:chemistry / Q000493:pharmacokinetics*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D008938:Mitosis / Q000187:drug effects; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D016499:Radioimmunotherapy / Q000379:methods; D011868:Radioisotopes; D011878:Radiotherapy; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D011868:Radioisotopes; D001729:Bismuth