title: Alpha-particle radioimmunotherapy of disseminated peritoneal disease using a (212)Pb-labeled radioimmunoconjugate targeting HER2.
abstract: These studies demonstrate the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using (212)Pb-labeled Herceptin as an in vivo generator of (212)Bi. In vitro studies compare the potential of the bismuth radioisotopes, (213)Bi and (212)Bi, to that of (212)Pb. Overall, (212)Pb results in a higher therapeutic index than either bismuth radioisotope, requiring lower radioactivity (microCi) for effective cytotoxic response. A pilot radioimmunotherapy (RIT) experiment treating mice bearing 5 d LS-174T intraperitoneally (i.p.) xenografts determined a maximum tolerated dose (MTD) of 20-40 microCi with i.p. administration. A specific dose response was observed and 10 microCi was selected as the effective operating dose for future experiments. Median survival of tumor-bearing mice receiving 10 microCi increased from 19 to 56 days (p = 0.008). The efficacy of (212)Pb-Herceptin was also assessed in a human pancreatic carcinoma xenograft (Shaw; i.p.) animal model previously reported as unresponsive to 213Bi-Herceptin (p = 0.002). Multiple dosing of (212)Pb-Herceptin was evaluated in both animal models. The median survival of mice bearing 3 d LS-174T i.p. xenografts increased to 110 days, with up to 3 doses of (212)Pb-Herceptin given at approximately monthly intervals; however, there was no evidence of a correlation with the second and third doses (p = 0.98). No improvement in median survival was noted with a similar regimen in the Shaw xenograft model.
authors.affiliation: Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC-1088, Building 10, Bethesda, MD 20892, USA. dm71q@nih.gov
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.forename: Kayhan
authors.initials: K
authors.lastname: Garmestani
authors.forename: Erik D
authors.initials: ED
authors.lastname: Brady
authors.forename: Paul S
authors.initials: PS
authors.lastname: Albert
authors.forename: Dangshe
authors.initials: D
authors.lastname: Ma
authors.forename: Alia
authors.initials: A
authors.lastname: Abdulla
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000512:Alpha Particles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D018734:Genes, erbB-2; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry; D007856:Lead Radioisotopes; D020714:Maximum Tolerated Dose; D051379:Mice; D009368:Neoplasm Transplantation; D010532:Peritoneal Diseases / Q000628:therapy*; D011863:Radioimmunoassay; D016499:Radioimmunotherapy / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D007856:Lead Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab