title: 213Bi (alpha-emitter)-antibody targeting of breast cancer metastases in the neu-N transgenic mouse model.
abstract: Treatment failure in breast cancer is largely the failure to control metastatic dissemination. In this study, we investigated the efficacy of an antibody against the rat variant of HER-2/neu, labeled with the alpha-particle emitter (213)Bi to treat widespread metastases in a rat/neu transgenic mouse model of metastatic mammary carcinoma. The model manifests wide-spread dissemination of tumor cells leading to osteolytic bone lesions and liver metastases, common sites of clinical metastases. The maximum tolerated dose was 120 muCi of (213)Bi-7.16.4. The kinetics of marrow suppression and subsequent recovery were determined. Three days after left cardiac ventricular injection of 10(5) rat HER-2/neu--expressing syngeneic tumor cells, neu-N mice were treated with (a) 120 muCi (213)Bi-7.16.4, (b) 90 muCi (213)Bi-7.16.4, (c) 120 muCi (213)Bi-Rituximab (unreactive control), and (d) unlabeled 7.16.4. Treatment with 120 muCi (213)Bi-7.16.4 increased median survival time to 41 days compared with 28 days for the untreated controls (P < 0.0001); corresponding median survival times for groups b, c, and d were 36 (P < 0.001), 31 (P < 0.01), and 33 (P = 0.05) days, respectively. Median survival relative to controls was not significantly improved in mice injected with 10-fold less cells or with multiple courses of treatment. We concluded that alpha-emitter (213)Bi-labeled monoclonal antibody targeting the HER-2/neu antigen was effective in treating early-stage HER-2/neu--expressing micrometastases. Analysis of the results suggests that further gains in efficacy may require higher specific activity constructs or target antigens that are more highly expressed on tumor cells.
authors.affiliation: Divisions of Nuclear Medicine and Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Song
authors.forename: Karineh
authors.initials: K
authors.lastname: Shahverdi
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Caroline
authors.initials: C
authors.lastname: Esaias
authors.forename: James
authors.initials: J
authors.lastname: Fox
authors.forename: Alyson
authors.initials: A
authors.lastname: Liedy
authors.forename: Allison
authors.initials: A
authors.lastname: Liedy
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: R Todd
authors.initials: RT
authors.lastname: Reilly
authors.forename: Christos
authors.initials: C
authors.lastname: Apostolidis
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: George
authors.initials: G
authors.lastname: Sgouros
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D007700:Kinetics; D015674:Mammary Neoplasms, Animal / Q000473:pathology* / Q000532:radiotherapy*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy / Q000295:instrumentation / Q000379:methods*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000069283:Rituximab; D018874:Spheroids, Cellular / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018719:Erb-b2 Receptor Tyrosine Kinases; D000069283:Rituximab