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²¹³Bi (-Emitter)–Antibody Targeting of Breast Cancer Metastases in the neu-N Transgenic Mouse Model

Divisions of ¹ Nuclear Medicine and ² Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, ³ Department of Molecular and Comparative Pathobiology, and ⁴ Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland and ⁵ Institute for Transuranium Elements, Karlsruhe, Germany

Requests for reprints: George Sgouros, Cancer Research Building II, Room 4M.61, 1550 Orleans Street, Johns Hopkins University School of Medicine, Baltimore, MD 21231. Phone: 410-614-0116; Fax: 413-487-3753; E-mail: gsgouros{at}jhmi.edu.

Key Words: -particle • ²¹³Bi • radioimmunotherapy • metastasis • rat HER-2/neu

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 -particle emitter ²¹³Bi 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 µCi of ²¹³Bi-7.16.4. The kinetics of marrow suppression and subsequent recovery were determined. Three days after left cardiac ventricular injection of 10⁵ rat HER-2/neu--expressing syngeneic tumor cells, neu-N mice were treated with (a) 120 µCi ²¹³Bi-7.16.4, (b) 90 µCi ²¹³Bi-7.16.4, (c) 120 µCi ²¹³Bi-Rituximab (unreactive control), and (d) unlabeled 7.16.4. Treatment with 120 µCi ²¹³Bi-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 -emitter ²¹³Bi-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. [Cancer Res 2008;68(10):3873–80]

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				H. Song, K. Shahverdi, D. L. Huso, Y. Wang, J. J. Fox, R. F. Hobbs, B. Gimi, K. L. Gabrielson, M. G. Pomper, B. M. Tsui, et al. An Immunotolerant HER-2/neu Transgenic Mouse Model of Metastatic Breast Cancer Clin. Cancer Res., October 1, 2008; 14(19): 6116 - 6124. [Abstract] [Full Text] [PDF]

				Correction: {alpha}-Particle Radioimmunotherapy of Metastases Cancer Res., June 15, 2008; 68(12): 4958 - 4958. [Full Text] [PDF]