213Bi (α-emitter)-antibody targeting of breast cancer metastases in the neu-N transgenic mouse model

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 Bi-213 to treat widespread metastases in a rat/neu transgenic mouse model of metastatic mammary carcinoma. The model manifests wide-spread dissemination or tumor cells leading to osteolytic bone lesions and liver metastases, common sites of clinical metastases. The maximum tolerated dose was 120 mu Ci of Bi-213-7.16.4. 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 mu Ci Bi-213-7.16.4, (b) 90 mu Ci Bi-213-7.16.4, (c) 120 mu Ci Bi-213-Rituximab (unreactive control), and (d) unlabeled 7.16.4. Treatment with 120 mu Ci Bi-213-7.16.4 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 Bi-213-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.