TY - JOUR
T1 - 213Bi (α-emitter)-antibody targeting of breast cancer metastases in the neu-N transgenic mouse model
AU - Song, Hong
AU - Shahverdi, Karineh
AU - Huso, David L.
AU - Esaias, Caroline
AU - Fox, James
AU - Liedy, Allison
AU - Zhang, Zhe
AU - Reilly, R. Todd
AU - Apostolidis, Christos
AU - Morgenstern, Alfred
AU - Sgouros, George
PY - 2008/5/15
Y1 - 2008/5/15
N2 - 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 α-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 α-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.
AB - 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 α-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 α-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.
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U2 - 10.1158/0008-5472.CAN-07-6308
DO - 10.1158/0008-5472.CAN-07-6308
M3 - Article
C2 - 18483272
AN - SCOPUS:45549088490
SN - 0008-5472
VL - 68
SP - 3873
EP - 3880
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -