RADIOIMMUNOTHERAPY TARGETING OF HER2 NEU ONCOPROTEIN ON OVARIAN TUMORUSING LEAD-212-DOTA-AE1/

The specificity, toxicity and efficacy of lead (Pb-212) radioimmunothe rapy were evaluated in nude mice bearing the SK-OV-3 human ovarian tum or cell line expressing the HER2/neu proto-oncogene. Methods: The ther apeutic agent used was the tumor-specific anti-HER2/neu monoclonal ant ibody AE1 conjugated to Pb-212, Bi-212 being the daughter and thus the source of the alpha-particle and beta emissions. A bifunctional deriv ative of tetraazacyclododecanetetraacetic acid (p-SCN-Bz-DOTA) was use d to couple Pb-212 to the anti-HER2/neu monoclonal antibody AE1. The c helating agent did not alter the binding affinity to its antigenic tar get or the pharmacokinetics and tissue distribution of the AE1 antibod y, Toxicity and therapeutic efficacy of Pb-212-AE1 were evaluated in n ude mouse ascites or solid tumor models, wherein SK-OV-3 cells were ad ministered i.p. or s.c., respectively. Results: The dose-limiting acut e toxicity after i.v. administration of Pb-212-AE1 was bone marrow sup pression, which was observed at doses above 25 mu Ci. Therefore, doses of 10 and 20 mu Ci were used in efficacy trials. The i.p. administrat ion of Pb-212-AE1 3 days after i.p. tumor inoculation led to a signifi cant (p(2) = 0.015) prolongation of tumor-free survival. In a second m odel, i.v. treatment with Pb-212-AE1 3 days after s.c. tumor inoculati on prevented subsequent tumor development in all animals treated with 10 or 20 mu Ci of Pb-212-AE1 (p(2) = 0.002 compared to control groups) . This efficacy in the adjuvant setting was antibody specific because treatments with equivalently labeled control antibody or unlabeled AE1 antibody or no treatment were less effective. The rate of growth of s mall (mean tumor volume, 15 mm(3)) SK-OV-3 tumors was modestly inhibit ed. However, tumor growth was not inhibited in mice bearing larger (me an tumor volume, 146 mm(3)) SK-OV-3 tumors by the administration of a single dose of 10 or 20 mu Ci of Pb-212-AE1. Conclusion: Lead-212-AE1 as an intact radiolabeled monoclonal antibody may be of only modest va lue in the therapy of bulky solid tumors due to the short physical hal f-life of Pb-212 and time required to achieve a useful tumor-to-normal tissue ratio of radionuclide after administration. However, the radio labeled monoclonal antibody may be useful in therapy of tumors in the adjuvant setting. Furthermore, Pb-212 may be of value in select situat ions, including treatment of leukemia, intercavitary therapy or strate gies that target vascular endothelial cells of tumors.