The overall objective of this proposal is to develop a more effective therapeutic approach for the selective destruction of cancer cells. We propose to investigate the feasibility of combining the potential tumor specificity of monoclonal antibodies directed against tumor-associated antigens with the high linear energy transfer, short-range alpha radiations emitted in the decay of 211At. Astatine-211-labeled monoclonal antibodies offer the attractive possibility of matching the cellular specificity of an antibody with radiation of approximately cellular range. The antibody chosen for these studies is OC 125, a monoclonal antibody directed against a surface antigen present on human ovarian cancer cells. We have labeled OC 125 with I125, studied its interaction with human ovarian carcinoma cells in vitro and demonstrated selective uptake of I125 activity in human ovarian tumor implants in athymic mice.
The specific aims are: (1) to label OC 125 with At211 using an acylation reaction without decreasing its affinity for ovarian cancer cells; (2) to measure the radiotoxicity of At211-labeled OC 125 in ovarian cancer cell lines; (3) to measure the therapeutic efficacy of At211-labeled OC 125 administered intraperitoneally to mice with malignant ascites; (4) to study the effects of several factors including antibody dose and circulating antigen level on the pharmacokinetics of labeled OC 125 and F(ab')2 and Fab' fragments in nude mouse models of ovarian cancer; and (5) to study the therapeutic utility of At211-labeled OC 125 in nude mice bearing human ovarian tumor xenografts. Although the proposed studies are limited to the study of in vitro and in vivo model systems, it is important to bear in mind that if the proposed experiments are successful, treatment of ovarian cancer might be possible via intraperitoneal and/or intravenous administration of At211-labeled antibodies.
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