Target mediated disposition of T84.66, a monoclonal anti-CEA antibody: Application in the detection of colorectal cancer xenografts

Carcinoembryonic antigen (CEA) is a glycosylated cell surface antigen known to be highly overexpressed in several adenocarcinomas, including colorectal cancer, while demonstrating limited expression in normal tissues. Prior work has shown that the plasma clearance of T84.66, a monoclonal anti-CEA antibody, is enhanced by several-fold in a CEAexpressing xenograft mouse model, suggesting the presence of a target mediated elimination pathway. The purpose of this study is to investigate the influence of tumor volume on the plasma clearance of T84.66, and test the hypothesis that the plasma pharmacokinetics of T84.66 may be used as a sensitive and selective test for the diagnosis of CEA-positive tumors. T84.66 plasma pharmacokinetics were studied following intravenous (i.v.) administration of a 1 mg/kg dose in animals without tumor and mice bearing low (20-75 mm3), medium (400-570 mm3), and high volume (800-1,200 mm3) LS174T xenografts. Based on comparison of the disposition of T84.66 in non-tumor bearing mice and mice bearing low-volume tumors, it was predicted that a single plasma concentration of T84.66, obtained 7-days after dosing, would provide a sensitive and selective means of determining the presence of tumor in mice. A blinded follow-up study was conducted using athymic mice with or without intraperitoneal LS174T xenografts. 1 mg/kg of 125I-T84.66 was administered i.v., and plasma samples were collected on day 7. Comparison of the observed concentration of 125I-T84.66 to the pre-determined threshold value (7.63 nM) enabled identification of tumor bearing mice with a sensitivity of 93.3% and specificity of 100%.