Enhancement of tumor-to-nontumor localization ratios by hepatocyte-directed blood clearance of antibodies labeled with certain residualizing radiolabels

To increase tumor-to-nontumor localization ratios of injected radiolabeled antibodies (Abs), several interrelated methods were used. Methods: The mode l systems used were two human carcinoma xenografts grown in nude mice, targ eted by antibodies RS11 (antiepithelial glycoprotein-2) or MN-14 (anticarci noembryonic antigen). The Abs were conjugated with biotin and (111)ln-benzy l diethylenetriamine pentaacetic acid, and, at various times after injectio n, were cleared by intraperitoneal injection of galactosylated streptavidin , which delivers the complexes to hepatocytes. The radiolabel used was sele cted because it is retained within tumors after catabolism of the Ab by the tumor cell but is quite rapidly excreted from hepatocytes into bile. Resul ts: With blood clearance induced at 24 h, and dissection 5 h later, high tu mor-to-nontumor ratios were attained. Depending on the model used, tumor-to -blood ratios were 16:1 to 31:1, and tumor-to-nontumor ratios for the kidne y, lungs and bone were also high and greatly increased by the clearance reg imen. Despite clearance into the liver, tumor-to-liver ratios remained >1, due to fairly rapid biliary excretion of the label. The absolute antibody u ptake by the tumors was also high, because 24 h was allowed for the Ab to p enetrate and bind to cells within the subcutaneous tumors. Conclusion: The method described produced high tumor-to-nontumor ratios at 1 d after inject ion and may be advantageous for tumor imaging with antibodies. Radiation do simetry calculations indicate that there is only a slight advantage with th is approach for radioimmunotherapy.