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Enhancement of Tumor-to-Nontumor Localization Ratios by Hepatocyte-Directed Blood Clearance of Antibodies Labeled with Certain Residualizing Radiolabels

Garden State Cancer Center at the Center for Molecular Medicine and Immunology, Belleville, New Jersey

Correspondence: For correspondence or reprints contact: M. Jules Mattes, PhD, Center for Molecular Medicine and Immunology, 520 Belleville Ave., Belleville, NJ 07109.

ABSTRACT

To increase tumor-to-nontumor localization ratios of injected radiolabeled antibodies (Abs), several interrelated methods were used. Methods: The model systems used were two human carcinoma xenografts grown in nude mice, targeted by antibodies RS11 (antiepithelial glycoprotein-2) or MN-14 (anticarcinoembryonic antigen). The Abs were conjugated with biotin and ¹¹¹In-benzyl diethylenetriamine pentaacetic acid, and, at various times after injection, were cleared by intraperitoneal injection of galactosylated streptavidin, which delivers the complexes to hepatocytes. The radiolabel used was selected because it is retained within tumors after catabolism of the Ab by the tumor cell but is quite rapidly excreted from hepatocytes into bile. Results: With blood clearance induced at 24 h, and dissection 5 h later, high tumor-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 kidney, lungs and bone were also high and greatly increased by the clearance regimen. Despite clearance into the liver, tumor-to-liver ratios remained >1, due to fairly rapid biliary excretion of the label. The absolute antibody uptake by the tumors was also high, because 24 h was allowed for the Ab to penetrate and bind to cells within the subcutaneous tumors. Conclusion: The method described produced high tumor-to-nontumor ratios at 1 d after injection and may be advantageous for tumor imaging with antibodies. Radiation dosimetry calculations indicate that there is only a slight advantage with this approach for radioimmunotherapy.

Key Words: antibody conjugates • tumor imaging • ¹¹¹In-diethylenetriamine pentaacetic acid antibody conjugates

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