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⁶⁷Ga-labeled Antibodies for Immunoscintigraphy and Evaluation of Tumor Targeting of Drug-Antibody Conjugates in Mice

Faculty of Medicine [M. K., K. E., M. K., H. S., T. N., Y. K., Y. W., T. S., J. K., T. Y., S. H.], Viral Institute [S. T.], and Pharmaceutical Sciences [Y. A., A. Y.], Kyoto University, Kyoto 606, Japan

To assess the in vivo behavior of cytotoxic agents linked to antibodies, deferoxamine, known to form stable chelates with ⁶⁷Ga, was conjugated with monoclonal antibodies using three different methods. One method used a homocoupling reagent, glutaraldehyde, whereas two other methods used heterocoupling reagents, N-succinimidyl-3-(2-pyridyldithio)propionate and succinimidyl-6-maleimidohexanoate, linking deferoxamine to antibodies through alkylamine, disulfide, and thioether bonds, respectively. Antibodies were efficiently labeled with ⁶⁷Ga through chelation with deferoxamine without losing antigen-binding capability. ⁶⁷Ga-labeled antibodies clearly visualized transplanted tumors in nude mice. However, the biodistribution of radioactivity was markedly different with the coupling methods used for the conjugation of deferoxamine and antibodies. High nonspecific uptake in the liver and spleen was observed with ⁶⁷Ga-labeled antibodies prepared by the glutaraldehyde method. ⁶⁷Ga-labeled antibodies linked by thioether bonds demonstrated in vivo stability and the highest tumor:liver ratio, whereas ⁶⁷Ga-labeled antibodies conjugated with disulfide bonds were rapidly cleared from the circulation. These results indicate that antibody conjugates linked by thioether bonds are a better choice for drug targeting and that ⁶⁷Ga-labeled antitumor monoclonal antibodies are useful not only for the immunoscintigraphy but also for the quantitative assessment and visualization of the biodistribution of drug-antibody conjugates.

¹ To whom requests for reprints should be addressed, at Department of Nuclear Medicine, Kyoto University Hospital, Shogoin, Sakyo-ku, Kyoto 606, Japan.

Received 7/24/87. Revised 11/24/87. Accepted 12/ 1/87.

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