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Comparative Cellular Catabolism and Retention of Astatine-, Bismuth-, and Lead-Radiolabeled Internalizing Monoclonal Antibody

Department of Nuclear Medicine and PET Department, Warren G. Magnuson Clinical Center; and Metabolism and Radiation Oncology Branches, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Monoclonal antibodies (mAbs) labeled with -emitting radionuclides such as ²¹¹At, ²¹²Bi, ²¹³Bi, and ²¹²Pb (which decays by ß-emission to its -emitting daughter, ²¹²Bi) are being evaluated for their potential applications for cancer therapy. The fate of these radionuclides after cells are targeted with mAbs is important in terms of dosimetry and tumor detection. Methods: In this study, we attached various radionuclides that result in -emissions to T101, a rapidly internalizing anti-CD5 mAb. We then evaluated the catabolism and cellular retention and compared them with those of ¹²⁵I- and ¹¹¹In-labeled T101. T101 was labeled with ²¹¹At, ¹²⁵I, ^205,6Bi, ¹¹¹In, and ²⁰³Pb. CD5 antigen–positive cells, peripheral blood mononuclear cells (PBMNC), and MOLT-4 leukemia cells were used. The labeled T101 was incubated with the cells for 1 h at 4°C for surface labeling. Unbound activity was removed and 1 mL medium added. The cells were then incubated at 37°C for 0, 1, 2, 4, 8, and 24 h. The activity on the cell surface that internalized and the activity on the cell surface remaining in the supernatant were determined. The protein in the supernatant was further precipitated by methanol for determining protein-bound and non–protein-bound radioactivity. Sites of internal cellular localization of radioactivity were determined by Percoll gradient centrifugation. Results: All radiolabeled antibodies bound to the cells were internalized rapidly. After internalization, ^205,6Bi, ²⁰³Pb, and ¹¹¹In radiolabels were retained in the cell, with little decrease of cell-associated radioactivity. However, ²¹¹At and ¹²⁵I were released from cells rapidly (²¹¹At < ¹²⁵I) and most of the radioactivity in the supernatant was in a non–protein-bound form. Intracellular distribution of radioactivity revealed a transit of the radiolabel from the cell surface to the lysosome. The catabolism patterns of MOLT-4 cells and PBMNC were similar. Conclusion: ²¹¹At catabolism and release from cells were somewhat similar to that of ¹²⁵I, whereas ^205,6Bi and ²⁰³Pb showed prolonged cell retention similar to that of ¹¹¹In. These catabolism differences may be important in the selection of -radionuclides for radioimmunotherapy.

Key Words: -emitter • internalization • cellular retention • monoclonal antibody

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