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Inhibition of Catabolism of Radiolabeled Antibodies by Tumor Cells Using Lysosomotropic Amines and Carboxylic Ionophores¹

Departments of Medicine (Division of Oncology) [O. W. P., S. K. A.], Pediatrics [K. D.], and Biological Structure [O. W. P., F. G.], University of Washington, and the Fred Hutchinson Cancer Research Center [O. W. P.], Seattle, Washington 98195

The rates of degradation of radioiodinated monoclonal antibodies (MoAbs) by malignant T- and B-lymphoid cells were studied in the presence and absence of a variety of pharmacological agents known to affect the intracellular metabolism of internalized ligands. ¹²⁵I-MoAbs directed against the CD2, CD3, CD5, and anti-µ surface antigens underwent rapid endocytosis, followed by prompt degradation with release of 50% of the initially bound radioactivity as free, trichloroacetic acid-soluble ¹²⁵I within 24 h. Lysosomotropic amines (chloroquine, ammonium chloride, amantadine), carboxylic ionophores (monensin, nigericin), calcium channel blockers (verapamil), thionamides (propylthiouracil), lysosomal enzyme inhibitors (leupeptin), and colchicine all inhibited metabolism of radioiodinated MoAbs and enhanced retention of ¹²⁵I-MoAbs by tumor cells. The most effective agents (e.g., monensin, nigericin) diminished the release of free ¹²⁵I by >90% and enhanced retention of radioactivity by >300% at 24 h. Experiments with immunoperoxidase electron microscopy and Percoll gradient fractionation of organelles from disrupted cells suggested that high concentrations of monensin (10–20 µM) delayed transfer of ¹²⁵I-MoAbs to lysosomes, but other mechanisms (e.g., pH neutralization) were operative at lower concentrations (1–3 µM). Clinical administration of these agents may enhance retention of radioimmunoconjugates by tumor cells, resulting in improved radioimmunoscintigraphy and radioimmunotherapy.

¹ This work was supported by Department of Energy Grant DE-FG06-88ER60719. During portions of this research Dr. Press was the recipient of a First Independent Research and Training Award from the NIH (CA-46134) and of an Elsa Pardee Award.

² To whom requests for reprints should be addressed, at University Hospital Cancer Center, RC-08, University of Washington, Seattle WA 98195.

Received 7/14/89. Revised 10/13/89. Accepted 10/24/89.