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Intracellular Catabolism of Radiolabeled Anti-µ Antibodies by Malignant B-Cells¹

Departments of Biological Structure [F. G., S. K. A., O. P.], Radiology (Division of Nuclear Medicine) [P. V.], and Medicine (Division of Oncology) [S. K. A., O. P.], University of Washington, Seattle, Washington 98195, and the Fred Hutchinson Cancer Research Center, Seattle, Washington 98104 [O. P.]

The endocytosis and degradation of ¹²⁵I-labeled anti-µ monoclonal antibody DA4-4 by a Burkitt's lymphoma cell line was investigated using biochemical, chromatographic, electrophoretic, radioautographic, and electron microscopic techniques. ¹²⁵I-DA4-4 was rapidly internalized by Ramos cells and routed from endosomes to lysosomes. Proteolysis of radiolabeled antibodies began in a late endosomal compartment, but lysosomes were primarily responsible for the terminal degradation of ¹²⁵I-DA4-4. Catabolism of ¹²⁵I-DA4-4 could be inhibited by 74–95% by blocking its delivery to late endosomes and lysosomes by incubation at 18°C, by neutralizing the pH in intracellular organelles with monensin or ammonium chloride, or by inhibiting lysosomal enzymes with leupeptin. Radiolabeled antibodies synthesized using the chloramine T or Iodo-Gen techniques were degraded three times faster than conjugates made using a nonmetabolizable ¹²⁵I-tyramine cellobiose adduct. Five major intermediate metabolites (M_r 48,000, 42,000, 25,000, 15,000, and 10,000) were generated during the intracellular catabolism of ¹²⁵I-DA4-4, but ¹²⁵I-tyrosine was responsible for 95% of the small-molecular-weight metabolites released by cells into the culture medium. We anticipate that a full comprehension of the catabolism of radiolabeled antibodies by tumor cells will make possible the development of clinical interventions which will enhance the retention of radioimmunoconjugates by hematologic malignancies and improve the efficacy of radioimmunotherapy.

¹ Supported in part by Department of Energy Grant DE-FG06-88ER60719 and NIH R01 CA55596-01. F. G. is the recipient of a W. M. Keck Foundation Bioimaging Research Fellowship.

² To whom correspondence should be addressed, at the University of Washington Cancer Center, Mailstop RC-08, Seattle, WA 98195.

Received 11/11/91. Accepted 3/11/92.

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