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Metabolite Production in Patients with Lymphoma After Radiometal-Labeled Antibody Administration

Department of Internal Medicine, University of California Davis Medical Center, Sacramento; and Department of Chemistry, University of California Davis, Davis, California

Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given ¹¹¹In- and ⁹⁰Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Lym-1 (¹¹¹In/⁹⁰Y-2IT-BAD-Lym-1). Methods: Nineteen patients with non-Hodgkin’s lymphoma (NHL) received ¹¹¹In- and ⁹⁰Y-2IT-BAD-Lym-1; ¹¹¹In was used as a surrogate tracer for ⁹⁰Y, which emits no -photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate ¹¹¹In in organs and tumors. Results: Metabolites and complexes were observed in the plasma of every patient who received ¹¹¹In-2IT-BAD-Lym-1. At 3 d, the mean percentages of ¹¹¹In in the patients’ plasma in monomeric, metabolite, and complexed forms were 54%, 36%, and 10%, respectively. Metabolites of ⁹⁰Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate ¹¹¹In-2IT-BAD-m170, 91% and 94% of ¹¹¹In in the patients’ plasma were in monomeric form, respectively. Metabolites and complexes of ¹¹¹In-2IT-BAD-Lym-1 contributed a mean 10% of the total area under the time–activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of ¹¹¹In/⁹⁰Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites. Conclusion: Metabolites of ¹¹¹In/⁹⁰Y-2IT-BAD-Lym-1 accounted for 10% of blood AUC in patients. The therapeutic index was adversely affected by metabolism of ¹¹¹In/⁹⁰Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.

Key Words: antibodies • antibody conjugates • cancer • lymphoma • Lym-1 • metabolism • radioimmunotherapy

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