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

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

Gerald L. DeNardo, Sally J. DeNardo, David L. Kukis, Robert T. O’Donnell, Sui Shen, Gary R. Mirick and Claude F. Meares

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

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FIGURE 1. Radioanalytic HPLC traces of ¹¹¹In-2IT-BAD-Lym-1 radiopharmaceutical before injection in NHL patient (front trace) and of patient plasma 24, 48, and 72 h after injection. Percentage of ¹¹¹In in patient’s plasma associated with metabolites (elution volume, 12–18 mL) and complexes (elution volume, 7–9 mL) increased over time. Similar pattern was observed for every NHL patient who received ¹¹¹In-2IT-BAD-Lym-1. Standard curve from MW standard proteins was used to relate elution volume to MW.

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FIGURE 2. Comparison of metabolism of ¹¹¹In-2IT-BAD-Lym-1 in NHL patients (A), ¹¹¹In-2IT-BAD-m170 in prostate cancer patients (B), and ¹¹¹In-2IT-BAD-m170 in breast cancer patients (C). Of ¹¹¹In-2IT-BAD-Lym-1 or ¹¹¹In-2IT-BAD-m170 in patients’ plasma at specific points in time, percentage in monomeric (•), metabolite ( ${blacksquare}$ ), and complexed ( ${blacktriangleup}$ ) forms was measured by HPLC. In NHL patients receiving ¹¹¹In-2IT-BAD-Lym-1, metabolites and complexes constituted substantially larger fractions of ¹¹¹In in plasma compared with prostate and breast cancer patients receiving ¹¹¹In-2IT-BAD-m170. Decay-corrected mean percentage injected dose (%ID) of ¹¹¹In in patients’ blood decreased over time (dashed lines). Thus, metabolites and complexes of ¹¹¹In-2IT-BAD-Lym-1 showed relative growth over time as fractions of total ¹¹¹In activity, but not absolute growth in terms of %ID.

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FIGURE 3. Comparison of formation of metabolites and complexes of ¹¹¹In-2IT-BAD-Lym-1 and ⁹⁰Y-2IT-BAD-Lym-1. Each graph represents 1 NHL patient who received ¹¹¹In- and ⁹⁰Y-2IT-BAD-Lym-1 in close temporal proximity. Of ¹¹¹In-2IT-BAD-Lym-1 in patients’ plasma at specific points in time, percentage in monomeric (•), metabolite ( ${blacksquare}$ ), and complexed ( ${blacktriangleup}$ ) forms was measured by HPLC. Of ⁹⁰Y-2IT-BAD-Lym-1 in patients’ plasma at specific points in time, percentage in monomeric ( ${circ}$ ), metabolite ( ${square}$ ), and complexed ( ${triangleup}$ ) forms was measured by HPLC. Extent of formation of nonmonomeric forms of ¹¹¹In- and ⁹⁰Y-2IT-BAD-Lym-1 was similar in individual patients.

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FIGURE 4. Simplified model for distribution of ¹¹¹In/⁹⁰Y-2IT-BAD-Lym-1 RIC in circulation in blood. Monomeric RIC is preferentially distributed to tumor, whereas metabolites and complexes of RIC are excreted or distributed to normal tissues. Thus, formation of metabolites and complexes of ¹¹¹In/⁹⁰Y-2IT-BAD-Lym-1 resulted in reduced cumulated activity in tumor and increased cumulated activity in normal tissues (lower TIs and higher toxicity).

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FIGURE 5. Planar anterior view of pelvis of NHL patient given ¹¹¹In-2IT-BAD-Lym-1 (A) and breast (B) and prostate (C) cancer patients given ¹¹¹In-2IT-BAD-m170, 3 d after injection. In addition to ¹¹¹In in lymphoma ( $<-$ ) and marrow ( $<-$ ), ¹¹¹In was present in GI tract (

) of patient with NHL but not in patients with breast and prostate cancer. Specific hepatocyte receptors have been documented for mouse IgG2a antibodies, such as Lym-1, but not for mouse IgG1 antibodies, such as m170.