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Pharmacokinetics of ¹¹¹In- and ¹²⁵I-Labeled AntiTac Single-Chain Fv Recombinant Immunotoxin

Department of Nuclear Medicine, Warren G. Magnuson Clinical Center
Chemistry Section, Radiation Oncology Branch
Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Correspondence: For correspondence or reprints contact: Jorge A. Carrasquillo, MD, Department of Nuclear Medicine, National Institutes of Health, Bldg. 10, Rm. 1C496, 10 Center Dr., MSC 1180, Bethesda, MD 20892-1180.

ABSTRACT

The use of immunotoxins for cancer therapy is an attractive strategy that exploits the targeting specificity of monoclonal antibodies and their fragments as well as the exquisite toxicity of the toxins. However, few studies of immunotoxins have evaluated their biodistribution in vivo. Previous studies have used ¹²⁵I for tracing immunotoxin biodistribution in mice. Because the immunotoxin works only when it is internalized and because of known problems with quick dehalogenation after internalization of antibodies, we decided to use ¹¹¹In, which has greater intracellular retention than iodine. Methods: To trace the in vivo pharmacokinetics of the immunotoxin in mice, we labeled the antiTac(Fv)-PE38 with ¹¹¹In and compared it with ¹²⁵I-labeled antiTac(Fv)-PE38. We successfully labeled antiTac(Fv)-PE38 with ¹¹¹In at up to 2.96 GBq/mg. A 3- to 4-fold decrease in cytotoxicity was observed for both radiolabeled preparations. We evaluated the internalization of ¹¹¹In- and ¹²⁵I-labeled antiTac(Fv)-PE38 into ATAC4 cells (Tac-positive) as well as their biodistribution and pharmacokinetics in vivo in mice. In addition, some mice receiving these reagents were co-infused with 30 mg L-lysine to inhibit renal accumulation. Results: Significantly more ¹¹¹In- than ¹²⁵I-labeled antiTac(Fv)-PE38 accumulated in the ATAC4 cells (20% versus 5% of initial surface-bound radioactivity; P < 0.001). In vivo, significantly more ¹¹¹In- than ¹²⁵I-labeled antiTac(Fv)-PE38 accumulated in the kidney (119 versus 31 percentage injected dose per gram [%ID/g]; P < 0.001). The tumor accumulation of ¹¹¹In-labeled antiTac(Fv)-PE38 at 96 h was 13-fold greater than that of ¹²⁵I-labeled antiTac(Fv)-PE38 (1.4 versus 0.1 %ID/g; P < 0.001). No antiTac(Fv)-PE38 was excreted into the urine in its intact form unless lysine was co-infused. Co-injected lysine reduced the renal accumulation of ¹¹¹In-labeled antfTac(Fv)-PE38 by 62%. Conclusion: We evaluated the biodistribution, pharmacokinetics, and catabolism of ¹¹¹In-labeled antiTac(Fv)-PE38 and found that it differed from ¹²⁵I-labeled antiTac(Fv)-PE38. These studies suggest that ¹¹¹In-labeled antiTac(Fv)-PE38 can be used to trace the fate of antiTac(Fv)-PE38 in humans.

Key Words: interleukin-2 receptor subunit • immunotoxin • ¹¹¹In • ¹²⁵I • monoclonal antibody

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