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Pharmacokinetics of 111In- and 125I-labeled antiTac single-chain Fv recombinant immunotoxin
H Kobayashi1, C H Kao, R J Kreitman
1Department of Nuclear Medicine, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1180, USA.
Unlabelled:
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 111ln 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 antiTac(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.
Insights
This study shows indium-111 (111In)-labeled immunotoxins offer superior tumor accumulation and intracellular retention compared to iodine-125 (125I)-labeled versions for cancer therapy research. This improved biodistribution suggests 111In is a better radiotracer for tracking immunotoxin fate in vivo.
Area of Science:
- Oncology
- Radiochemistry
- Pharmacokinetics
Background:
- Immunotoxins combine antibody targeting with potent toxin payloads for cancer therapy.
- Evaluating immunotoxin biodistribution in vivo is crucial for therapeutic development.
- Previous studies used 125I for tracing, but dehalogenation issues limit accuracy.
Purpose of the Study:
- To compare the in vivo biodistribution and pharmacokinetics of 111In-labeled antiTac(Fv)-PE38 versus 125I-labeled antiTac(Fv)-PE38.
- To assess the utility of 111In as a radiotracer for immunotoxins due to its greater intracellular retention.
- To evaluate the impact of L-lysine co-infusion on renal accumulation.
Main Methods:
- Radiolabeling of antiTac(Fv)-PE38 with 111In and 125I.
- Assessing cytotoxicity of radiolabeled immunotoxins.
- Evaluating cellular internalization in ATAC4 cells.
- Determining in vivo biodistribution and pharmacokinetics in mice, with and without L-lysine.
Main Results:
- 111In-labeled immunotoxin showed significantly higher accumulation in target cells (20% vs 5%) and tumors (1.4% vs 0.1% ID/g at 96h) compared to 125I-labeled.
- Kidney accumulation was significantly higher for 111In-labeled immunotoxin (119% vs 31% ID/g).
- L-lysine reduced renal accumulation of 111In-labeled immunotoxin by 62% and prevented excretion of intact immunotoxin.
Conclusions:
- 111In-labeled antiTac(Fv)-PE38 exhibits distinct biodistribution and pharmacokinetic properties compared to its 125I-labeled counterpart.
- 111In demonstrates superior tumor targeting and intracellular retention, making it a promising radiotracer for immunotoxin studies.
- These findings support the use of 111In-labeled immunotoxins for tracing their fate in preclinical and potentially clinical settings.
