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Pharmacokinetics of the recombinant fusion protein DAB486IL-2 in animal models

Cancer Chemotherapy and Pharmacology volume 26, pages 409–414 (1990)Cite this article

Summary

The kinetics of the in vitro cytotoxicity of DAB486IL-2, a genetically engineered fusion protein containing a portion of diphtheria toxin and human interleukin-2, were examined in the C91/PL cell line, which constitutively expresses IL-2 receptors. Maximal inhibition of protein synthesis was observed by 4–6 h after DAB486 IL-2 addition at a concentration of 300 ng/ml. The tissue distribution, urinary excretion, and plasma pharmacokinetics of DAB486IL-2 in the rat and its plasma pharmacokinetics in the monkey were also examined. In rats the primary site of distribution of [35S]-DAB486IL-2 outside the vasculature appears to be the liver, followed by the kidney, spleen, and lung. Persistence of radioactive material in the liver and urinary excretion of metabolic degradation products suggest that labeled protein is metabolized by hepatic tissue. Following i.v. bolus administration of DAB486IL-2, the initial serum half-life for both the rat and the monkey was approximately 5 min. The overall clearance rate of drug for the two species differed, with DAB486IL-2 being cleared from circulation 2–3 times more rapidly in the monkey. Presence of high levels of neutralizing antibodies to diphtheria toxin in the rat significantly influenced the clearance of bioactive DAB486IL-2. However, the question as to whether the presence of in vitro biological activity for the molecule is masked by the presence of antibodies cannot be clearly answered.

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Affiliations

  1. Seragen, Inc., 97 South St., 01748, Hopkinton, MA, USA

    Patricia Bacha, Serene Forte, Nasim Kassam, Jenifer Thomas, Donna Akiyoshi, Cory Waters & Jean Nichols

  2. Department of Clinical Immunopharmacology and Biological Therapy, University of Texas M. D. Anderson Cancer Center, 77030, Houston, TX, USA

    Michael Rosenblum

Authors
  1. Patricia Bacha
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  2. Serene Forte
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  3. Nasim Kassam
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  4. Jenifer Thomas
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  5. Donna Akiyoshi
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  6. Cory Waters
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  7. Jean Nichols
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  8. Michael Rosenblum
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Bacha, P., Forte, S., Kassam, N. et al. Pharmacokinetics of the recombinant fusion protein DAB486IL-2 in animal models. Cancer Chemother Pharmacol 26, 409–414 (1990). https://doi.org/10.1007/BF02994090

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  • DOI: https://doi.org/10.1007/BF02994090

Keywords

  • Diphtheria Toxin
  • Bolus Administration
  • Neutralize Antibody Titer
  • Leucine Incorporation
  • Engineer Fusion Protein