© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 10, 741-749,
May 21, 2003
© 2003 Oxford University Press
ARTICLE |
Identification of a Protein Fragment of Interleukin 2 Responsible for Vasopermeability
Affiliation of authors: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Correspondence to: Alan L. Epstein, M.D., Ph.D., Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., HMR 205, Los Angeles, CA 90033 (e-mail: aepstein{at}usc.edu).
Background: The cytokine interleukin 2 (IL-2) is involved in the activation of T cells and has been shown to play a central role in cancer immunotherapy. The full therapeutic potential of IL-2, however, has not been realized because of its dose-limiting systemic toxicity. We sought to identify a region of IL-2 that is responsible for the induction of vasopermeability (leaky tumor endothelium), a property associated with the toxicity of the molecule. Methods: Intact IL-2 or overlapping synthetic peptides of IL-2 that were chemically conjugated to tumor-targeting monoclonal antibodies (TNT-1 or Lym-1) were injected into groups of mice (n = 4) that had previously been xenotransplanted with human tumor cells (ME-180 cervical carcinoma and Raji lymphoma). Two hours later, mice received intravenous injections of radiolabeled tracer antibody, and 3 days later they were subjected to biodistribution analysis to measure the ability of each immunoconjugate to enhance tumor uptake of the tracer antibody (i.e., vasopermeability activity). The cytokine activity of the immunoconjugates was determined by assaying their ability to promote the proliferation of a mouse IL-2-dependent cell line. Results: Pretreatment of mice with an antibody/IL-2 immunoconjugate resulted in an approximately fourfold increase in radiolabeled tracer antibody uptake in the xenograft tumor as compared with uptake in mice injected with antibody alone. One synthetic fragment consisting of amino acids 22–58 contained 100% of the vasopermeability activity of IL-2 and was designated permeability-enhancing peptide (PEP). PEP had vasopermeability activity only when conjugated to a tumor-targeting antibody, had maximal activity as a dimer, and was devoid of cytokine activity. Conclusions: The identification of PEP should aid in the discovery of ways to decrease the toxicity of IL-2. Moreover, PEP is a promising candidate for the generation of agents that can enhance the delivery of antibodies and drugs to tumors.
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