Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15

Cancer Res. 2000 Jul 1;60(13):3577-83.

Abstract

Interleukin-2 (IL-2) and interleukin-15 (IL-15) are T-cell tropic factors that share beta and gammac subunits of their receptors on T/NK-cells. Although these two cytokines share receptor components, the IL-15Ralpha molecule is expressed constitutively by various tissue cells, whereas the IL-2Ralpha expression is mostly restricted to activated mononuclear cells. Consequently, we postulated that the biodistribution of IL-15 might be different from that of IL-2 and that individual alpha chains play an important role in this respect. This study investigated the differences between IL-2 and IL-15 in pharmacokinetics, biodistribution, and their tumor-targeting abilities. It found that only IL-2 showed specific binding to a protein, alpha2-macroglobulin, which may be the reason that IL-2 displays longer blood clearance than IL-15. Upon injection of these cytokines into mice, we observed that IL-15 accumulated significantly more than IL-2 in kidney, spleen, and bone. These are all tissues that express IL-15 receptor alpha but not IL-2 receptor alpha. To evaluate the tumor-targeting ability of each cytokine, we used nude mice xenografted with three A431 tumors, parental and cells transfected with alpha subunit of the receptor for either IL-2 or IL-15. When examined using radioiodinated IL-2 or IL-15, each cytokine accumulated on the target cells, expressing its respective alpha chain, suggesting that the expression of the alpha chains is sufficient to define specific biodistribution of IL-2 and IL-15, although these cytokines share the beta and yc molecules of their receptors. IL-15 displayed better target-specific accumulation and more rapid clearance from the circulation than did IL-2, and thus it can be considered to be a novel and unique therapeutic agent.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / immunology
  • Carcinoma, Squamous Cell / metabolism*
  • Female
  • Humans
  • Interleukin-15 / blood
  • Interleukin-15 / pharmacokinetics*
  • Interleukin-2 / blood
  • Interleukin-2 / pharmacokinetics*
  • Iodine Radioisotopes
  • Metabolic Clearance Rate
  • Mice
  • Mice, Nude
  • Recombinant Proteins / blood
  • Recombinant Proteins / pharmacokinetics
  • Tissue Distribution
  • Transfection
  • Transplantation, Heterologous
  • alpha-Macroglobulins / metabolism

Substances

  • Interleukin-15
  • Interleukin-2
  • Iodine Radioisotopes
  • Recombinant Proteins
  • alpha-Macroglobulins