Reduced secondary cytokine induction by BAY 50-4798, a high-affinity receptor-specific interleukin-2 analog

J Interferon Cytokine Res. 2006 Mar;26(3):171-8. doi: 10.1089/jir.2006.26.171.

Abstract

Recombinant interleukin-2 (IL-2) (aldesleukin, Proleukin, Chiron, Emeryville, CA) is approved for treatment of cancer patients and under investigation in HIV-infected individuals. However, treatment with aldesleukin is associated with toxicity, which may be due to its elicitation of inflammatory mediators from cells that express the intermediate-affinity IL-2 receptor. BAY 50-4798, a novel IL-2 analog, is a selective agonist for the high-affinity receptor. It induces the proliferation of activated T cells with a potency similar to that of aldesleukin but has reduced activity on cells expressing the intermediate-affinity receptor. In the current study, we compared cytokine responses elicited in peripheral blood mononuclear cell (PBMC) cultures stimulated with BAY 50-4798 or aldesleukin. BAY 50-4798 induced approximately 5-fold lower mean levels of endogenous IL-2 than aldesleukin, and at least 50% lower levels of proinflammatory cytokines, such as tumor necrosis fctor-alpha (TNF-alpha), IL-1beta, IL-6, and interferon-gamma (IFN-gamma). Furthermore, statistically significant reductions in the levels of IL-5, IL-8, IL-10, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were observed in response to BAY 50-4798. These findings increase our understanding of the biologic action of BAY 50-4798 and suggest a mechanism by which it may exhibit better safety than aldesleukin in humans.

Publication types

  • Comparative Study

MeSH terms

  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chemistry, Pharmaceutical
  • Concanavalin A / pharmacology
  • Cytokines / biosynthesis*
  • Dose-Response Relationship, Drug
  • Humans
  • Interleukin-2 / analogs & derivatives*
  • Interleukin-2 / pharmacology
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Kinetics
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Mitogens / pharmacology
  • RNA, Messenger / analysis
  • Receptors, Interleukin-2 / metabolism*
  • Recombinant Proteins / pharmacology
  • Transcription, Genetic / drug effects

Substances

  • Cytokines
  • Interleukin-2
  • Mitogens
  • RNA, Messenger
  • Receptors, Interleukin-2
  • Recombinant Proteins
  • Concanavalin A
  • aldesleukin