A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo

Nat Biotechnol. 2000 Nov;18(11):1197-202. doi: 10.1038/81199.


Human interleukin 2 (IL-2; Proleukin) is an approved therapeutic for advanced-stage metastatic cancer; however, its use is restricted because of severe systemic toxicity. Its function as a central mediator of T-cell activation may contribute to its efficacy for cancer therapy. However, activation of natural killer (NK) cells by therapeutically administered IL-2 may mediate toxicity. Here we have used targeted mutagenesis of human IL-2 to generate a mutein with approximately 3,000-fold in vitro selectivity for T cells over NK cells relative to wild-type IL-2. We compared the variant, termed BAY 50-4798, with human IL-2 (Proleukin) in a therapeutic dosing regimen in chimpanzees, and found that although the T-cell mobilization and activation properties of BAY 50-4798 were comparable to human IL-2, BAY 50-4798 was better tolerated in the chimpanzee. BAY 50-4798 was also shown to inhibit metastasis in a mouse tumor model. These results indicate that BAY 50-4798 may exhibit a greater therapeutic index than IL-2 in humans in the treatment of cancer and AIDS.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Agents / toxicity
  • Cell Division
  • Cell Separation
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • Humans
  • Interleukin-2 / analogs & derivatives
  • Interleukin-2 / genetics*
  • Interleukin-2 / therapeutic use*
  • Interleukin-2 / toxicity
  • Kidney / drug effects
  • Killer Cells, Natural / metabolism
  • Kinetics
  • Leukocytes, Mononuclear / metabolism
  • Liver / drug effects
  • Male
  • Melanoma, Experimental / drug therapy
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutation*
  • Neoplasm Transplantation
  • Pan troglodytes
  • Protein Binding
  • Protein Structure, Secondary
  • Recombinant Proteins / genetics
  • Recombinant Proteins / therapeutic use
  • Recombinant Proteins / toxicity
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism*
  • Temperature
  • Time Factors


  • Antineoplastic Agents
  • Interleukin-2
  • Recombinant Proteins
  • aldesleukin