Down-regulation of the pharmacokinetic-pharmacodynamic response to interleukin-12 during long-term administration to patients with renal cell carcinoma and evaluation of the mechanism of this "adaptive response" in mice

Clin Pharmacol Ther. 1999 Jun;65(6):615-29. doi: 10.1016/S0009-9236(99)90083-8.


Background: Interleukin-12 (IL-12) is a cytokine that promotes type-1 helper T-cell responses and may have therapeutic utility in the treatment of cancer, asthma, and a variety of infectious diseases.

Methods: In a phase I trial, recombinant human IL-12 (rHuIL-12) was administered subcutaneously once a week at a fixed dose of 0.1 to 1.0 microg/kg to 24 patients with renal cell carcinoma. A similar study was later performed in mice to evaluate the mechanism of down-regulation of pharmacokinetic-pharmacodynamic response observed in patients with cancer.

Results: Adverse events, serum IL-12 levels, and serum levels of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) produced in response to IL- 12 were all maximum in the week after the first dose of rHuIL-12 and decreased after long-term administration. Similar to these results, repetitive subcutaneous administration of recombinant mouse IL-12 (rMoIL-12) to normal mice led to down-regulation of serum levels of IL-12 and IFN-gamma measured 5 hours after rMoIL-12 injection. Down-regulation of IL-12 serum levels was inversely correlated with the up-regulation of IL-12 receptor expression and may be the result of increased clearance of rMoIL-12 from serum by binding to lymphoid cells expressing increased amounts of IL-12 receptor. The down-regulation of serum IFN-gamma levels correlated with decreased IFN-gamma messenger ribonucleic acid expression and may result from feedback inhibition of IL-12 signaling or from a more specific inhibition of IFN-gamma synthesis.

Conclusion: Administration of rHuIL-12 in fixed weekly doses resulted in decreased serum levels of IL-12 and of IFN-gamma, a secondary cytokine believed to be critical to response of IL-12. A better understanding of the complex regulation of the pharmacokinetic-pharmacodynamic response to IL-12 should facilitate the development of more effective dosing regimens for its use in the clinic.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Multicenter Study

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Adjuvants, Immunologic / adverse effects
  • Adjuvants, Immunologic / pharmacokinetics
  • Adjuvants, Immunologic / pharmacology*
  • Adult
  • Aged
  • Animals
  • Carcinoma, Renal Cell / blood
  • Carcinoma, Renal Cell / drug therapy*
  • Down-Regulation
  • Drug Administration Schedule
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interferon-gamma / blood
  • Interferon-gamma / genetics
  • Interleukin-12 / administration & dosage
  • Interleukin-12 / adverse effects
  • Interleukin-12 / blood
  • Interleukin-12 / pharmacokinetics
  • Interleukin-12 / pharmacology*
  • Kidney Neoplasms / blood
  • Kidney Neoplasms / drug therapy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • RNA, Messenger / analysis
  • Recombinant Proteins / pharmacology
  • beta 2-Microglobulin / metabolism


  • Adjuvants, Immunologic
  • RNA, Messenger
  • Recombinant Proteins
  • beta 2-Microglobulin
  • Interleukin-12
  • Interferon-gamma