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

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 μg/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‐ˠ (IFN‐ˠ) 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‐ˠ 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‐ˠ levels correlated with decreased IFN‐ˠ messenger ribonucleic acid expression and may result from feedback inhibition of IL‐12 signaling or from a more specific inhibition of IFN‐ˠ synthesis. Conclusion Administration of rHuIL‐12 in fixed weekly doses resulted in decreased serum levels of IL‐12 and of IFN‐ˠ, 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. Clinical Pharmacology & Therapeutics (1999) 65, 615–629; doi: 10.1016/S0009-9236(99)90083-8