Zeuzem S, Hopf U, Carreno V, Diago M, Shiffman M, Grüne S, Dudley F J, Rakhit A, Rittweger K, Yap S H, Koff R S, Thomas H C
Medizinische Klinik II, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany.
Hepatology. 1999 Apr;29(4):1280-7. doi: 10.1002/hep.510290429.
Interleukin-12 (IL-12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The present open-label, multicenter, dose-escalation phase I/II study was designed to assess tolerability, pharmacokinetics, pharmacodynamics, and efficacy of subcutaneously administered recombinant human interleukin-12 (rHuIL-12) in the treatment of chronic hepatitis C. Sixty patients (42 men, 18 women, aged 24-60) were treated with 0.03 microgram/kg (n = 16), 0.1 microgram/kg (n = 14), 0.25 microgram/kg (n = 15), or 0.5 microgram/kg rHuIL-12 (n = 15) for 10 consecutive weeks. rHuIL-12 was generally well tolerated, with 2 patients (3.3%) being withdrawn from treatment for adverse events. Treatment was associated with temporary decreases in neutrophils and lymphocyte counts and with elevations in serum transaminases and bilirubin. Serum IL-12 levels observed were higher at 0.5 microgram/kg compared with 0.25 microgram/kg doses, suggesting a dose-related increase in systemic exposure of IL-12. Measurable levels of interferon gamma (IFN-gamma) were also observed at the highest dose of 0.5 microgram/kg. At the end of treatment hepatitis C virus (HCV) RNA was detectable in all patients. A more than 50% decrease in pretreatment HCV RNA levels was observed in 3 of 16 patients of the 0.03-microgram/kg dose group, in 3 of 14 of the 0.10-microgram/kg dose group, in 6 of 15 of the 0.25-microgram/kg dose group, and in 8 of 15 patients of the 0.5-microgram/kg dose group. Although in several cases serum alanine transaminase (ALT) levels decreased either during or after treatment, ALT normalization was observed in only 4 patients at the end of treatment and in 5 patients at the end of follow-up. Significant anti-rHuIL-12 antibody titers were not detectable in any patient. In conclusion, antiviral activity of rHuIL-12 in patients with chronic hepatitis C does not appear advantageous in comparison with other currently available treatments.
白细胞介素-12（IL-12）在引发针对消除细胞内病原体的有效细胞免疫反应中起核心作用。本项开放标签、多中心、剂量递增的I/II期研究旨在评估皮下注射重组人白细胞介素-12（rHuIL-12）治疗慢性丙型肝炎的耐受性、药代动力学、药效学及疗效。60例患者（42例男性，18例女性，年龄24 - 60岁）接受0.03微克/千克（n = 16）、0.1微克/千克（n = 14）、0.25微克/千克（n = 15）或0.5微克/千克rHuIL-12（n = 15）治疗，连续治疗10周。rHuIL-12总体耐受性良好，2例患者（3.3%）因不良事件退出治疗。治疗导致中性粒细胞和淋巴细胞计数暂时下降，血清转氨酶和胆红素升高。与0.25微克/千克剂量相比，0.5微克/千克剂量时观察到的血清IL-12水平更高，提示IL-12全身暴露量呈剂量相关增加。在最高剂量0.5微克/千克时也观察到可测量水平的干扰素γ（IFN-γ）。治疗结束时，所有患者均可检测到丙型肝炎病毒（HCV）RNA。0.03微克/千克剂量组16例患者中有3例、0.1微克/千克剂量组14例患者中有3例、0.25微克/千克剂量组15例患者中有6例、0.5微克/千克剂量组15例患者中有8例，治疗前HCV RNA水平下降超过50%。尽管在几例患者中，血清丙氨酸转氨酶（ALT）水平在治疗期间或治疗后有所下降，但治疗结束时仅4例患者ALT恢复正常，随访结束时5例患者ALT恢复正常。未在任何患者中检测到显著的抗rHuIL-12抗体滴度。总之，与目前其他可用治疗方法相比，rHuIL-12在慢性丙型肝炎患者中的抗病毒活性似乎并无优势。
