Herzyk Danuta J, Soos Jeanne M, Maier Curtis C, Gore Elizabeth R, Narayanan Padma K, Nadwodny Kimberly L, Liu Susan, Jonak Zdenka L, Bugelski Peter J
Department of Safety Assessment, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
Cytokine. 2002 Oct 7;20(1):38-48. doi: 10.1006/cyto.2002.1978.
Recombinant human interleukin (IL)-18 (rHuIL-18) has a potential as a therapeutic agent in cancer and is currently in drug development. Since human IL-18 displays 96% and 100% amino acid sequence homology with cynomolgus monkey and chimpanzee IL-18, respectively, the biological responses to rHuIL-18 were evaluated in these species. A single intravenous dose of rHuIL-18 at 1 or 10mg/kg in cymonolgus monkeys caused a transient reduction in lymphocyte counts, induction of IL-1alpha and tumour necrosis factor alpha (TNF-alpha) mRNA in whole blood cells and a marked increase in plasma neopterin. rHuIL-18 administered to cynomolgus monkeys at doses of 0.3 or 3mg/kg for two 5-day cycles (Days 1-5 and 15-19) resulted in increased monocyte counts, induction of NK cells and concomitant increases in plasma IL-12 and neopterin. Administration of repeat doses of rHuIL-18 at 10mg/kg to chimpanzees was associated with increased monocyte counts, upregulation of FcgammaRI surface expression on monocytes, and increased IL-8, IL-12 and neopterin in plasma. These studies demonstrate, for the first time, the immunostimulatory activity of rHuIL-18 in vivo. The described pharmacological profile of rHuIL-18 in both cynomolgus monkeys and chimpanzees is indicative of the immunotherapeutic potential of rHuIL-18 in the treatment of cancer.
重组人白细胞介素（IL）-18（rHuIL-18）具有作为癌症治疗药物的潜力，目前正处于药物研发阶段。由于人IL-18与食蟹猴和黑猩猩的IL-18分别具有96%和100%的氨基酸序列同源性，因此在这些物种中评估了对rHuIL-18的生物学反应。在食蟹猴中静脉注射单次剂量为1或10mg/kg的rHuIL-18会导致淋巴细胞计数短暂减少、全血细胞中IL-1α和肿瘤坏死因子α（TNF-α）mRNA的诱导以及血浆新蝶呤显著增加。以0.3或3mg/kg的剂量给食蟹猴注射rHuIL-18，进行两个5天周期（第1 - 5天和第15 - 19天），会导致单核细胞计数增加、NK细胞诱导以及血浆中IL-12和新蝶呤随之增加。以10mg/kg的剂量给黑猩猩重复注射rHuIL-18与单核细胞计数增加、单核细胞表面FcγRI表达上调以及血浆中IL-8、IL-12和新蝶呤增加有关。这些研究首次证明了rHuIL-18在体内的免疫刺激活性。所描述的rHuIL-18在食蟹猴和黑猩猩中的药理学特征表明rHuIL-18在癌症治疗中具有免疫治疗潜力。
