Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production.
Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production.
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发表时间：
1997
期刊：
影响因子：
20.3
通讯作者：
J. Leonard;M. Sherman;G. Fisher;L. Buchanan;G. Larsen;M. Atkins;J. Sosman;J. Dutcher;N. Vogelzang;J. Ryan
中科院分区：
文献类型：
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作者：
J. Leonard;M. Sherman;G. Fisher;L. Buchanan;G. Larsen;M. Atkins;J. Sosman;J. Dutcher;N. Vogelzang;J. Ryan
白介素12(IL-12)是细胞免疫的关键调节因子，在癌症和传染病中具有治疗潜力。在之前的第一阶段剂量递增研究中，重组人IL-12(rhIL-12)的单次测试剂量在14天后每3周连续五次静脉注射，我们表明，剂量水平高达500 ng/kg可以在可接受的安全水平下给予。基于这些结果，进行了第二阶段研究。然而，在第二阶段研究中，注射相同剂量的重组人白介素12会导致严重的毒性反应，一些患者无法耐受两次以上的连续剂量。在第二阶段研究中接受重组人白介素12治疗的17名患者中，12名患者入院治疗，2名患者死亡。一项彻底的科学调查，以确定这种意外毒性的原因，未能发现在使用的药物产品或在第一阶段和第二阶段研究中登记的患者群体之间有任何差异，这可能是毒性的巨大差异的原因。因此，调查的重点转移到了rhIL-12的给药时间表上。我们确定，在连续给药前2周单次注射rhIL-12，包括在第一阶段研究中，但不在第二阶段研究的给药时间表中，对IL-12诱导的干扰素-伽马(干扰素-γ)的产生和毒性有深远的消除作用。这种观察到的IL-12的时序依赖性毒性已经在小鼠以及非人类灵长类动物中得到证实。在这方面，在连续每日给药之前单次注射IL-12可保护小鼠和食蟹猴免受急性毒性，包括死亡率，并与减弱的干扰素-伽马反应有关。由于这种独特的生物学反应，需要仔细注意给药时间表，以确保这种极有希望的细胞因子的临床开发安全有效。
Interleukin-12 (IL-12) is a key regulator of cell-mediated immunity that has therapeutic potential in cancer and infectious disease. In a previous Phase 1 dose escalation study of a single test dose of recombinant human IL-12 (rhIL-12) followed 14 days later by cycles of five consecutive daily intravenous injections every 3 weeks, we showed that a dose level up to 500 ng/kg could be administered with acceptable levels of safety. Based on these results, a Phase 2 study was conducted. In the Phase 2 study, however, administration of rhIL-12 at this same dose level resulted in severe toxicities with some patients unable to tolerate more than two successive doses. Of the 17 patients receiving rhIL-12 in the Phase 2 study, 12 patients were hospitalized and two patients died. A thorough scientific investigation to determine the cause of this unexpected toxicity failed to identify any difference in the drug products used or the patient populations enrolled in the Phase 1 and Phase 2 studies that could have accounted for the profound difference in toxicity. The focus of the investigation therefore shifted to the schedule of rhIL-12 administration. We determined that a single injection of rhIL-12 2 weeks before consecutive dosing included in the Phase 1 study, but not in the schedule of administration in the Phase 2 study, has a profound abrogating effect on IL-12-induced interferon-gamma (IFN-gamma) production and toxicity. This observation of schedule-dependent toxicity of IL-12 has been verified in mice, as well as nonhuman primates. In this regard, a single injection of IL-12 before consecutive daily dosing protected mice and cynomolgus monkeys from acute toxicity including mortality and was associated with an attenuated IFN-gamma response. Because of this unique biologic response, careful attention to the schedule of administration is required to assure safe and effective clinical development of this highly promising cytokine.