Identification of Granulocyte Colony-Stimulating Factor and Interleukin-6 as Candidate Biomarkers of CBLB502 Efficacy as a Medical Radiation Countermeasure
Identification of Granulocyte Colony-Stimulating Factor and Interleukin-6 as Candidate Biomarkers of CBLB502 Efficacy as a Medical Radiation Countermeasure
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DOI：
10.1124/jpet.112.196071
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发表时间：
2012-11-01
影响因子：
3.5
通讯作者：
Feinstein, Elena
中科院分区：
文献类型：
--
作者：
Krivokrysenko, Vadim I.;Shakhov, Alexander N.;Feinstein, Elena
鉴于核和放射性紧急情况的风险不断增加，迫切需要开发安全、易于管理且有效预防和/或减轻由急性高剂量辐射暴露引起的潜在致命组织损伤的医疗辐射对策（MRC）。由于MRCs对这一适应症的疗效无法在人类中进行伦理学测试，因此此类药物的开发受食品和药物管理局的动物疗效规则指导。根据这一规则，基于药物对相应物种中疗效生物标志物的作用的等效性，可以从实验确定的动物有效剂量预测人类有效剂量。因此，根据动物有效性规则，有效性生物标志物的鉴定对于药物开发至关重要。CBLB 502是沙门氏菌鞭毛蛋白的截短衍生物，其通过触发Toll样受体5（TLR 5）信号传导起作用，并且目前正在开发作为MRC。在这里，我们报告了两种细胞因子，粒细胞集落刺激因子（G-CSF）和白细胞介素-6（IL-6），作为CBLB 502的辐射防护/缓解功效的候选生物标志物的鉴定。CBLB 502对G-CSF和IL-6的诱导1）是严格的TLR 5依赖性的，2）在未辐照和辐照的哺乳动物（包括非人灵长类动物）中以CBLB 502剂量依赖性方式在其有效剂量范围内发生，3）对于CBLB 502拯救辐照动物免于死亡的能力至关重要。在评估CBLB 502对人体G-CSF和IL-6水平的影响后，这些生物标志物将有助于准确预测人体有效CBLB 502剂量，这是开发这种前瞻性辐射对策的关键步骤。
Given an ever-increasing risk of nuclear and radiological emergencies, there is a critical need for development of medical radiation countermeasures (MRCs) that are safe, easily administered, and effective in preventing and/or mitigating the potentially lethal tissue damage caused by acute high-dose radiation exposure. Because the efficacy of MRCs for this indication cannot be ethically tested in humans, development of such drugs is guided by the Food and Drug Administration's Animal Efficacy Rule. According to this rule, human efficacious doses can be projected from experimentally established animal efficacious doses based on the equivalence of the drug's effects on efficacy biomarkers in the respective species. Therefore, identification of efficacy biomarkers is critically important for drug development under the Animal Efficacy Rule. CBLB502 is a truncated derivative of the Salmonella flagellin protein that acts by triggering Toll-like receptor 5 (TLR5) signaling and is currently under development as a MRC. Here, we report identification of two cytokines, granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), as candidate biomarkers of CBLB502's radioprotective/mitigative efficacy. Induction of both G-CSF and IL-6 by CBLB502 1) is strictly TLR5-dependent, 2) occurs in a CBLB502 dose-dependent manner within its efficacious dose range in both nonirradiated and irradiated mammals, including nonhuman primates, and 3) is critically important for the ability of CBLB502 to rescue irradiated animals from death. After evaluation of CBLB502 effects on G-CSF and IL-6 levels in humans, these biomarkers will be useful for accurate prediction of human efficacious CBLB502 doses, a key step in the development of this prospective radiation countermeasure.