MedImmune, Translational Sciences, One MedImmune Way, Gaithersburg, MD 20878, USA.
Arthritis Res Ther. 2010;12 Suppl 1(Suppl 1):S6. doi: 10.1186/ar2887. Epub 2010 Apr 14.
Type I interferons are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Type I interferon-inducible mRNAs are widely and concordantly overexpressed in the periphery and involved tissues of a subset of SLE patients, and provide utility as pharmacodynamic biomarkers to aid dose selection, as well as potential indicators of patients who might respond favorably to anti-IFNα therapy in SLE. We implemented a three-tiered approach to identify a panel of type I interferon-inducible mRNAs to be used as potential pharmacodynamic biomarkers to aid dose selection in clinical trials of sifalimumab, an anti-IFNα monoclonal antibody under development for the treatment of SLE. In a single-dose escalation phase 1 trial, we observed a sifalimumab-specific and dose-dependent inhibition of the overexpression of type I interferon-inducible mRNAs in the blood of treated subjects. Inhibition of expression of type I interferon-inducible mRNAs and proteins was also observed in skin lesions of SLE subjects from the same trial. Inhibiting IFNα resulted in a profound downstream effect in these SLE subjects that included suppression of mRNAs of B-cell activating factor belonging to the TNF family and the signaling pathways of TNFα, IL-10, IL-1β, and granulocyte-macrophage colony-stimulating factor in both the periphery and skin lesions. A scoring method based on the expression of type I interferon-inducible mRNAs partitioned SLE patients into two distinct subpopulations, which suggests the possibility of using these type I interferon-inducible genes as predictive biomarkers to identify SLE patients who might respond more favorably to anti-type I interferon therapy.
I 型干扰素与系统性红斑狼疮(SLE)的发病机制有关。I 型干扰素诱导的 mRNA 在一部分 SLE 患者的外周血和受累组织中广泛且一致地过度表达,它们可作为药效动力学生物标志物,有助于选择剂量,并且可能是对 SLE 中抗 IFNα 治疗有良好反应的患者的潜在指标。我们采用了一种三级方法来鉴定一组 I 型干扰素诱导的 mRNA,作为潜在的药效动力学生物标志物,以辅助西法利单抗(一种用于治疗 SLE 的正在开发的抗 IFNα 单克隆抗体)临床试验中的剂量选择。在一项单剂量递增的 1 期临床试验中,我们观察到在接受治疗的患者的血液中,西法利单抗特异性地且呈剂量依赖性抑制 I 型干扰素诱导的 mRNA 的过度表达。在同一试验中的 SLE 患者的皮肤损伤中也观察到 I 型干扰素诱导的 mRNA 和蛋白的表达抑制。抑制 IFNα 在这些 SLE 患者中产生了深远的下游效应,包括抑制 B 细胞激活因子属于 TNF 家族和 TNFα、IL-10、IL-1β 和粒细胞-巨噬细胞集落刺激因子的信号通路的 mRNAs,在周围组织和皮肤损伤中均如此。基于 I 型干扰素诱导的 mRNA 表达的评分方法将 SLE 患者分为两个不同的亚群,这表明这些 I 型干扰素诱导的基因可能被用作预测生物标志物,以识别可能对 I 型干扰素治疗反应更好的 SLE 患者。