I型干扰素靶向治疗有望用于狼疮…

I型干扰素靶向治疗有望用于狼疮治疗

作者：Kalunian KC, et al.
翻译：北医三院柴静（chaijing16@aliyun.com）
摘要：系统性红斑狼疮临床试验的研究药物过去一直集中在靶点为失调的B及T淋巴细胞药物上；但是，进来转化医学研究关于狼疮固有免疫系统调节异常的重要发现促使了针对干扰素临床试验的出现。在活动性系统性红斑狼疮患者中已经有3种靶向I型干扰素生物制剂有效性和安全性得到检验；这些II期试验已经检验了下调干扰素相关基因表达（干扰素谱）减少狼疮临床负担的假说。Rontalizumab，抗干扰素α单克隆抗体，已被研究用于停止使用免疫抑制剂的患者。通过2项结果评估该研究未能证明其有效性。但是，在低干扰素谱患者，Rontalizumab治疗患者应答率更高，糖皮质激素使用更少。Sifalimumab，另一种抗干扰素α单克隆抗体，被研究用于保持标准治疗的患者。该研究显示2种剂量的Sifalimumab治疗的患者效果明显更好；在高干扰素谱患者中差异更显著。在一个与Sifalimumab研究设计及人群类似的研究中，anifrolumab，结合I型干扰素受体的单克隆抗体，被研究用于保持标准治疗的患者。该研究中，1个剂量组证明有效而次要研究终点两组均有统计学意义。1个测试剂量组口服激素达到减量至每天≤7.5mg且在该组中器官特异性结局明显改善。所有研究中，未发现严重副作用存在有意义的差异；虽然，带状疱疹感染在sifalimumab和anifrolumab治疗患者中增多但流感在anifrolumab治疗患者中增多。目前Anifrolumab在Ⅲ期试验重要阶段。数据看起来支持该观念: 在狼疮患者中I型干扰素靶向治疗临床有效且安全。很快将得到进一步的Anifrolumab三期临床试验数据。既然树突状细胞和toll样受体能够影响干扰素产生，其他药物研发应该考虑针对树突状细胞和toll样受体。

附原文：Clinical trials of investigational agents in systemic lupus erythematosus (SLE) have focused on targeting dysregulated B and T cells; however, recent translational research findings of the importance of the dysregulation of the innate immune system in SLE have led to clinical trials that target interferon. Three biologics that target type I interferons have been tested for their efficacy and safety in active SLE patients; these phase II trials have tested the hypothesis that down-regulation of interferon-regulated gene expression (the interferon signature) lessen the clinical burden of SLE. Rontalizumab, an anti-interferon-α monoclonal antibody, was studied in patients who had discontinued immunosuppressants. This study failed to show efficacy as assessed by both two outcome assessments; however, in low interferon signature patients, response was higher andcorticosteroid usage was less in rontalizumab-treated patients. Sifalimumab, another anti-interferon-α monoclonal antibody, was studied in patients who remained on standard of care therapy. This study showed significantly better efficacy in patients treated with two sifalimumab dosages; significant differences were seen in the high interferon signature group. In a similar design and in a similar population as the sifalimumab study, anifrolumab, a monoclonal antibody that binds to a type I interferon receptor, was studied in patients who remained on standard of care therapy. In this study, one dosage group demonstrated efficacy and statistically significant effects were achieved in both tested dosage groups with secondary end points. Oral corticosteroid reduction to ≤7.5 mg daily was achieved in one of the tested dosage groups and organ-specific outcomes were significantly improved in that same group. For all studies, no significant differences in serious adverse effects were seen; although, herpes zoster infections were increased in sifalimumab- and anifrolumab-treated patients and influenza rates were increased in anifrolumab-treated patients. Anifrolumab is currently in pivotal phase III studies. Data appear to support the concept that targeting type I interferon in SLE patients associates with clinical efficacy and safety. Further data are forthcoming from ongoing phase III clinical trials of anifrolumab. Other drug development efforts should be considered that targetplasmacytoid dendritic cells and toll like receptors given the effects these components have on interferon production.

引自：Kalunian KC. Interferon-targeted therapy in systemic lupus erythematosus: Is this an alternative to targeting B and T cells? Lupus. 2016 Sep;25(10):1097-101. doi: 10.1177/0961203316652495.