AP-HP, Groupement Hospitalier Pitié-Salpêtrière, Service de médecine interne 2, Institut E3M, Centre de Référence National pour le Lupus et le Syndrome des Antiphospholipides, 83 boulevard de l'hôpital, 75013, Paris, France.
Drugs. 2015 May;75(8):835-46. doi: 10.1007/s40265-015-0394-x.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown aetiology that can be debilitating and life threatening. As new insights are gained into the underlying pathology of SLE, there have been an unprecedented number of new agents under development to treat the disease via a diverse range of targets. One such class of emerging agents target interferon (IFN) signalling. In this article, we review the preclinical evidence that the inhibition of the secretion and downstream effectors of both IFN-α and IFN-γ may be effective for the treatment of SLE. The primary agents that are currently in clinical development to treat SLE via the targeting of interferon pathways are monoclonal neutralising antibodies (Mab) that bind to and neutralise IFN-γ (AMG 811), IFN-α (sifalimumab, rontalizumab and AGS-009) or its receptor (anifrolumab), and IFN-α kinoid, which is a drug composed of inactivated IFN-α molecules coupled to the keyhole limpet haemocyanin protein. Phase I and II trials have demonstrated acceptable short-term safety with no increase in severe viral infections or reactivation, favourable pharmacokinetic profiles and an inhibition of IFN-associated gene overexpression; however, the impact of these drugs on disease activity must still be assessed in phase III clinical trials. This review concludes with a summary of the challenges that are inherent to this approach to managing SLE.
系统性红斑狼疮（SLE）是一种病因不明的慢性自身免疫性疾病，可能导致身体虚弱和危及生命。随着对 SLE 潜在病理学的深入了解，已经有大量新型药物正在开发中，通过多种靶点来治疗这种疾病。其中一类新兴药物针对干扰素（IFN）信号通路。在本文中，我们回顾了抑制 IFN-α和 IFN-γ分泌及其下游效应物可能对治疗 SLE 有效的临床前证据。目前，通过靶向干扰素通路治疗 SLE 的主要临床开发药物是单克隆中和抗体（Mab），这些抗体可以结合并中和 IFN-γ（AMG 811）、IFN-α（sifalimumab、rontalizumab 和 AGS-009）或其受体（anifrolumab），以及 IFN-α类似物，这是一种由失活的 IFN-α分子与 keyhole limpet haemocyanin 蛋白偶联而成的药物。I 期和 II 期临床试验表明，这些药物具有良好的短期安全性，没有增加严重病毒感染或再激活的风险，具有有利的药代动力学特征，并抑制 IFN 相关基因的过度表达；然而，这些药物对疾病活动的影响仍需在 III 期临床试验中进行评估。本文的结论是对这种治疗 SLE 方法所固有的挑战进行了总结。
