针对系统性红斑狼疮的干扰素信号:经验教训。

IF 13 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Drugs Pub Date : 2024-06-01 Epub Date: 2024-05-28 DOI:10.1007/s40265-024-02043-2
Sarah A Jones, Eric F Morand
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引用次数: 0

摘要

治疗系统性红斑狼疮(SLE)的新药开发一直未能满足临床需求,在过去的 60 年里,只有三种治疗系统性红斑狼疮的药物获得了监管部门的批准,其中一种是专门用于治疗狼疮性肾炎的。在过去的 20 年里,人们已经清楚地认识到,在大多数系统性红斑狼疮患者体内都能重复检测到 1 型干扰素(IFN)的激活,而且 IFN 在免疫系统和靶组织中的作用与系统性红斑狼疮的致病作用是一致的。这些发现引发了大量的药物研发活动,首先是直接针对 IFN 家族细胞因子的药物,结果令人鼓舞,但效果不佳。相反,用单克隆抗体阿尼洛单抗(anifrolumab)靶向I型IFN受体,从而阻断所有IFN家族成员,在II期临床试验中取得了成效。随后又进行了两项 III 期试验,其中一项为阴性,另一项为阳性,这反映出在这种复杂的疾病中很难从试验中获得结果。尽管如此,权衡证据后,从 2021 年起,阿尼洛单抗在多个司法管辖区获得批准。针对 1 型 IFN 通路的多种方法随后进行了积极的 II 期临床试验,包括针对产生 IFN 的细胞的抗体,以及针对 IFN 信号所需的受体激酶 TYK2 的小分子药物。尽管面临重重障碍,但很明显,IFN靶向治疗系统性红斑狼疮的前景依然光明。IFN靶向疗法在系统性红斑狼疮中的应用为该疾病的整体药物研发提供了借鉴。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Targeting Interferon Signalling in Systemic Lupus Erythematosus: Lessons Learned.

Targeting Interferon Signalling in Systemic Lupus Erythematosus: Lessons Learned.

The development of new medicines for systemic lupus erythematosus (SLE) has not addressed unmet clinical need, with only three drugs receiving regulatory approval for SLE in the last 60 years, one of which was specifically licensed for lupus nephritis. In the last 20 years it has become clear that activation of type 1 interferons (IFN) is reproducibly detected in the majority of SLE patients, and the actions of IFN in the immune system and on target tissues is consistent with a pathogenic role in SLE. These findings led to considerable drug discovery activity, first with agents directly targeting IFN family cytokines, with results that were encouraging but underwhelming. In contrast, targeting the type I IFN receptor with the monoclonal antibody anifrolumab, thereby blocking all IFN family members, was effective in a phase II clinical trial. This led to a pair of phase III trials, one of which was negative and the other positive, reflecting the difficulty of obtaining outcomes from trials in this complex disease. Nonetheless, the balance of evidence resulted in approval of anifrolumab in multiple jurisdictions from 2021 onwards. Multiple approaches to targeting the type 1 IFN pathway have subsequently had positive phase II clinical trials, including antibodies targeting cells that produce IFN, and small molecules targeting the receptor kinase TYK2, required for IFN signalling. Despite multiple hurdles, it is clear that IFN targeting in SLE is here to stay. The story of IFN-targeting therapy in SLE has lessons for drug development overall in this disease.

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来源期刊
Drugs
Drugs 医学-毒理学
CiteScore
22.70
自引率
0.90%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Drugs is a journal that aims to enhance pharmacotherapy by publishing review and original research articles on key aspects of clinical pharmacology and therapeutics. The journal includes: Leading/current opinion articles providing an overview of contentious or emerging issues. Definitive reviews of drugs and drug classes, and their place in disease management. Therapy in Practice articles including recommendations for specific clinical situations. High-quality, well designed, original clinical research. Adis Drug Evaluations reviewing the properties and place in therapy of both newer and established drugs. AdisInsight Reports summarising development at first global approval. Moreover, the journal offers additional digital features such as animated abstracts, video abstracts, instructional videos, and podcasts to increase visibility and educational value. Plain language summaries accompany articles to assist readers with some knowledge of the field in understanding important medical advances.
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