Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Department of Dermatology, Tokyo Medical University, Tokyo, Japan.
J Dermatol. 2024 Nov;51(11):1379-1391. doi: 10.1111/1346-8138.17449. Epub 2024 Oct 7.
Inflammatory diseases that are driven by several pro-inflammatory cytokines has resulted in in the development of targeted therapies across different disease settings. Interleukin (IL)-36 cytokines have been implicated in several inflammatory diseases. In this review we describe the scientific evidence surrounding the use of the IL-36 receptor (IL-36R)-targeting antibody, spesolimab, in IL-36-mediated skin diseases: generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), hidradenitis suppurativa, and Netherton syndrome (NS). Spesolimab, a high affinity, specific, humanized, antagonistic immunoglobulin G1 antibody, targets the IL-36R at a binding site distinct from its agonists, IL-36α/β/γ, and at least one endogenous antagonist, IL-36R antagonist. In vitro and in vivo data for spesolimab show effective inhibition of IL-36R-mediated signaling pathways, and six Phase I studies in healthy volunteers presented a favorable safety and pharmacokinetic (PK) profile, leading to the development of a clinical trial program to evaluate spesolimab in the treatment of IL-36R-mediated diseases. Six studies (including an expanded access program) have evaluated the efficacy, safety, PKs, and pharmacogenomics of spesolimab in patients with GPP flares. Spesolimab treatment of GPP flares resulted in rapid and sustained improvements in pustular and skin clearance, and clinically significant improvements in patient-reported symptoms and quality of life. Spesolimab also significantly reduces the risk of GPP flares and flare occurrence, preventing disease worsening and has a favorable safety profile. There have been three trials of spesolimab in PPP; further evaluation is needed to better define those patients who might benefit from the treatment. A trial of spesolimab in NS is ongoing, while other spesolimab trials suggest that IL-36 may only play a secondary role in the pathogenesis of atopic dermatitis. In conclusion, research into spesolimab has provided much needed insight into the role of IL-36 in the human immune system and the mechanism behind IL-36-mediated inflammatory diseases. Spesolimab provides an efficacious targeted treatment for GPP, a disease with a high unmet medical need.
几种促炎细胞因子驱动的炎症性疾病已经导致针对不同疾病情况的靶向治疗的发展。白细胞介素 (IL)-36 细胞因子与几种炎症性疾病有关。在这篇综述中，我们描述了围绕使用 IL-36 受体 (IL-36R)-靶向抗体 spesolimab 治疗 IL-36 介导的皮肤疾病的科学证据：全身性脓疱性银屑病 (GPP)、掌跖脓疱病 (PPP)、化脓性汗腺炎和 Netherton 综合征 (NS)。Spesolimab 是一种高亲和力、特异性、人源化、拮抗 IgG1 抗体，靶向 IL-36R 的结合位点与其激动剂 IL-36α/β/γ 不同，并且与至少一种内源性拮抗剂 IL-36R 拮抗剂结合。Spesolimab 的体外和体内数据显示对 IL-36R 介导的信号通路具有有效抑制作用，并且在健康志愿者中进行的六项 I 期研究呈现出良好的安全性和药代动力学 (PK) 特征，从而开展了一项临床试验计划来评估 spesolimab 治疗 IL-36R 介导疾病的疗效。六项研究（包括扩展访问计划）评估了 spesolimab 在 GPP 发作患者中的疗效、安全性、PK 和药物基因组学。Spesolimab 治疗 GPP 发作可迅速和持续改善脓疱和皮肤清除率，并在患者报告的症状和生活质量方面具有显著改善。Spesolimab 还显著降低 GPP 发作和发作发生的风险，防止疾病恶化，并具有良好的安全性。在 PPP 中有三项 spesolimab 试验；需要进一步评估以更好地定义那些可能从治疗中受益的患者。一项 spesolimab 在 NS 的试验正在进行中，而其他 spesolimab 试验表明 IL-36 可能仅在特应性皮炎的发病机制中起次要作用。总之，对 spesolimab 的研究为 IL-36 在人类免疫系统中的作用以及 IL-36 介导的炎症性疾病的机制提供了急需的见解。Spesolimab 为 GPP 提供了一种有效的靶向治疗方法，GPP 是一种具有高度未满足医疗需求的疾病。
