Chen Yi-Ling, Gutowska-Owsiak Danuta, Hardman Clare S, Westmoreland Melanie, MacKenzie Teena, Cifuentes Liliana, Waithe Dominic, Lloyd-Lavery Antonia, Marquette Allison, Londei Marco, Ogg Graham
MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Institute of Biotechnology UG, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, 80-307 Gdańsk, Poland.
Sci Transl Med. 2019 Oct 23;11(515). doi: 10.1126/scitranslmed.aax2945.
Targeted inhibition of cytokine pathways provides opportunities to understand fundamental biology in vivo in humans. The IL-33 pathway has been implicated in the pathogenesis of atopy through genetic and functional associations. We investigated the role of IL-33 inhibition in a first-in-class phase 2a study of etokimab (ANB020), an IgG1 anti-IL-33 monoclonal antibody, in patients with atopic dermatitis (AD). Twelve adult patients with moderate to severe AD received a single systemic administration of etokimab. Rapid and sustained clinical benefit was observed, with 83% achieving Eczema Area and Severity Index 50 (EASI50), and 33% EASI75, with reduction in peripheral eosinophils at day 29 after administration. We noted significant reduction in skin neutrophil infiltration after etokimab compared with placebo upon skin challenge with house dust mite, reactivity to which has been implicated in the pathogenesis of AD. We showed that etokimab also inhibited neutrophil migration to skin interstitial fluid in vitro. Besides direct effects on neutrophil migration, etokimab revealed additional unexpected CXCR1-dependent effects on IL-8-induced neutrophil migration. These human in vivo findings confirm an IL-33 upstream role in modulating skin inflammatory cascades and define the therapeutic potential for IL-33 inhibition in human diseases, including AD.
对细胞因子通路的靶向抑制为在人体中理解基础生物学提供了机会。白细胞介素-33（IL-33）通路通过遗传和功能关联与特应性疾病的发病机制有关。我们在一项针对抗IL-33单克隆抗体艾托奇单抗（ANB020）的2a期首研研究中，调查了IL-33抑制在特应性皮炎（AD）患者中的作用。12名中重度AD成年患者接受了艾托奇单抗的单次全身给药。观察到快速且持续的临床获益，83%的患者实现了湿疹面积和严重程度指数改善50%（EASI50），33%的患者实现了EASI75，给药后第29天外周嗜酸性粒细胞减少。在用屋尘螨进行皮肤激发试验后，我们注意到与安慰剂相比，艾托奇单抗治疗后皮肤中性粒细胞浸润显著减少，屋尘螨反应性与AD的发病机制有关。我们表明，艾托奇单抗在体外也抑制中性粒细胞向皮肤间质液的迁移。除了对中性粒细胞迁移的直接影响外，艾托奇单抗还揭示了对IL-8诱导的中性粒细胞迁移的额外意外的CXCR1依赖性影响。这些人体体内研究结果证实了IL-33在调节皮肤炎症级联反应中的上游作用，并确定了IL-33抑制在包括AD在内的人类疾病中的治疗潜力。
