Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY; Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
Innovaderm Research, Montreal, Quebec, Canada.
J Allergy Clin Immunol. 2019 Jan;143(1):155-172. doi: 10.1016/j.jaci.2018.08.022. Epub 2018 Sep 5.
Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2-driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases.
This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD).
Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks.
Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4-16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and -10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P < .001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and T17/T22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P = .001; week 16, P = .0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs.
Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.
度普利尤单抗是一种白介素 4 受体 α 单克隆抗体，可抑制白介素 4 和白介素 13 的信号传导，这是 2 型炎症的关键驱动因素，其在特应性/过敏性疾病患者中的疗效证明了这一点。
这项安慰剂对照、双盲试验（NCT01979016）评估了度普利尤单抗对中重度特应性皮炎（AD）患者的皮肤病变和非病变表型的分子/细胞以及全身性 2 型生物标志物的疗效、安全性和影响。
对 54 名患者进行了皮肤活检标本和血液评估，这些患者按 1:1 随机分配至每周皮下接受 200mg 度普利尤单抗或安慰剂治疗 16 周。
度普利尤单抗（与安慰剂相比）显著改善了 AD 的临床体征和症状，具有良好的耐受性，并逐渐使病变转录组向非病变表型转变（第 4-16 周）。基于荟萃分析衍生的 AD 转录组（病变和非病变皮肤之间差异表达的基因）的平均改善度分别为 68.8%和 110.8%（第 4 和 16 周，均 P < 0.001）。度普利尤单抗显著降低了与 2 型炎症（IL13、IL31、CCL17、CCL18 和 CCL26）、表皮过度增生（角蛋白 16 [K16]和 MKi67）、T 细胞、树突状细胞（ICOS、CD11c 和 CTLA4）和 T17/T22 活性（IL17A、IL-22 和 S100As）相关的基因表达，并同时增加了表皮分化、屏障和脂质代谢基因（丝聚蛋白[FLG]、兜甲蛋白[LOR]、紧密连接蛋白和 ELOVL3）的表达。与安慰剂相比，度普利尤单抗降低了病变表皮厚度（第 4 周，P = 0.001；第 16 周，P = 0.0002）。临床和组织学指标的改善与基因表达的调节显著相关。度普利尤单抗还显著抑制了 2 型血清生物标志物，包括 CCL17、CCL18、periostin 以及总和过敏原特异性 IgE。
度普利尤单抗通过白介素 4 受体 α 阻断抑制白介素 4/白介素 13 信号传导，显著且逐渐改善疾病活动度，抑制炎症的细胞/分子皮肤标志物和全身性 2 型炎症标志物，并逆转 AD 相关的表皮异常。
