Objective Interleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone. Methods Preclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease-relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated. Results IL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals. Conclusions These data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions. Trial registration number NCT02141763; Results.

中文翻译：

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bimekizumab 在银屑病关节炎中的双重 IL-17A 和 IL-17F 中和作用：来自临床前实验和随机安慰剂对照临床试验的证据表明 IL-17F 有助于人类慢性组织炎症

目的 白细胞介素 (IL)-17A 已成为驱动免疫介导的炎症性疾病组织病理学的关键。具有 50% 序列同源性和重叠生物学功能的 IL-17F 的作用仍然不太清楚。我们假设 IL-17F 与 IL-17A 一起导致慢性组织炎症，并且与单独抑制 IL-17A 相比，双重中和可能导致对炎症的更深入抑制。方法 临床前实验使用疾病相关的人类细胞评估了 IL-17A 和 IL-17F 在组织炎症中的作用。一项安慰剂对照的概念验证 (PoC) 临床试验将银屑病关节炎 (PsA) 患者随机分配至 bimekizumab (n=39) 或安慰剂 (n=14)。多次给药的安全性、药代动力学和临床疗效（第 0、3、6 周（240 毫克/160 毫克/160 毫克；80 毫克/40 毫克/40 毫克；研究了 160 mg/80 mg/80 mg 和 560 mg/320 mg/320 mg)) 的 bimekizumab，一种中和 IL-17A 和 IL-17F 的人源化单克隆 IgG1 抗体。结果 IL-17F 在皮肤和关节细胞中诱导了对 IL-17A 的性质相似的炎症反应。与单独抑制 IL-17A 或 IL-17F 相比，用 bimekizumab 中和 IL-17A 和 IL-17F 能更有效地抑制体外细胞因子反应和中性粒细胞趋化性。PoC 试验符合两个预先指定的疗效成功标准，并在关节和皮肤中显示出快速、深刻的反应（第 8 周前三个剂量与安慰剂的汇总：美国风湿病学会 20% 反应标准 80.0% 与 16.7%（后验概率 >99%） )；银屑病面积和严重性指数 100% 响应标准 86.7% 与 0%)，持续至第 20 周，没有意外的安全信号。结论 这些数据支持 IL-17F 作为人类慢性组织炎症的关键驱动因素，以及在 PsA 和相关疾病中双重中和 IL-17A 和 IL-17F 的基本原理。试验注册号NCT02141763；结果。