Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Gastroenterology. 2021 Jun;160(7):2354-2366.e11. doi: 10.1053/j.gastro.2021.02.062. Epub 2021 Mar 2.
BACKGROUND & AIMS: A large unmet therapeutic need exists in inflammatory bowel disease (IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a complete IL6/IL6 receptor (IL6R) blockade is limited by profound immunosuppression. Evidence has emerged that chronic proinflammatory activity of IL6 is mainly mediated by trans-signaling via a complex of IL6 bound to soluble IL6R engaging the gp130 co-receptor without the need for membrane-bound IL6R. We have developed a decoy protein, sgp130Fc, that exclusively blocks IL6 proinflammatory trans-signaling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression.
We present a 12-week, open-label, prospective phase 2a trial (FUTURE) in 16 patients with active IBD treated with the trans-signaling inhibitor olamkicept (sgp130Fc) to assess the molecular mechanisms, safety, and effectiveness of IL6 trans-signaling blockade in vivo. We performed in-depth molecular profiling at various timepoints before and after therapy induction to identify the mechanism of action of olamkicept.
Olamkicept was well tolerated and induced clinical response in 44% and clinical remission in 19% of patients. Clinical effectiveness coincided with target inhibition (reduction of phosphorylated STAT3) and marked transcriptional changes in the inflamed mucosa. An olamkicept-specific transcriptional signature, distinguishable from remission signatures of anti-tumor necrosis factor (infliximab) or anti-integrin (vedolizumab) therapies was identified.
Our data suggest that blockade of IL6 trans-signaling holds great promise for the therapy of IBD and should undergo full clinical development as a new immunoregulatory therapy for IBD. (EudraCT no., Nu 2016-000205-36).
炎症性肠病（IBD）存在着巨大的未满足的治疗需求。抑制白细胞介素（IL）-6 似乎是有效的，但完全阻断 IL6/IL6 受体（IL6R）的治疗益处受到深刻免疫抑制的限制。有证据表明，IL6 的慢性促炎活性主要通过结合可溶性 IL6R 的 IL6 复合物与 gp130 共受体的转信号传导来介导，而不需要膜结合的 IL6R。我们已经开发了一种诱饵蛋白 sgp130Fc，它专门阻断 IL6 促炎转信号传导，并在 IBD 的临床前模型中显示出疗效，而没有免疫抑制的迹象。
我们提出了一项为期 12 周、开放标签、前瞻性 2a 期试验（FUTURE），该试验纳入了 16 例活动性 IBD 患者，使用转信号传导抑制剂 olamkicept（sgp130Fc）进行治疗，以评估 IL6 转信号传导阻断在体内的分子机制、安全性和有效性。我们在治疗诱导前后的不同时间点进行了深入的分子谱分析，以确定 olamkicept 的作用机制。
olamkicept 耐受性良好，44%的患者出现临床反应，19%的患者达到临床缓解。临床疗效与靶标抑制（磷酸化 STAT3 减少）和炎症黏膜的显著转录变化一致。鉴定出一种与抗肿瘤坏死因子（英夫利昔单抗）或抗整合素（vedolizumab）治疗的缓解特征不同的 olamkicept 特异性转录特征。
我们的数据表明，阻断 IL6 转信号传导为 IBD 的治疗提供了巨大的希望，应作为一种新的免疫调节治疗方法进行全面的临床开发。（EudraCT 编号，Nu 2016-000205-36）。
