A Phase 1 Clinical Trial of Siltuximab for the Treatment of Antibody-Mediated Rejection after Lung Transplantation

项目摘要/摘要 肺移植后的长期结果仍然令人失望，中位生存期为6.7年。 慢性同种异体肺移植功能障碍(Clad)是肺移植后第一年以上死亡的主要原因。 移植。抗体介导的排斥反应(AMR)在肺移植后得到越来越多的认可， 是由不匹配的人类白细胞抗原(HLA)的供者特异性抗体(DSA)引起的，经常 结果是衣冠楚楚和死亡。最近对AMR进行强化监测的多中心研究报告了一种发病率 超过25%。AMR的治疗通常集中在抗体耗竭和预防额外抗体的产生上。 发展。已经使用了各种组合，包括大剂量皮质类固醇、静脉免疫 球蛋白(IVIG)、利妥昔单抗、卡非佐米、抗胸腺细胞球蛋白(ATG)和血浆置换(PLEX)。然而， 目前还没有随机对照试验来指导治疗，AMR后的结果令人沮丧。 同种异体肾移植术后一年存活率约为50%，两年存活率仅为20%。IL-6，最初 被确认为B细胞刺激因子2(BSF-2)，是一种多效性细胞因子，推动有害的炎症， 同种异体免疫和纤维化反应。与其他细胞因子一起，IL-6负责正常 抗体的产生，对毛囊辅助T细胞的诱导和IL-21的产生是至关重要的 它调节免疫球蛋白的合成。IL-6对B细胞分化为浆母细胞也是至关重要的 提高浆母细胞存活率。这些特性使IL-6成为一种特别有吸引力的细胞因子 AMR的管理。检测IL-6信号阻断在治疗高血压中的作用的人体研究 肾移植后的AMR显示出有希望的结果，即使在难治性病例中也是如此。我们用了IL-6 在我们中心的极少数AMR肺移植受者中，信号阻断是令人鼓舞的 结果。我们的主要假设是在常规免疫抑制治疗的基础上加用IL-6信号传导阻断 对于AMR来说，将改善临床结果。然而，评估这种方法的安全性是必要的 在更大的临床试验中检查疗效，因为感染是最常见的严重不良事件 与IL-6信号传导受阻有关，也是肺移植后各时间点的常见死亡原因。 因此，我们建议在常规治疗的基础上，使用抗IL-6的单抗Siltuximab进行一期临床试验 AMR的免疫抑制治疗，以检查安全性并确定治疗AMR的最佳剂量。 主要终点是安全性和耐受性，次要终点包括药效学和 与AMR相关的功能生物学指标(例如，DSA、无细胞DNA)。这项试验的数据将为 设计一项评估疗效的未来第二阶段临床试验。精心设计和实施的临床试验 对于改善肺移植后的结果是必要的。

PROJECT SUMMARY/ABSTRACT Long-term outcomes after lung transplantation remain disappointing, and the median survival is 6.7 years. Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. Antibody-mediated rejection (AMR), which is increasingly recognized after lung transplantation, is caused by donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) and frequently results in CLAD and death. Recent multicenter studies using intensive monitoring for AMR report an incidence over 25%. Treatment for AMR has generally focused on antibody-depletion and prevention of additional antibody development. Various combinations have been used including high-dose corticosteroids, intravenous immune globulin (IVIG), Rituximab, Carfilzomib, anti-thymocyte globulin (ATG), and plasma exchange (PLEX). However, there have been no randomized controlled trials to guide management, and outcomes after AMR are dismal. One-year allograft survival after AMR is approximately 50%, and 2-year survival is only 20%. IL-6, initially identified as B-cell stimulating factor 2 (BSF-2), is a pleiotropic cytokine that drives deleterious inflammatory, alloimmune, and fibrogenic responses. In conjunction with other cytokines, IL-6 is responsible for normal antibody production and is critical for the induction of follicular helper T-cells as well as the production of IL-21 which regulates immunoglobulin synthesis. IL-6 is also crucial for B-cell differentiation into plasmablasts and for enhancing plasmablast survival. These characteristics make IL-6 an especially attractive cytokine to target in the management of AMR. Human studies examining the role of IL-6 signaling blockade in the management of AMR after kidney transplantation have shown promising results, even in refractory cases. We have used IL-6 signaling blockade in a very small number of lung transplant recipients with AMR at our center with encouraging results. Our principal hypothesis is that IL-6 signaling blockade added to routine immunosuppressive treatment for AMR would improve clinical outcomes. However, evaluating the safety of this approach is necessary before examining efficacy in larger clinical trials because infections are the most common serious adverse events associated with IL-6 signaling blockade and a common cause of death at all timepoints after lung transplantation. Thus, we propose a Phase 1 clinical trial using Siltuximab, a monoclonal antibody to IL-6, in addition to routine immunosuppressive therapy for AMR to examine safety and define the optimal dose for the treatment of AMR. The primary endpoint is safety and tolerability, and secondary endpoints include pharmacodynamics and functional biological measures relevant to AMR (e.g., DSA, cell-free DNA). Data from this trial will inform the design of a future Phase 2 clinical trial that assesses efficacy. Carefully designed and implemented clinical trials are necessary to improve outcomes after lung transplantation.