Targeting Inflammation and Alloimmunity in Lung Transplant Recipients With Clazakizumab

项目摘要/摘要 肺移植后的5年存活率只有53%，慢性移植肺功能障碍(CLAD) 成为取得更好长期成果的主要障碍。显然，目前的护理标准 免疫抑制疗法正在使肺移植受者失败，还有一个亟待改善的迫切需要。 生死存亡。原发性移植物功能障碍(PGD)、急性细胞排斥反应(ACR)、抗体介导的排斥反应 (AMR)和供者特异性抗体(DSA)的产生是公认的 包覆层的发展。此外，机制研究将这些炎症和同种异体免疫损伤与 以包皮为特征的纤维性病变。IL-6是一种多效性细胞因子，推动这些有害的炎症反应， 因此，免疫和致纤维化反应是一种特别吸引靶点的细胞因子。事实上，在试验性的 模型中，IL-6信号阻断已被证明扭曲Th17/Treg平衡，有利于调节细胞 承诺，从而扩大Treg数量，减少同种异体移植排斥反应，并减少记忆B细胞 数量和抗体形成(初级和召回)。在人体试验中，抑制IL-6R可降低同种异体抗体水平 高度致敏的同种异体肾移植受者，移植肾和患者存活率的改善 最严重的慢性抗体介导的排斥反应。这些数据构成了我们假设的基础 肺移植术后早期抑制IL-6将诱导一种保护/抗炎环境，这种环境将长期- 对宿主免疫系统和同种异体移植物的持久影响导致长期移植物和患者的改善 生死存亡。为了验证这一假设，我们建议进行阶段2，多中心，双盲，随机， 早期应用Clazakizumab抑制IL-6对无包膜同种异体移植物影响的安慰剂对照试验 肺移植后的存活率。Clazakizumab(CSL Behring)是一种基因工程的高亲和力， 与IL-6结合的人源化单抗(IgG1)是IL-6的完全竞争性拮抗剂- 诱导细胞功能。临床试验的主要终点是1)包裹、2)再次移植、 或3)死亡。关键辅助终端包括PGD、ACR、AMR、DSA。此外，我们计划利用富人 这项临床试验将产生的临床数据和人类生物样本，以确定几种非侵入性 作为风险评估、诊断和预测性检测策略的生物标志物。最后，我们将进行机械化 解释临床试验中观察到的clazakizumab效果的研究。这场审判是第一次 IL-6受体阻滞剂在肺移植中的应用及对临床实践的潜在改变和改进 肺移植受者的结局。如果CZK疗法成功，我们的全面和综合 机制研究将使我们能够阐明改善移植物结果的机制。如果治疗失败，我们会 能够理解其中的原因。无论如何，对同种异体月骨损伤机制的洞察 慢性同种异体肺移植功能障碍可能导致新的预防或治疗方案。

PROJECT SUMMARY/ABSTRACT The 5-year survival after lung transplantation is a dismal 53% and chronic lung allograft dysfunction (CLAD) has emerged as the primary obstacle to better long-term outcomes. Clearly, current standard-of-care immunosuppressive regimens are failing lung transplant recipients, and there is a critical unmet need to improve survival. Primary graft dysfunction (PGD), episodes of acute cellular rejection (ACR), antibody-mediated rejection (AMR), and the development of donor-specific antibodies (DSA) are widely recognized risk factors for the development of CLAD. Furthermore, mechanistic studies link these inflammatory and alloimmune injuries to the fibrotic lesions that characterize CLAD. IL-6 is a pleiotropic cytokine that drives these deleterious inflammatory, immune, and fibrogenic responses thus, an especially attractive cytokine to target. Indeed, in experimental models, IL-6 signaling blockade has been shown to skew the Th17/Treg balance in favor of regulatory cell commitment thereby expanding Treg numbers, reducing allograft rejection, and diminishing memory B cell numbers and antibody formation (primary and recall). In human trials, IL-6R inhibition reduced alloantibody levels in highly sensitized kidney allograft recipients and improved graft and patient survival in kidney recipients with the most severe form of chronic antibody-mediated rejection. These data form the basis of our hypothesis that early IL-6 inhibition after lung transplantation will induce a protective/anti-inflammatory milieu that will have long- lasting effects on the host's immune system and allograft resulting in improved long-term graft and patient survival. To test this hypothesis, we propose to conduct a phase 2, multicenter, double blind, randomized, placebo-controlled trial examining the impact of early IL-6 inhibition with clazakizumab on CLAD-free allograft survival after lung transplantation. Clazakizumab (CSL Behring) is a genetically engineered, high affinity, humanized monoclonal antibody (IgG1) which binds to IL-6 and is a full and competitive antagonist of IL-6- induced cell function. The primary endpoint of the clinical trial is a composite of 1) CLAD, 2) re-transplantation, or 3) death. Key secondary endpoints include PGD, ACR, AMR, DSA. Furthermore, we plan to leverage the rich clinical data and human biospecimens that this clinical trial will generate to define the utility of several noninvasive biomarkers as risk assessment, diagnostic, and predictive testing strategies. Finally, we will conduct mechanistic studies to explain the effects of clazakizumab observed in the clinical trial. This trial represents the first application of IL-6 blockade in lung transplantation and has the potential change clinical practice and improve outcomes for lung transplant recipients. If CZK therapy is successful, our comprehensive and integrated mechanistic studies will allow us to elucidate mechanisms of improved graft outcomes. If therapy fails, we will be able to understand why. Either way, insights into the mechanisms of alloimune injury and chronic lung allograft dysfunction could lead to new preventative or treatment regimens.