Targeting Inflammation and Alloimmunity in Lung Transplant Recipients With Clazakizumab

用 Clazakizumab 治疗肺移植受者的炎症和同种免疫

• 批准号: 10488647
• 负责人: Ramsey Hachem
• 金额: $ 306.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488647
• 关键词: Acute; Adrenal Cortex Hormones; Affect; Affinity; Allografting; Anti-Inflammatory Agents; Antibody Formation; Assessment tool; Autoantibodies; B cell differentiation; Binding; Biological Markers; Bronchiolitis; Canada; Categories; Cell Count; Cell physiology; Cells; Cessation of life; Chronic; Chronic Childhood Arthritis; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Complement-Dependent Cytotoxicity; Data; Development; Diagnostic tests; Disease; Dose; Double-Blind Method; Epitopes; Equilibrium; Experimental Models; FOXP3 gene; Fibrosis; Functional disorder; Future; Generations; Genetic Engineering; Hour; Human; IgG1; Immune; Immune response; Immune system; Immunity; Immunosuppression; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Interleukin-6; Interleukins; Isoantibodies; Kidney; Lead; Lesion; Link; Lung; Lung Transplantation; Lymphocyte; Maintenance; Mediating; Mediator of activation protein; Memory B-Lymphocyte; Morbidity - disease rate; Nature; Outcome; Pathogenicity; Pathway interactions; Patients; Phase; Placebos; Plasmablast; Production; Quality of life; Randomized; Randomized Controlled Trials; Refractory; Regimen; Regulatory T-Lymphocyte; Reperfusion Injury; Risk Assessment; Risk Factors; Saline; Signal Transduction; Surface; Survival Rate; T cell response; T-Lymphocyte; Tacrolimus; Testing; Time; Tissues; Transplant Recipients; Transplantation; Transplantation Immunology; Treatment Protocols; allograft rejection; antagonist; antibody-dependent cell cytotoxicity; antibody-mediated rejection; cell free DNA; clinical practice; cytokine; design; donor-specific antibody; graft dysfunction; humanized monoclonal antibodies; immunoregulation; improved; improved outcome; inflammatory milieu; insight; isoimmunity; kidney allograft; lung allograft; lung injury; mycophenolate mofetil; nano-string; novel; post-transplant; predictive test; preservation; prevent; primary endpoint; programs; prospective; randomized placebo controlled trial; randomized placebo-controlled clinical trial; receptor; response; secondary endpoint; standard of care; transcriptomics; transplant centers

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.

项目概要/摘要 肺移植后的 5 年生存率仅为 53%，并且慢性肺同种异体移植功能障碍 (CLAD) 已 成为取得更好长期成果的主要障碍。显然，目前的护理标准 免疫抑制方案正在使肺移植受者失败，并且迫切需要改进 生存。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）的发展是广泛公认的风险因素 CLAD的发展。此外，机制研究将这些炎症和同种免疫损伤与 以 CLAD 为特征的纤维化病变。 IL-6 是一种多效性细胞因子，可驱动这些有害的炎症、 因此，免疫和纤维化反应是一种特别有吸引力的细胞因子目标。确实，在实验中 模型中，IL-6 信号传导阻断已被证明会扭曲 Th17/Treg 平衡，有利于调节细胞 从而增加 Treg 数量、减少同种异体移植排斥并减少记忆 B 细胞 数量和抗体形成（初级和召回）。在人体试验中，IL-6R 抑制可降低同种抗体水平 在高度敏感的同种异体肾移植受者中，并改善了肾受者的移植物和患者的存活率 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 肺移植后的早期 IL-6 抑制将诱导一种保护性/抗炎环境，该环境将长期有效。 对宿主免疫系统和同种异体移植物产生持久影响，从而改善移植物和患者的长期状况 生存。为了检验这一假设，我们建议进行 2 期、多中心、双盲、随机、 安慰剂对照试验，检查 clazakizumab 早期抑制 IL-6 对无 CLAD 同种异体移植物的影响 肺移植后的存活率。 Clazakizumab (CSL Behring) 是一种基因工程、高亲和力、 人源化单克隆抗体 (IgG1)，与 IL-6 结合，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) CLAD、2) 再移植、 或3）死亡。主要次要终点包括 PGD、ACR、AMR、DSA。此外，我们计划利用富人 该临床试验将生成的临床数据和人体生物样本，用于定义几种非侵入性的实用性 生物标志物作为风险评估、诊断和预测测试策略。最后，我们将进行机械 研究解释临床试验中观察到的 clazakizumab 的效果。此次审判代表了第一次 IL-6阻断剂在肺移植中的应用有可能改变临床实践并改善 肺移植受者的结果。如果 CZK 疗法成功，我们的综合综合疗法 机制研究将使我们能够阐明改善移植结果的机制。如果治疗失败，我们将 能够理解为什么。无论哪种方式，对同种免疫损伤机制的深入了解和 慢性肺同种异体移植功能障碍可能会导致新的预防或治疗方案。