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

Siltuximab 治疗肺移植后抗体介导的排斥反应的 1 期临床试验

• 批准号: 10714920
• 负责人: Derek E Byers
• 金额: $ 37.14万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714920
• 关键词: Acute; Adrenal Cortex Hormones; Affinity; Allografting; Antibodies; Antibody Formation; Antibody Therapy; Antithymoglobulin; B cell differentiation; Binding; Biological; C-reactive protein; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cause of Death; Cell Count; Cell Proliferation; Cells; Cessation of life; Characteristics; Chronic; Clinical; Clinical Trials; Clinical Trials Design; Collagen; Communities; Conduct Clinical Trials; Data; Development; Diagnosis; Dose; Endothelial Cells; Equilibrium; Experimental Models; Failure; Fibroblasts; Functional disorder; Future; Gastroesophageal reflux disease; HLA Antigens; Helper-Inducer T-Lymphocyte; Human; IL2RA gene; IL2RB gene; Immunoglobulin G; Immunoglobulins; Immunosuppressive Agents; Incidence; Individual; Infection; Inflammatory; Inflammatory Response; Interleukin 6 Receptor; Interleukin-2; Interleukin-6; Intravenous Immunoglobulins; Kidney; Kidney Transplantation; Link; Lung; Lung Transplantation; Lung diseases; Measurement; Measures; Membrane; Memory; Memory B-Lymphocyte; Monitor; Monoclonal Antibodies; Multicenter Studies; Multicentric Angiofollicular Lymphoid Hyperplasia; Mus; Myofibroblast; Outcome; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Placebos; Plasma Exchange; Plasmablast; Play; Prevention; Production; Randomized, Controlled Trials; Receptor Inhibition; Recurrence; Refractory; Regimen; Regulatory T-Lymphocyte; Reporting; Role; Safety; Schedule; Serious Adverse Event; Signal Transduction; Smooth Muscle Myocytes; Specificity; Testing; Therapeutic; Therapeutic immunosuppression; Transplant Recipients; United States Food and Drug Administration; Vascular Smooth Muscle; Viral Respiratory Tract Infection; allograft rejection; antibody-mediated rejection; cell free DNA; cytokine; design; donor-specific antibody; efficacy evaluation; efficacy study; experience; improved; improved outcome; infection risk; interleukin-21; lung allograft; lung injury; mortality; novel; prevent; primary endpoint; prospective; receptor; response; rituximab; safety assessment; safety testing; secondary endpoint; standard of care

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.

项目摘要/摘要 肺移植后的长期结局仍然令人失望，中位生存期为6。7年。 慢性肺同种异体功能障碍（CLAD）是肺后第一年的主要死亡原因 移植。抗体介导的排斥（AMR），肺移植后越来越识别， 是由对不匹配的人白细胞抗原（HLA）的供体特异性抗体（DSA）引起的，并且经常 导致外壳和死亡。最近使用密集监控进行AMR报告的多中心研究报告率 超过25％。 AMR的治疗通常集中于抗体止动和预防其他抗体 发展。已经使用了各种组合，包括高剂量皮质类固醇，静脉免疫 球蛋白（IVIG），利妥昔单抗，carfilzomib，抗胸腺细胞球蛋白（ATG）和血浆交换（PLEX）。然而， 没有随机对照试验来指导管理，AMR后的结果令人沮丧。 AMR后的一年同种异体移植生存率约为50％，2年生存率仅为20％。 IL-6，最初 被识别为B细胞刺激因子2（BSF-2），是一种多效细胞因子，可驱动有害炎症， 同种免疫和纤维化反应。与其他细胞因子结合使用，IL-6负责正常 抗体产生，对于诱导卵泡辅助T细胞以及IL-21的产生至关重要 调节免疫球蛋白合成。 IL-6对于b细胞分化为浆质和 增强血浆生存。这些特征使IL-6成为针对目标的特别有吸引力的细胞因子 AMR的管理。人类研究检查了IL-6信号阻塞在管理中的作用 肾脏移植后的AMR即使在难治性病例中也显示出令人鼓舞的结果。我们使用了IL-6 在我们中心的AMR的肺部移植受者中发出信号封锁，鼓励 结果。我们的主要假设是IL-6信号阻塞添加到常规免疫抑制作用中 因为AMR将改善临床结果。但是，必须先评估这种方法的安全性 在较大的临床试验中检查功效，因为感染是最常见的严重不良事件 与IL-6信号阻塞和肺移植后所有时间点的常见死亡原因相关。 因此，我们提出了一项使用Siltuximab（一种与IL-6的单克抗体抗体）提出的1期临床试验 用于检查安全性并定义AMR治疗的最佳剂量的AMR的免疫抑制疗法。 主要终点是安全性和耐受性，次要终点包括药效学和 与AMR相关的功能生物学测量（例如DSA，无细胞DNA）。该试验的数据将告知 评估功效的未来2期临床试验的设计。精心设计和实施临床试验 对于改善肺移植后的预后是必要的。