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.

项目概要/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）是肺移植术后第一年之后死亡的主要原因 移植。抗体介导的排斥反应（AMR）在肺移植后越来越受到重视， 是由与人类白细胞抗原 (HLA) 不匹配的供体特异性抗体 (DSA) 引起的，并且经常 导致 CLAD 和死亡。最近使用强化监测 AMR 的多中心研究报告了一个发生率 超过25%。 AMR 的治疗通常侧重于抗体耗竭和预防额外抗体 发展。已使用各种组合，包括大剂量皮质类固醇、静脉注射免疫 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。 AMR 后一年的同种异体移植存活率约为 50%，而 2 年存活率仅为 20%。 IL-6，最初 被确定为 B 细胞刺激因子 2 (BSF-2)，是一种多效性细胞因子，可驱动有害炎症， 同种免疫和纤维化反应。 IL-6 与其他细胞因子一起负责正常 抗体的产生，对于诱导滤泡辅助 T 细胞以及 IL-21 的产生至关重要 它调节免疫球蛋白的合成。 IL-6 对于 B 细胞分化为浆母细胞以及 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。人体研究检查 IL-6 信号传导阻断在管理中的作用 即使在难治性病例中，肾移植后的 AMR 也显示出有希望的结果。我们用过IL-6 我们中心对极少数患有 AMR 的肺移植受者进行信号阻断，令人鼓舞 结果。我们的主要假设是 IL-6 信号传导阻断添加到常规免疫抑制治疗中 AMR 将改善临床结果。然而，在之前有必要评估这种方法的安全性 在大型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 信号传导阻断相关，也是肺移植后所有时间点的常见死亡原因。 因此，除了常规治疗外，我们建议使用 Siltuximab（一种针对 IL-6 的单克隆抗体）进行 1 期临床试验。 针对 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 相关的功能性生物学测量（例如 DSA、游离 DNA）。此次试验的数据将告知 设计未来评估疗效的 2 期临床试验。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。