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.

项目总结/文摘