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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

基本信息

批准号：
10282620
负责人：
Ramsey Hachem
金额：
$ 271.03万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10282620
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 Immunology 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 Treatment Protocols allograft rejection antibody-dependent cell cytotoxicity antibody-mediated rejection cell free DNA clinical practice cytokine design donor-specific antibody 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

项目摘要

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.

项目总结/文摘