Targeting Inflammation and Alloimmunity in Lung Transplant Recipients With Clazakizumab

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.