Biomarker Guided CNI Substitution in Kidney Transplantation

摘要 肾移植受者在目前的治疗中长期效果不佳，主要是由于非肾脏移植。 以钙调神经磷酸酶抑制剂(CNI)为基础的方案的靶向效应和/或它们未能控制免疫反应 为了嫁接。要改善患者的预后，将需要新型的治疗药物来抑制 受体的免疫反应不受基于CNI的治疗的控制。白介素6是一种促进 T细胞致炎表型(即Tfh，Th1，Th17细胞)，同时抑制调节性T细胞，以及 通过诱导B细胞分化为浆母细胞来促进抗体的形成。白介素2的关键参与 这些途径使其成为尝试改善肾移植结果的一个有吸引力的目标，尤其是 在CNI替代战略的背景下。此外，虽然CNI的停用/替代可以改善肾脏 功能，由我们小组和其他人进行的CNI退出/替代的随机对照试验，在 临床上，“低风险”的肾移植接受者失败了。因此，当前的临床风险分层策略和 现有的免疫抑制疗法不足以指导个体化免疫抑制。联席- 本建议的PI已经确定了人类白细胞抗原-DR/DQ分子错配水平(MMM)：A)对肾脏进行分类 移植受者发展为初级同种异体免疫反应的高、中或低风险(即 拒绝)，以及b)确定低风险类别是那些可能容忍CNI最小化/退出的类别。基座 根据这些数据，FDA接受了人类白细胞抗原DR/DQ MMM进入其生物标记物资格认证计划，但有警告 需要进行预期的多中心验证。为此，我们提出了一种前瞻性观测， 多中心，人类白细胞抗原MMM验证研究(AIM 1)，包括，在300名免疫平静患者的子集中， 用抗IL-6单抗(Clazakizumab[Claza])代替CNI(Aim 2)的随机对照试验，检测 干预对2年预后的影响。机械学研究将勾勒出Claza 影响CNI替代后的结果。在这个框架内，我们将测试假设，在没有 在既有的DSA中，人类白细胞抗原-DR/DQ MMM评分既是预测预后的生物标志物，也是能够 指导肾移植中的免疫抑制治疗。此外，我们的财团已经确定了多个 亚临床/临床排斥反应的非侵入性诊断生物标志物。在目标3中，我们将：a)验证每个 生物标记物单独和联合作为检测真实肾脏排斥反应的非侵入性诊断试验 移植队列，以及b)评估每个生物标志物在检测排斥反应的解决方面的效用 通过治疗后活组织检查确定治疗方法。R34提案的目标是完成这项研究 方案设计，完成机理研究设计，最终确定统计分析方案，建立 试运行和管理框架，以便能够提交FDA试行IND申请； IRB批准的最终申请和U01申请。

Abstract Kidney transplant recipients have suboptimal long-term outcomes on current therapy predominantly due to off- target effects of calcineurin inhibitor (CNI)-based protocols, and/or their failure to control the immune response to the graft. Improving patient outcomes will require novel therapeutic agents that inhibit components of the recipient’s immune response not controlled by CNI-based therapy. Interleukin (IL)-6 is a cytokine that promotes T cell proinflammatory phenotypes (i.e. Tfh, Th1, Th17 cells) while inhibiting regulatory T cells, as well as promoting antibody formation by inducing B cell differentiation into plasmablasts. The critical involvement of IL- 6 in these pathways makes it an attractive target for attempts to improve kidney transplant outcomes, especially in the context of CNI substitution strategies. Additionally, while CNI withdrawal/substitution can improve kidney function, randomized controlled trials of CNI withdrawal/substitution performed by our group and others, in clinically “low risk” kidney transplant recipients have failed. Thus, current clinical risk stratification strategies and available immunosuppressive therapies are inadequate for guiding individualized immunosuppression. The co- PIs of this proposal have identified that the level of HLA-DR/DQ molecular mismatch (mMM): a) classifies kidney transplant recipients as high, intermediate or low risk for developing a primary alloimmune response (i.e. rejection), and b) identifies the low-risk category as those likely to tolerate CNI minimization/withdrawal. Based on these data the FDA accepted HLA-DR/DQ mMM into its Biomarker Qualification Program with the caveat that prospective multicenter validation is required. To this end, we propose a prospective observational, multicenter, HLA mMM validation study (Aim 1) that includes, in a subset of 300 immune quiescence patients, a randomized controlled trial substituting anti-IL-6 mAb (Clazakizumab [Claza]) for CNI (Aim 2), testing the impact of the intervention on 2 year outcomes. Mechanistic studies will delineate the pathways by which Claza impacts outcomes after CNI substitution. Within this framework, we will test the hypothesis that in the absence of pre-existing DSA, the HLA-DR/DQ mMM score is both a prognostic and predictive biomarker capable of guiding immunosuppressive therapy in kidney transplantation. In addition, our consortium has identified multiple non-invasive diagnostic biomarkers of subclinical/clinical rejection. In Aim 3 we will: a) validate the utility of each biomarker alone and together as non-invasive diagnostic tests for detect rejection in a real-world kidney transplant cohort, and b) assess the utility of each biomarker to detect resolution of rejection in response to therapy as determined by a post-treatment biopsy. The goal of this R34 proposal is to complete the study protocol design, finish designing the mechanistic studies, finalize the statistical analysis plan, and establish the framework for trial operation and management in order to be in a position to submit an FDA trial IND application, a final application for IRB approval and a U01 application.