Biomarker Guided CNI Substitution in Kidney Transplantation

摘要 肾移植受者在目前的治疗中具有次优的长期结局，主要是由于非- 基于钙调磷酸酶抑制剂（CNI）的方案的靶向作用，和/或其未能控制免疫应答 移植物改善患者的预后将需要新的治疗剂，其抑制肿瘤细胞的组分。 接受者的免疫反应不受基于CNI的治疗控制。白细胞介素（IL）-6是一种细胞因子， T细胞促炎表型（即Tfh、Th 1、Th 17细胞），同时抑制调节性T细胞，以及 通过诱导B细胞分化成浆母细胞来促进抗体形成。IL的关键参与- 6在这些途径中的作用使其成为试图改善肾移植结果的有吸引力的靶点， 在CNI替代策略的背景下。此外，虽然CNI停药/替代可以改善肾脏 功能，随机对照试验CNI撤出/替代由我们的小组和其他人， 临床上“低风险”的肾移植接受者失败了。因此，目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的免疫抑制。该公司- 本提案的PI已经确定HLA-DR/DQ分子错配（mMM）水平：a）将肾脏分类为 移植受者为发展原发性同种免疫应答的高、中或低风险（即， 拒绝），以及B）将低风险类别识别为可能耐受CNI最小化/撤销的那些。基于 根据这些数据，FDA接受HLA-DR/DQ mMM进入其生物标志物鉴定程序， 需要进行前瞻性多中心验证。为此，我们提出了一个前瞻性的观察， 一项多中心HLA mMM验证研究（Aim 1），在300例免疫静止患者的亚组中， 一项用抗IL-6 mAb（克拉扎珠单抗[Claza]）替代CNI（目标2）的随机对照试验， 干预对2年结果的影响。机制研究将描绘出克拉扎 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 在既存DSA中，HLA-DR/DQ mMM评分是一种预后和预测生物标志物，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 单独和一起作为非侵入性诊断测试用于检测真实世界肾脏中排斥的生物标记 移植群组，和B）评估每种生物标志物检测响应于移植物的排斥的消退的效用， 通过治疗后活检确定的治疗。本R34提案的目标是完成研究 方案设计，完成机制研究设计，最终确定统计分析计划，并建立 试验操作和管理框架，以便能够提交FDA试验IND申请， IRB批准的最终申请和U 01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.