Biomarker Guided CNI Substitution in Kidney Transplantation

生物标志物引导肾移植中的 CNI 替代

• 批准号: 9926399
• 负责人: Peter Scott Heeger
• 金额: $ 20.71万
• 依托单位: UNIVERSITY OF MANITOBA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926399
• 关键词: Acute; Address; Adverse event; Aftercare; Allografting; Antibodies; Antibody Formation; B cell differentiation; B-Lymphocytes; Biological Markers; Biopsy; Calcineurin inhibitor; Categories; Cells; Chronic; Clinical; Clinical Trials; Complement; Data; Diagnostic tests; Enrollment; Exclusion Criteria; FOXP3 gene; Failure; Fibrosis; Generations; Goals; Graft Rejection; Grant; HLA-DR Antigens; Human; Immune; Immune response; Immunosuppression; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Institutional Review Boards; Interleukin-6; Intervention; Kidney Transplantation; Link; Maintenance; Mediating; Mediator of activation protein; Molecular; Monitor; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mycophenolate; Natural Immunity; Observational Study; Outcome; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Plasma Cells; Plasmablast; Positioning Attribute; Prednisone; Prognostic Marker; Protocols documentation; Randomized Controlled Trials; Regulatory T-Lymphocyte; Renal function; Reperfusion Injury; Resolution; Risk; Risk stratification; Safety; Statistical Data Interpretation; T cell differentiation; T-Lymphocyte; Testing; Therapeutic Agents; Therapeutic immunosuppression; Time; Transplant Recipients; Transplantation; Treatment Protocols; Validation; Withdrawal; Work; adaptive immunity; arm; base; clinical risk; cohort; cytokine; design; diagnostic biomarker; experience; improved; improved outcome; isoimmunity; mTOR Inhibitor; noninvasive diagnosis; novel marker; novel therapeutics; operation; post-transplant; predictive marker; programs; prospective; recruit; response; side effect; standard of care; subcutaneous; validation studies

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.

抽象的 肾脏移植受者对当前治疗的长期结局主要是由于非局部治疗 基于钙调神经蛋白抑制剂（CNI）的方案的靶向效应和/或无法控制免疫反应 到移植物。改善患者预后将需要新型的治疗剂，以抑制 接受者的免疫反应不受基于CNI的治疗控制。白介素（IL）-6是一种促进的细胞因子 T细胞促炎表型（即TFH，Th1，Th17细胞），同时抑制调节性T细胞，以及 通过诱导B细胞分化为浆体促进抗体形成。 IL-的关键参与 6在这些途径中，它使其成为尝试改善肾脏移植结果的吸引力的目标，尤其是 在CNI替代策略的背景下。此外，虽然CNI提取/取代可以改善肾脏 功能，我们的小组和其他人进行的CNI撤回/替换的随机对照试验， 临床上“低风险”的肾脏移植受者失败了。这是当前的临床风险分层策略和 可用的免疫抑制疗法不足以指导个性化的免疫抑制。共同 该提案的PI已经确定HLA-DR/DQ分子不匹配（MMM）的水平：a）肾脏 移植受者是产生主要同种异体反应的高，中间或低风险（即 拒绝），b）将低风险类别识别为可能耐受CNI最小化/戒断的类别。基于 在这些数据上，FDA接受了警告，将HLA-DR/DQ MMM接受为其生物标志物资格计划 需要该潜在的多中心验证。为此，我们提出了一个前瞻性观察， 多中心，HLA MMM验证研究（AIM 1），其中包括300例免疫传球患者的子集 一项随机对照试验代替抗IL-6 mAb（clazakizumab [claza]）用于CNI（AIM 2），测试 干预对两年结局的影响。机械研究将描述claza的途径 CNI替代后影响结果。在此框架内，我们将测试以下假设 在先前存在的DSA中，HLA-DR/DQ MMM分数既是预后又是预测性生物标志物 指导肾脏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AIM 3中，我们将：a）验证每个效用 单独使用生物标记物作为非侵入性诊断测试，以检测现实世界中的排斥反应 移植队列和b）评估每个生物标志物的效用 通过治疗后活检确定的治疗。该R34提案的目的是完成研究 协议设计，完成设计机械研究，确定统计分析计划并建立 试用操作和管理框架，以便提交FDA IND申请， IRB批准和U01申请的最终申请。