Clazakizumab in late antibody-mediated rejection: study protocol of a randomized controlled pilot trial
Clazakizumab in late antibody-mediated rejection: study protocol of a randomized controlled pilot trial
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DOI：
10.1186/s13063-018-3158-6
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发表时间：
2019-01-11
期刊：
影响因子：
2.5
通讯作者：
Boehmig, Georg A.
中科院分区：
文献类型：
--
作者：
Eskandary, Farsad;Duerr, Michael;Boehmig, Georg A.
供体特异性抗体（DSA）引起的晚期抗体介导的排斥反应（ABMR）是导致移植肾功能障碍和移植肾功能丧失的主要原因。这种排斥类型的诊断标准已经建立，但有效的治疗仍然是一个重大挑战。最近的随机对照试验（RCT）未能证明广泛使用的治疗，如利妥昔单抗加静脉注射免疫球蛋白或蛋白酶体抑制剂（硼替佐米）的疗效，加强了对新的治疗概念的巨大需求。在这种情况下，一个有前途的目标可能是白细胞介素-6（IL-6），一个多效性细胞因子已知发挥重要作用，在炎症和适应性immunity.MethodsThis促发剂驱动的随机对照试验的目的是评估clazakizumab，基因工程的人源化单克隆抗体针对IL-6的安全性和有效性。该研究将包括20例DSA阳性的肾移植受者，在移植后365天诊断为ABMR。将在奥地利和德国的两个研究中心（维也纳医科大学;柏林Charite医科大学）招募受试者。首先，患者将进入为期3个月的双盲RCT（1，1随机化，根据ABMR表型和研究中心分层），并将接受clazakizumab（每月皮下给药25 mg）或安慰剂。在试验的第二个开放标签部分（第4-12个月），所有患者将每月接受25 mg的clazakizumab。主要终点是安全性和耐受性。次要终点是clazakizumab的药代动力学和药效学，其对肝脏中药物代谢的影响，DSA特征，3个月和12个月方案活检中的形态学ABMR病变和分子基因表达模式，炎症和内皮活化/损伤的血清/尿生物标志物，作为总体免疫抑制指标的Torque Teno病毒载量，肾功能，尿蛋白排泄，以及移植和患者生存。讨论目前，没有治疗被证明是有效的，在停止晚期ABMR的进展。基于拮抗IL-6的作用通过对抗DSA触发的炎症和B细胞/浆细胞驱动的同种免疫来改善DSA阳性晚期ABMR的结果的假设，我们认为我们的试验有可能为这种类型的排斥反应的新型治疗提供概念证明。registrationClinicalTrials.gov于2018年2月23日注册（追溯注册）。
BackgroundLate antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials (RCT) have failed to demonstrate the efficacy of widely used therapies, such as rituximab plus intravenous immunoglobulin or proteasome inhibition (bortezomib), reinforcing a great need for new therapeutic concepts. One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity.MethodsThis investigator-driven RCT was designed to assess the safety and efficacy of clazakizumab, a genetically engineered humanized monoclonal antibody directed against IL-6. The study will include 20 DSA-positive kidney allograft recipients diagnosed with ABMR 365days after transplantation. Participants will be recruited at two study sites in Austria and Germany (Medical University of Vienna; Charite University Medicine Berlin). First, patients will enter a three-month double-blind RCT (1,1 randomization, stratification according to ABMR phenotype and study site) and will receive either clazakizumab (subcutaneous administration of 25mg in monthly intervals) or placebo. In a second open-label part of the trial (months 4-12), all patients will receive clazakizumab at 25mg every month. The primary endpoint is safety and tolerability. Secondary endpoints are the pharmacokinetics and pharmacodynamics of clazakizumab, its effect on drug metabolism in the liver, DSA characteristics, morphological ABMR lesions and molecular gene expression patterns in three- and 12-month protocol biopsies, serum/urinary biomarkers of inflammation and endothelial activation/injury, Torque Teno viral load as a measure of overall immunosuppression, kidney function, urinary protein excretion, as well as transplant and patient survival.DiscussionCurrently, there is no treatment proven to be effective in halting the progression of late ABMR. Based on the hypothesis that antagonizing the effects of IL-6 improves the outcome of DSA-positive late ABMR by counteracting DSA-triggered inflammation and B cell/plasma cell-driven alloimmunity, we suggest that our trial has the potential to provide proof of concept of a novel treatment of this type of rejection.Trial registrationClinicalTrials.gov, NCT03444103. Registered on 23 February 2018 (retrospective registration).