背景:抗体介导的排斥反应(ABMR)是同种异体肾移植丢失的主要原因。这种拒绝类型,这可能发生在移植后的任何时间,通常表现为微血管炎症(MVI)的连续性,最终导致慢性组织损伤。虽然ABMR的临床意义得到了广泛认可,其治疗,特别是移植后很长一段时间,仍然是一个巨大的挑战。抵消ABMR的有希望的策略可能是使用CD38定向治疗来消耗产生同种抗体的浆细胞(PC)和自然杀伤(NK)细胞。
方法:这项由研究者发起的试验是一项随机试验,安慰剂对照,双盲,平行组,旨在评估安全性和耐受性(主要终点)的多中心2期试验,药代动力学,免疫原性,和全人CD38单克隆抗体felzartamab(MOR202)在晚期ABMR中的功效。该试验将包括20名抗HLA供体特异性抗体(DSA)阳性的同种异体肾移植受者,这些受者在移植后诊断为活动性或慢性活动性ABMR≥180天。受试者将以1:1随机接受felzartamab(每次输注16mg/kg)或安慰剂持续6个月(在第0天以及在1、2、3、4、8、12、16和20周后静脉内施用)。将在第24周和第52周进行两次随访同种异体移植物活检。次要终点(初步评估)将包括肾脏活检的形态学和分子排斥活性,血液和尿液中的免疫生物标志物,和预测同种异体移植失败进展的替代参数(肾功能斜率;iBOX预测评分)。
结论:基于felzartamab能够通过靶向产生抗体的PC和NK细胞来阻止ABMR的进展的假设,我们认为,我们的试验有可能为基于前瞻性随机临床试验的ABMR新疗法的概念提供第一个证据.
背景:欧盟临床试验注册(EudraCT)2021-000545-40。2021年6月23日注册。
结果:govNCT05021484。2021年8月25日注册
BACKGROUND: Antibody-mediated rejection (ABMR) is a cardinal cause of renal allograft loss. This rejection type, which may occur at any time after transplantation, commonly presents as a continuum of microvascular inflammation (MVI) culminating in chronic tissue injury. While the clinical relevance of ABMR is well recognized, its treatment, particularly a long time after transplantation, has remained a big challenge. A promising strategy to counteract ABMR may be the use of CD38-directed treatment to deplete alloantibody-producing plasma cells (PC) and natural killer (NK) cells.
METHODS: This investigator-initiated trial is planned as a randomized, placebo-controlled, double-blind, parallel-group, multi-center phase 2 trial designed to assess the safety and tolerability (primary endpoint), pharmacokinetics, immunogenicity, and efficacy of the fully human CD38 monoclonal antibody
felzartamab (MOR202) in late ABMR. The trial will include 20 anti-HLA donor-specific antibody (DSA)-positive renal allograft recipients diagnosed with active or chronic active ABMR ≥ 180 days post-transplantation. Subjects will be randomized 1:1 to receive
felzartamab (16 mg/kg per infusion) or placebo for a period of 6 months (intravenous administration on day 0, and after 1, 2, 3, 4, 8, 12, 16, and 20 weeks). Two follow-up allograft biopsies will be performed at weeks 24 and 52. Secondary endpoints (preliminary assessment) will include morphologic and molecular rejection activity in renal biopsies, immunologic biomarkers in the blood and urine, and surrogate parameters predicting the progression to allograft failure (slope of renal function; iBOX prediction score).
CONCLUSIONS: Based on the hypothesis that
felzartamab is able to halt the progression of ABMR via targeting antibody-producing PC and NK cells, we believe that our trial could potentially provide the first proof of concept of a new treatment in ABMR based on a prospective randomized clinical trial.
BACKGROUND: EU Clinical Trials Register (EudraCT) 2021-000545-40 . Registered on 23 June 2021.
RESULTS: gov NCT05021484 . Registered on 25 August 2021.