Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejectionresults from a first-in-patient phase 1 trial
Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejectionresults from a first-in-patient phase 1 trial
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DOI：
10.1111/ajt.14528
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发表时间：
2018-04-01
影响因子：
8.8
通讯作者：
Boehmig, G. A.
中科院分区：
文献类型：
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作者：
Eskandary, F.;Jilma, B.;Boehmig, G. A.
补体经典途径（CP）可能参与了抗体介导的排斥反应（ABMR）的发病机制。选择性CP阻断可能是对抗排斥反应的有希望的策略。这项首次在患者中进行的Ib期试验旨在评价抗C1 s抗体BIVV 009每周4次给药（60 mg/kg）治疗补体介导疾病的安全性/耐受性和CP阻断潜力。在此，我们描述了一组10例稳定的肾移植受者（平均移植后4.3年）的结果，这些受者具有晚期活动性ABMR和CP激活的特征，如毛细血管C4d或补体结合供体特异性抗体（DSA）。在7周随访期间，未报告重度不良事件，BIVV 009可显著抑制血清中的总体和DSA触发的CP活化。在5周的随访活检中，8例C4d阳性受者中有5例转为C4d阴性，而另外2例受者的C4d评分大幅下降。然而，微循环炎症、基因表达模式、DSA水平或肾功能没有变化。总之，我们证明BIVV 009可有效阻断同种抗体触发的CP激活，即使短期治疗对晚期ABMR的活性指数无影响。这项初步试验为将来旨在阐明CP阻断在移植中的治疗价值的研究提供了有价值的基础。ClinicalTrials.gov该首次患者I期试验证明了新型人源化抗C1 s单克隆抗体在具有晚期抗体介导的排斥的10个肾同种异体移植物接受者的队列中的安全性、耐受性和显著的补体抑制功效。
The classical pathway (CP) of complement may contribute to the pathogenesis of antibody-mediated rejection (ABMR). Selective CP blockade may be a promising strategy to counteract rejection. The objective of this first-in-patient phase 1b trial was to evaluate the safety/tolerability and CP-blocking potential of 4 weekly doses (60mg/kg) of the anti-C1s antibody BIVV009 in complement-mediated disorders. Here we describe the results in a cohort of 10 stable kidney transplant recipients (median of 4.3years posttransplantation) with late active ABMR and features of CP activation, such as capillary C4d or complement-fixing donor-specific antibodies (DSA). During 7 weeks follow-up, no severe adverse events were reported, and BIVV009 profoundly inhibited overall and DSA-triggered CP activation in serum. Five of 8 C4d-positive recipients turned C4d-negative in 5-week follow-up biopsies, while another 2 recipients showed a substantial decrease in C4d scores. There was, however, no change in microcirculation inflammation, gene expression patterns, DSA levels, or kidney function. In conclusion, we demonstrate that BIVV009 effectively blocks alloantibody-triggered CP activation, even though short-course treatment had no effect on indices of activity in late ABMR. This initial trial provides a valuable basis for future studies designed to clarify the therapeutic value of CP blockade in transplantation. ClinicalTrials.gov NCT#02502903.This first-in-patient phase 1 trial demonstrates safety, tolerability, and profound complement inhibition efficacy of a novel humanized anti-C1s monoclonal antibody in a cohort of 10 kidney allograft recipients with late antibody- mediated rejection.