A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis
A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis
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DOI：
10.1002/art.21975
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发表时间：
2006-08-01
影响因子：
--
通讯作者：
Tak, Paul P.
中科院分区：
文献类型：
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作者：
Haringman, Jasper J.;Gerlag, Danielle M.;Tak, Paul P.
Objective.趋化因子如CCL 2/单核细胞趋化蛋白1（MCP-1）在白细胞迁移中起关键作用，并且是治疗慢性炎性疾病的潜在靶点。本研究的目的是评价抗CCL 2/MCP-1单克隆抗体（ABN 912）治疗类风湿关节炎（RA）患者的疗效。活动性RA患者入组ABN 912的随机、安慰剂对照、剂量递增研究。在第1天和第15天进行输注。在剂量递增阶段，4个队列各8例患者接受了滑膜组织的连续关节镜活检。免疫组织化学和数字图像分析用于表征滑膜组织中的生物标志物。实验室评价包括药代动力学分析和外周血单个核细胞的免疫学研究。为了评估ABN 912治疗的临床效果，另外21名患者接受了最高耐受剂量的治疗。总研究人群包括45名患者：33名患者接受ABN 912，12名患者接受安慰剂。ABN 912治疗耐受性良好。出乎意料的是，外周血中ABN 912复合的总CCL 2/MCP-1水平呈剂量相关性增加，高达2，000倍。与安慰剂相比，ABN 912没有可检测的临床获益，研究药物治疗也没有导致滑膜组织和外周血中生物标志物水平的显著变化。ABN 912治疗未导致临床或免疫组织学改善，并且可能与接受最高剂量治疗的患者的RA恶化相关。结果可能与ABN 912处理后观察到的血清中总CCL 2/ MCP-1水平的大幅增加有关。该观察结果可能与多种基于抗体的疗法相关。
Objective. Chemokines such as CCL2/monocyte chemotactic protein 1 (MCP-1) play a key role in leukocyte migration and are potential targets in the treatment of chronic inflammatory disorders. The objective of this study was to evaluate the effects of human anti-CCL2/MCP-1 monoclonal antibody (ABN912) treatment in patients with rheumatoid arthritis (RA).Methods. Patients with active RA were enrolled in a randomized, placebo-controlled, dose-escalation study of ABN912. Infusions were administered on day 1 and day 15. In the dose-escalation phase, 4 cohorts of 8 patients each underwent serial arthroscopic biopsy of synovial tissue. Immunohistochemistry and digital image analysis were used to characterize biomarkers in synovial tissue. Laboratory evaluation included pharmacokinetic analysis and immunotypic studies of peripheral blood mononuclear cells. To assess the clinical effects of treatment with ABN912, an additional 21 patients were treated with the highest dose tolerated.Results. The total study population comprised 45 patients: 33 patients received ABN912, and 12 patients received placebo. ABN912 treatment was well tolerated. Unexpectedly, there was a dose-related increase in ABN912-complexed total CCL2/MCP-1 levels in peripheral blood, up to 2,000-fold. There was no detectable clinical benefit of ABN912 compared with placebo, nor did treatment with the study drug result in a significant change in the levels of biomarkers in synovial tissue and peripheral blood.Conclusion. ABN912 treatment did not result in clinical or immunohistologic improvement and may have been associated with worsening of RA in patients treated with the highest dose. The results might be related to the greatly increased level of total CCL2/ MCP-1 in serum that was observed following treatment with ABN912. This observation may be relevant for a variety of antibody-based therapies.