Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study
Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study
复制标题
DOI：
10.1136/ard.2010.146225
复制
发表时间：
2011-09-01
影响因子：
27.4
通讯作者：
Magrini, Fabio
中科院分区：
文献类型：
--
作者：
Burmester, Gerd R.;Feist, Eugen;Magrini, Fabio
目的评价针对粒细胞-巨噬细胞集落刺激因子受体α的人源单克隆抗体mavrilimumab治疗类风湿关节炎（rheumatoid arthritis，RA）患者的安全性、耐受性、药代动力学和药效学特征。受试者接受单次静脉内递增剂量的mavrilimumab（0.01-10.0 mg/kg）或安慰剂。结果32名受试者入组本研究（1名揭盲受试者接受0.01 mg/kg，另一名接受0.03 mg/kg，随后是5个连续双盲队列，每个队列n=6，分别接受0.1、0.3、1.0、3.0和10.0 mg/kg治疗）。不良事件为轻度或中度，所有治疗队列的报告频率相似。1例受试者（10.0 mg/kg）在输注期间出现中度面部和颈部荨麻疹，经对症治疗后消退。剂量>1.0 mg/kg时，马威利姆单抗的全身清除率接近内源性IgG的清除率;通过抑制细胞因子信号传导抑制因子3 mRNA转录物，在1.0和3.0 mg/kg队列中证实了药效学活性。在探索性分析中，在基线时C反应蛋白（>5 mg/l）和红细胞沉降率（>= 20.0 mm/h）升高的受试者中观察到急性期反应物减少。在任何队列中均未观察到疾病活动性评分28-关节评估（DAS 28）的显著变化。在基线DAS 28>3.2的mavrilimumab治疗受试者（n=15）中，平均疾病活动度（DAS 28）在4周时显著降低。重要的是，mavrilimumab的安全性和药代动力学特征支持RA的进一步临床研究。
Objective To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-alpha, in subjects with rheumatoid arthritis (RA).Methods A randomised, double-blind, placebo-controlled, dose-escalating phase I study in subjects with RA who received stable methotrexate treatment for >= 3 months before enrolment. Subjects received single intravenous escalating doses of mavrilimumab (0.01-10.0 mg/kg) or placebo.Results 32 subjects were enrolled in this study (1 unblinded subject at 0.01 mg/kg and another at 0.03 mg/kg were followed by five sequential double-blinded cohorts, n=6 each, treated with 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg, respectively). Adverse events were mild or moderate and were reported with similar frequency across all treatment cohorts. One subject (10.0 mg/kg) experienced moderate face and neck urticaria during infusion that resolved with symptomatic treatment. Systemic clearance of mavrilimumab approached that of endogenous IgG at doses >1.0 mg/kg; pharmacodynamic activity was confirmed in the 1.0 and 3.0 mg/kg cohorts by suppression of suppressor of cytokine signalling 3 mRNA transcripts. In exploratory analyses, reductions of acute phase reactants were observed in subjects with elevated C-reactive protein (>5 mg/l) and erythrocyte sedimentation rate (>= 20.0 mm/h) at baseline. No significant change in Disease Activity Score 28-joint assessment (DAS28) was seen in any of the cohorts. In mavrilimumab-treated subjects (n=15) with baseline DAS28 >3.2, mean disease activity (DAS28) was significantly reduced at 4 weeks.Conclusion In this first-in-human study, mavrilimumab showed preliminary evidence of pharmacodynamic activity. Importantly, the safety and pharmacokinetic profiles of mavrilimumab support further clinical studies in RA.