Safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the monoclonal antibody ASK8007 blocking osteopontin in patients with rheumatoid arthritis: a randomised, placebo controlled, proof-of-concept study
Safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the monoclonal antibody ASK8007 blocking osteopontin in patients with rheumatoid arthritis: a randomised, placebo controlled, proof-of-concept study
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DOI：
10.1136/annrheumdis-2011-200298
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发表时间：
2012-02-01
影响因子：
27.4
通讯作者：
Tak, P. P.
中科院分区：
文献类型：
--
作者：
Boumans, M. J. H.;Houbiers, J. G. A.;Tak, P. P.
目的骨桥蛋白是一种具有多种免疫调节功能的细胞外基质蛋白。作者评估了阻断骨桥蛋白的人源化单克隆抗体ASK8007的安全性、耐受性、药代动力学、药效学和初始疗效。（I期，A部分）和概念验证，多次给药（IIA期，B部分）研究中，患有活动性疾病的类风湿性关节炎（RA）患者被随机分配静脉内接受ASK 8007或安慰剂。在整个研究期间进行安全性监测、药代动力学和药效学分析以及临床评估。通过免疫组织化学和数字图像分析，在基线和治疗开始后43天（B部分）获得的滑膜组织活检样本中评价表型细胞标志物的表达。两个协同主要疗效终点是在28个关节中评价的疾病活动性评分（DAS 28）中较基线的变化和CD 68滑膜下层巨噬细胞数量较基线的变化，两者均在第43天进行评估（部分B）。在滑液中检测到可定量浓度的ASK8007。在ASK8007和安慰剂治疗患者之间，未观察到DAS 28和CD68亚衬巨噬细胞较基线的变化存在差异。在ASK8007治疗组中，也没有明显的临床反应或下层巨噬细胞的变化。此外，ASK8007治疗并没有改变其他评估的biologicals.Conclusions骨桥蛋白阻滞剂耐受性良好，不相关的安全性问题。这些结果一致表明，骨桥蛋白阻断不太可能诱导RA患者的稳健临床改善。
Objectives Osteopontin is an extracellular matrix protein with diverse immunomodulatory functions. The authors assessed the safety, tolerability, pharmacokinetics, pharmacodynamics and initial efficacy of the humanised monoclonal antibody ASK8007, which blocks osteopontin.Methods In this double-blind, multicentre, combined first-in-man, single-dose escalation (phase I, part A) and proof-of-concept, multiple-dose (phase IIA, part B) study, rheumatoid arthritis (RA) patients with active disease were randomly assigned to receive ASK8007 or placebo intravenously. Safety monitoring, pharmacokinetic and pharmacodynamic analyses and clinical assessments were performed throughout the study. The expression of phenotypic cell markers was evaluated in synovial tissue biopsy samples obtained at baseline and 43 days after initiation of treatment (part B) by immunohistochemistry and digital image analysis. Two co-primary efficacy endpoints were the change from baseline in the disease activity score evaluated in 28 joints (DAS28) and the change from baseline in the number of CD68 synovial sublining macrophages, both assessed on day 43 (part B).Results ASK8007 was overall safe and well tolerated up to the highest studied dose (20 mg/kg). Quantifiable concentrations of ASK8007 were detected in synovial fluid. No differences were observed for changes from baseline in DAS28 and CD68 sublining macrophages between ASK8007 and placebo-treated patients. Within the ASK8007 treatment group, there were also no apparent clinical responses or changes in sublining macrophages. In addition, ASK8007 treatment did not change other assessed biomarkers.Conclusions Osteopontin blockade is well tolerated and not related to safety concerns. These results consistently show that osteopontin blockade is unlikely to induce robust clinical improvement in RA patients.