Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, The Netherlands.
Ann Rheum Dis. 2012 Feb;71(2):180-5. doi: 10.1136/annrheumdis-2011-200298. Epub 2011 Sep 14.
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.
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).
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.
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.
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、药效学和初步疗效。
在这项双盲、多中心、联合首次人体、单剂量递增（I 期，A 部分）和概念验证、多剂量（IIA 期，B 部分）研究中，患有活动性疾病的类风湿关节炎（RA）患者被随机分配接受 ASK8007 或安慰剂静脉注射。在整个研究过程中进行安全性监测、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）评估滑膜组织活检样本中表型细胞标志物的表达。两个共同的主要疗效终点是从基线开始的 28 个关节疾病活动评分（DAS28）的变化和从基线开始的 CD68 滑膜下 lining 巨噬细胞数量的变化，均在第 43 天（B 部分）评估。
ASK8007 在最高研究剂量（20mg/kg）下总体上是安全且耐受良好的。在滑液中检测到可量化浓度的 ASK8007。与安慰剂治疗的患者相比，ASK8007 治疗的患者从基线开始的 DAS28 和 CD68 滑膜下 lining 巨噬细胞变化没有差异。在 ASK8007 治疗组中，也没有明显的临床反应或滑膜下 lining 巨噬细胞的变化。此外，ASK8007 治疗不会改变其他评估的生物标志物。
骨桥蛋白阻断是可耐受的，与安全性问题无关。这些结果一致表明，骨桥蛋白阻断不太可能在 RA 患者中引起明显的临床改善。
