Treatment of experimental arthritis by targeting synovial endothelium with a neutralizing recombinant antibody to C5
Treatment of experimental arthritis by targeting synovial endothelium with a neutralizing recombinant antibody to C5
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DOI：
10.1002/art.34430
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发表时间：
2012-08-01
影响因子：
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通讯作者：
Tedesco，Francesco
中科院分区：
文献类型：
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作者：
Macor，Paolo;Durigutto，Paolo;Tedesco，Francesco
目的通过滑膜归巢肽与C5中和抗体融合获得一种新的重组蛋白（MT07），该蛋白可选择性递送至炎症滑膜，并能有效控制关节炎实验模型的关节炎症。方法采用免疫荧光法评估MT07与人、大鼠和小鼠滑膜组织的体外结合，并采用时域光学成像法记录MT07在大鼠炎症关节中的选择性定位。在大鼠抗原诱导关节炎（AIA）模型和小鼠胶原抗体诱导关节炎（CAIA）模型中测试了MT07的抗炎作用。结果smt07能够与人、小鼠和大鼠的炎症滑膜结合，而不能识别未炎症的滑膜以及炎症的小鼠肺或大鼠肾。体内对MT07生物分布的分析证实，它优先归巢于发炎关节，对循环C5水平的抑制可以忽略不计。MT07在AIA大鼠模型中预防和解决了已建立的炎症，通过关节肿胀、滑膜洗涤中的多形核细胞计数、白细胞介素- 6和肿瘤坏死因子α的释放以及组织损伤的变化证明了这一点。在CAIA模型中检测MT07获得了类似的治疗效果。我们的研究结果表明，新的重组分子MT07具有选择性靶向炎症关节的独特能力，并通过中和补体系统在不干扰循环C5水平的情况下局部控制炎症过程。我们相信这种方法可以扩展到目前用于治疗类风湿性关节炎患者的其他抗炎药物。
ObjectiveTo show that a new recombinant protein (MT07) obtained by fusing a synovial‐homing peptide to a neutralizing antibody to C5 can be selectively delivered to inflamed synovium and can effectively control joint inflammation in experimental models of arthritis.MethodsBinding of MT07 to human, rat, and mouse synovial tissue was evaluated in vitro by immunofluorescence, and selective localization in the inflamed joints of rats was documented in vivo using time‐domain optical imaging. The antiinflammatory effect of MT07 was tested in a rat model of antigen‐induced arthritis (AIA) and in a mouse model of collagen antibody–induced arthritis (CAIA).ResultsMT07 was able to bind to samples of inflamed synovium from humans, mice, and rats while failing to recognize uninflamed synovium as well as inflamed mouse lung or rat kidney. In vivo analysis of the biodistribution of MT07 confirmed its preferential homing to inflamed joints, with negligible inhibition of circulating C5 levels. MT07 prevented and resolved established inflammation in a rat model of AIA, as demonstrated by changes in joint swelling, polymorphonuclear cell counts in synovial washes, release of interleukin‐6 and tumor necrosis factor α, and tissue damage. A similar therapeutic effect was obtained testing MT07 in a CAIA model.ConclusionOur findings show that the novel recombinant molecule MT07 has the unique ability to selectively target inflamed joints and to exert local control of the inflammatory process by neutralizing the complement system without interfering with circulating C5 levels. We believe that this approach can be extended to other antiinflammatory drugs currently used to treat patients with rheumatoid arthritis.