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首页> 外文期刊>Journal of Translational Medicine >A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo
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A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo

机译：功能阻断抗小鼠整联蛋白α5β1抗体抑制血管生成并阻碍体内肿瘤生长

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Background Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin α5β1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, volociximab (M200), inhibits endothelial cell growth and movement in vitro, independent of the growth factor milieu, and inhibits tumor growth in vivo in the rabbit VX2 carcinoma model. Although volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of volociximab has been limited because this antibody does not cross-react with murine α5β1, precluding its use in standard mouse xenograft models. Methods We generated a panel of rat-anti-mouse α5β1 antibodies, with the intent of identifying an antibody that recapitulated the properties of volociximab. Hybridoma clones were screened for analogous function to volociximab, including specificity for α5β1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis in vitro. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models. Results A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin α5β1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC50 = 5.3 nM). In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40–60% (p Conclusion The results herein demonstrate that 339.1, like volociximab, exhibits potent anti-α5β1 activity and confirms that inhibition of integrin α5β1 impedes angiogenesis and slows tumor growth in vivo.
机译：背景技术整合蛋白是调节肿瘤和内皮细胞存活，增殖和迁移的重要粘合分子。已显示整合素α5β1在血管生成期间发挥着关键作用。该整联素，Volociximab（M200）的抑制剂抑制了内皮细胞生长和体外运动，与生长因子Milieu无关，并抑制兔VX2癌模型中体内肿瘤生长。虽然valociximab已经在开放标签中进行了测试，但是在黑色素瘤中的试验期II临床试验，胰腺和肾细胞癌中，Volociximab作用机制的评价受到限制，因为该抗体不会与鼠α5β1交叉反应，预先妨碍其使用在标准鼠标异种移植型号中。方法我们产生了大鼠抗小鼠α5β1抗体的面板，意图鉴定综合体血小叶草的性质的抗体。筛选杂交瘤克隆以类似于Volociximab的类似功能，包括α5β1异二聚体的特异性并阻断整联蛋白与纤连蛋白的结合。符合这些标准的抗体的子集进一步表征其与小鼠内皮细胞结合的能力，抑制体外细胞迁移和阻断血管生成。包含所有这些属性，339.1的一种抗体选自该面板并在异种移植模型中进行测试。结果抗体面板的特征在于特异性和效力。通过Biacore测量，测定对小鼠整合蛋白α5β1的抗体339.1的亲和力为0.59nm。该抗体与人体整联蛋白没有显着交叉反应，但是339.1抑制鼠内皮细胞迁移和管形成，并引发细胞死亡在这些细胞中（EC 50 = 5.3nm）。在多种异种移植模型中，339.1抑制已建立的肿瘤的生长40-60％（P这里的结果证明了339.1像volociximab，表现出有效的抗α5β1活性，并证实整联蛋白α5β1阻碍血管生成并减慢肿瘤生长体内。

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