Synergy between anti-endoglin (CD105) monoclonal antibodies and TGF-β in suppression of growth of human endothelial cells
Synergy between anti-endoglin (CD105) monoclonal antibodies and TGF-β in suppression of growth of human endothelial cells
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DOI：
10.1002/ijc.11551
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发表时间：
2004-01-10
影响因子：
6.4
通讯作者：
Seon, BK
中科院分区：
文献类型：
--
作者：
She, XW;Matsuno, F;Seon, BK
内皮糖蛋白（CD 105）是内皮细胞增殖相关的细胞膜抗原，在实体瘤的血管生成血管系统中强烈表达。内皮糖蛋白对于血管生成/血管发育和辅助转化生长因子β（TGF-β）受体是必需的。某些抗内皮糖蛋白单克隆抗体（mAb），称为SN 6系列mAb，抑制小鼠中的血管生成、肿瘤生长和转移。我们研究了抗endoglin单克隆抗体抑制增殖内皮细胞生长的机制。我们发现，4个SN 6系列单克隆抗体抑制人脐静脉内皮细胞（HUVEC）的生长，在没有任何效应细胞或补体的剂量依赖性的方式。观察到定义不同表位的4种抗内皮糖蛋白mAb之间的生长抑制的显著差异。这些差异不是由mAb的抗原结合亲和力决定的。TGF-β 1和4种抗内皮糖蛋白单克隆抗体的组合对HUVEC的生长具有协同抑制作用。抗内皮糖蛋白单克隆抗体与内皮糖蛋白表达细胞的结合并不阻断随后的TGF-β 1结合。相反，与TGF-β 1预孵育的HUVECs没有改变内皮糖蛋白的细胞表面表达。目前的结果表明，SN 6系列单克隆抗体直接抑制内皮细胞生长是抗内皮糖蛋白单克隆抗体在体内发挥抗血管生成和肿瘤抑制活性的潜在机制之一。结果进一步表明，TGF-β 1通过协同增强这些mAb的活性，在抗内皮糖蛋白mAb的体内抗血管生成功效中起重要作用。进一步研究这些新发现可能为内皮糖蛋白和抗内皮糖蛋白单克隆抗体在TGF-β介导的细胞调节中的功能作用提供有价值的信息。(C)2003 Wiley-Liss，Inc.
Endoglin (CD105) is a proliferation-associated cell membrane antigen of endothelial cells and strongly expressed in the angiogenic vasculature of solid tumors. Endoglin is essential for angiogenesis/vascular development and an ancillary transforming growth factor beta (TGF-beta) receptor. Certain anti-endoglin monoclonal antibodies (mAbs), termed SN6 series mAbs, inhibited angiogenesis, tumor growth and metastasis in mice. We investigated the mechanisms by which anti-endoglin mAbs suppress growth of proliferating endothelial cells. We found that 4 SN6 series mAbs suppressed growth of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner in the absence of any effector cells or complement. Significant differences in the growth suppression between the 4 anti-endoglin mAbs defining different epitopes were observed. These differences were not determined by antigen-binding avidities of the mAbs. Combination of TGF-beta1 and each of the 4 anti-endoglin mAbs exerted synergistic growth suppression of HUVECs. Binding of anti-endoglin mAbs to endoglin-expressing cells did not block the subsequent binding of TGF-beta1. Conversely, preincubation of HUVECs with TGF-beta1 did not change cell surface expression of endoglin. The present results suggest that direct suppression of the endothelial cell growth by SN6 series mAbs is one of the underlying mechanisms by which anti-endoglin mAbs exert antiangiogenic and tumor-suppressive activity in vivo. The results further suggest that TGF-beta1 plays an important role in the in vivo antiangiogenic efficacy of anti-endoglin mAbs by synergistically enhancing the activity of these mAbs. Further studies of the present novel findings may provide valuable information about the functional roles of endoglin and anti-endoglin mAbs in the TGF-beta-mediated cell regulation. (C) 2003 Wiley-Liss, Inc.