Antagonistic Anti-urokinase Plasminogen Activator Receptor (uPAR) Antibodies Significantly Inhibit uPAR-mediated Cellular Signaling and Migration
Antagonistic Anti-urokinase Plasminogen Activator Receptor (uPAR) Antibodies Significantly Inhibit uPAR-mediated Cellular Signaling and Migration
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DOI：
10.1074/jbc.m109.077677
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发表时间：
2010-08-27
影响因子：
4.8
通讯作者：
Craik, Charles S.
中科院分区：
文献类型：
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作者：
Duriseti, Sai;Goetz, David H.;Craik, Charles S.
尿激酶型纤溶酶原激活物受体（uPAR）及其各种配体之间的相互作用调节肿瘤的生长、侵袭和转移。结合特异性uPAR表位的抗体可以破坏这些相互作用，从而抑制这些过程。使用抗原结合（Fab）噬菌体展示文库的高度多样性和幼稚的人片段，我们鉴定了12个结合uPAR的独特的人Fab。这些抗体中的两种与尿激酶纤溶酶原激活物（uPA）竞争uPAR结合，而第三种与β 1整联蛋白竞争uPAR结合。这些竞争性抗体抑制uPAR依赖性细胞信号传导和非小细胞肺癌细胞系H1299中的侵袭。此外，整联蛋白阻断抗体消除uPAR/β 1整联蛋白介导的H1299细胞与纤连蛋白和玻连蛋白的粘附。该抗体和uPAR/uPA拮抗剂抗体之一在抑制通过基质胶/胶原I或胶原I基质的细胞侵袭中显示出显著的组合效果。我们的研究结果表明，这些拮抗性抗体具有检测和治疗uPAR表达肿瘤的潜力。
Interactions between urokinase plasminogen activator receptor (uPAR) and its various ligands regulate tumor growth, invasion, and metastasis. Antibodies that bind specific uPAR epitopes may disrupt these interactions, thereby inhibiting these processes. Using a highly diverse and naive human fragment of the antigen binding (Fab) phage display library, we identified 12 unique human Fabs that bind uPAR. Two of these antibodies compete against urokinase plasminogen activator (uPA) for uPAR binding, whereas a third competes with beta 1 integrins for uPAR binding. These competitive antibodies inhibit uPAR-dependent cell signaling and invasion in the non-small cell lung cancer cell line, H1299. Additionally, the integrin-blocking antibody abrogates uPAR/beta 1 integrin-mediated H1299 cell adhesion to fibronectin and vitronectin. This antibody and one of the uPAR/uPA antagonist antibodies shows a significant combined effect in inhibiting cell invasion through Matrigel/Collagen I or Collagen I matrices. Our results indicate that these antagonistic antibodies have potential for the detection and treatment of uPAR-expressing tumors.