A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity
A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity
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DOI：
10.1158/1535-7163.mct-13-0318
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发表时间：
2013-11-01
影响因子：
5.7
通讯作者：
Audoly, Laurent
中科院分区：
文献类型：
--
作者：
Olwill, Shane A.;Joffroy, Christian;Audoly, Laurent
MET致癌通路的激活与目前化疗难以治疗的侵袭性癌症的发展有关。这导致人们对开发靶向MET途径的新疗法的兴趣增加。然而，大多数现有的药物形式由于它们不能特异性靶向和/或拮抗该途径而被混淆。Anticalins是一类新型的单价小分子生物制剂，被假设为“适合目的”，用于开发高度特异性和有效的癌症途径拮抗剂。在这里，我们描述了一种单价全MET拮抗剂PRS-110，在配体依赖性和配体非依赖性癌症模型中均显示出疗效。PRS-110以高亲和力特异性结合MET，并阻断肝细胞生长因子（HGF）相互作用。磷酸化测定显示PRS-110有效抑制HGF介导的MET受体信号传导，并且没有激动活性。共聚焦显微镜显示，在不存在HGF的情况下，PRS-110导致MET运输至晚期内体/溶酶体隔室。在配体依赖性（U87-MG）和配体非依赖性（Caki-1）异种移植模型中，PRS-110的体内给药导致显著的剂量依赖性肿瘤生长抑制。对异种移植物活检样品的MET蛋白水平的分析显示，用PRS-110治疗后总MET显著降低，支持其配体非依赖性作用机制。总之，这些数据表明MET抑制剂PRS-110具有潜在的广泛抗癌活性，值得在患者中进行评价。(C)2013年AACR。
Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients. (C) 2013 AACR.