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首页> 外文期刊>The journal of clinical investigation >Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy
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Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy

机译：抗EGFL7抗体增强应激诱导的内皮细胞死亡和抗VEGF功效

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Many oncology drugs are administered at their maximally tolerated dose without the knowledge of their optimal efficacious dose range. In this study, we describe a multifaceted approach that integrated preclinical and clinical data to identify the optimal dose for an antiangiogenesis agent, anti-EGFL7. EGFL7 is an extracellular matrix–associated protein expressed in activated endothelium. Recombinant EGFL7 protein supported EC adhesion and protected ECs from stress-induced apoptosis. Anti-EGFL7 antibodies inhibited both of these key processes and augmented anti-VEGF–mediated vascular damage in various murine tumor models. In a genetically engineered mouse model of advanced non–small cell lung cancer, we found that anti-EGFL7 enhanced both the progression-free and overall survival benefits derived from anti-VEGF therapy in a dose-dependent manner. In addition, we identified a circulating progenitor cell type that was regulated by EGFL7 and evaluated the response of these cells to anti-EGFL7 treatment in both tumor-bearing mice and cancer patients from a phase I clinical trial. Importantly, these preclinical efficacy and clinical biomarker results enabled rational selection of the anti-EGFL7 dose currently being tested in phase II clinical trials.
机译：许多肿瘤药物以其最大耐受剂量给药，而不知道其最佳有效剂量范围。在这项研究中，我们描述了一种综合了临床前和临床数据的多方面方法，以确定抗血管生成剂抗EGFL7的最佳剂量。 EGFL7是在激活的内皮细胞中表达的细胞外基质相关蛋白。重组EGFL7蛋白支持EC粘附并保护EC免受应激诱导的细胞凋亡。在各种鼠类肿瘤模型中，抗EGFL7抗体抑制了这两个关键过程，并增强了抗VEGF介导的血管损伤。在晚期非小细胞肺癌的基因工程小鼠模型中，我们发现抗EGFL7以剂量依赖性方式增强了抗VEGF治疗带来的无进展生存期和总体生存期收益。此外，我们从I期临床试验中鉴定了受EGFL7调节的循环祖细胞类型，并评估了这些细胞对荷瘤小鼠和癌症患者中抗EGFL7治疗的反应。重要的是，这些临床前疗效和临床生物标志物结果使得能够合理选择目前在II期临床试验中测试的抗EGFL7剂量。

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