Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy
Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy
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DOI：
10.1172/jci67892
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发表时间：
2013-09-01
影响因子：
15.9
通讯作者：
Hegde, Priti S.
中科院分区：
文献类型：
--
作者：
Johnson, Leisa;Huseni, Mahrukh;Hegde, Priti S.
许多肿瘤药物在不知道其最佳有效剂量范围的情况下以其最大耐受剂量给药。在这项研究中，我们描述了一种综合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 是一种在活化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。抗 EGFL7 抗体抑制这两个关键过程，并在各种小鼠肿瘤模型中增强抗 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抗 VEGF 治疗带来的无进展生存和总体生存获益。此外，我们还鉴定了一种受 EGFL7 调节的循环祖细胞类型，并通过 I 期临床试验评估了这些细胞对荷瘤小鼠和癌症患者的抗 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正在 II 期临床试验中测试的抗 EGFL7 剂量。
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.