Long-Acting VEGF Binding Proteins for Treating Cancer

描述（由申请人提供）： 血管内皮生长因子（VEGF）是肿瘤发生发展的关键因子 在移植肿瘤和自然发生的肿瘤中，血管生成因子是唯一最常上调的血管生成因子。VEGF通过与其酪氨酸激酶受体VEGF-R1（Flt-1）和VEGF-R2（Flk-1/KDR）结合发挥其生物学活性。临床前研究已经检查了不同类型的VEGF拮抗剂的生物活性，包括抗VEGF中和抗体、受体分子的可溶形式和VEGF-R2酪氨酸激酶抑制剂。在每种情况下，观察到肿瘤生长的显著抑制和血管减少。我们建议制备和评估这些拮抗剂之一的长效版本，特别是VEG-R1受体（Fit-I）。在第一阶段，我们将确定在可溶性部分的Flt-1（sFlt-1），可以用惰性聚合物修饰，而不会显着影响蛋白质的体外生物活性的网站。在第二阶段，我们将生产足够数量的修饰的sFlt-1蛋白，用于在癌症动物模型中进行测试。基于我们以前的工作，这些修饰的sFlt-1蛋白质应该是上级优于目前制备的重组可溶性Flt-1。特别是，我们期望看到改善的稳定性、更高的效力、更大的溶解度、更长的循环半衰期、更少的给药频率和降低的抗原性。这些改善的生物学和物理特性应加速sFlt-1作为抗血管生成剂的临床前和临床评价。

DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF) has been identified as a key mediator of tumor angiogenesis and has emerged as the single most commonly upregulated angiogenic factor in both grafted and naturally occurring tumors. VEGF exerts its biological activity by binding to its tyrosine kinase receptors, VEGF-R1 (Flt-1) and VEGF-R2 (Flk-1/KDR). Preclinical studies have examined the biological activities of different types of VEGF antagonists, including anti-VEGF neutralizing antibodies, soluble versions of the receptor molecules, and inhibitors of VEGF-R2 tyrosine kinase. In each case, significant inhibition of tumor growth and reduced vasculature was observed. We propose to prepare and evaluate long acting versions of one of these antagonists, specifically VEG-R1 receptor (Fit-l). During Phase I we will identify sites in the soluble portion of Flt-1 (sFlt-1) that can be modified with an inert polymer without significantly affecting the protein's in vitro bioactivity. During Phase II, we will manufacture sufficient quantities of the modified sFlt-1 proteins for testing in animal models of cancer. Based on our previous work, these modified sFlt-1 proteins should be superior to the present preparations of recombinant soluble Flt-1. In particular we expect to see improved stability, higher potency, greater solubility, longer circulating half-lives, less frequent dosing and reduced antigenicity. These improved biological and physical characteristics should expedite pre-clinical and clinical evaluation of sFlt-1 as an anti-angiogenesis agent.