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)被认为是肿瘤的关键介质 血管生成，并已成为单一的最常见的血管生成因子在移植和自然发生的肿瘤。血管内皮生长因子通过与其酪氨酸激酶受体--血管内皮生长因子-1(Flt-1)和血管内皮生长因子-R2(Flk-1/KDR)结合发挥生物学活性。临床前研究已经检测了不同类型的血管内皮生长因子拮抗剂的生物活性，包括抗血管内皮生长因子中和抗体，受体分子的可溶性版本，以及血管内皮生长因子-R2酪氨酸激酶的抑制剂。在每个病例中，都观察到明显的肿瘤生长抑制和血管减少。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-L)。在第一阶段中，我们将确定Flt-1(sFlt-1)的可溶性部分的位点，这些位点可以用惰性聚合物修饰，而不会显著影响蛋白质的体外生物活性。在第二阶段，我们将生产足够数量的修饰sFlt-1蛋白，用于在癌症动物模型中进行测试。在我们前期工作的基础上，这些修饰的sFlt-1蛋白应该会优于目前的重组可溶性flt-1的制备方法。特别是，我们预计会看到稳定性提高，效力提高，溶解度增加，循环半衰期延长，给药频率减少，抗原性降低。这些改进的生物学和物理特性将加快sFlt-1作为抗血管生成药物的临床前和临床评估。

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.