LONG-ACTING STABILIZED ANGIOSTATIN PROTEINS FOR CANCER

描述：血管抑素是纤溶酶原的38 kDa蛋白水解内部片段 （kringles 1-4）和血管生成和肿瘤生长的内源性抑制剂。通过 血管抑素抑制内皮细胞增殖， 通过限制血管形成的过程进行检查。重组人 当给予小鼠时，血管抑素抑制人和 没有观察到毒性或耐药性的鼠肿瘤。我们建议 创造出比现有的血管抑制素更上级的修饰的血管抑制素样蛋白 重组血管抑素的制备。修饰的血管抑素蛋白 应该具有改进的稳定性、更高的效力、更大的溶解度、更长的 给药频率较低、抗原性降低和批次的循环半衰期 很多一致性。在第一阶段，我们将确定血管抑素的位点， 可以在不显著影响蛋白质的情况下进行修饰？体外试验 生物活性在第二阶段，我们将生产足够数量的 用于在癌症动物模型中测试的修饰的血管抑素样蛋白。的 这些新蛋白质的改进特性将允许快速 在癌症的临床前和临床研究中验证疗效。

DESCRIPTION: Angiostatin is 38 kDa proteolytic internal fragment of plasminogen (kringles 1-4) and an endogenous inhibitor of angiogenesis and tumor growth. By inhibiting endothelial proliferation, angiostatin presumably keeps cancers in check by restricting the process of blood vessel formation. Recombinant human angiostatin when administered to mice inhibited the growth of both human and murine tumors with no observed toxicity or drug resistance. We propose to create modified angiostatin-like proteins that are superior to the present preparations of recombinant angiostatin. The modified angiostatin proteins should have improved stability, higher potency, greater solubility, longer circulating half-lives for less frequent dosing, reduced antigenicity, and lot to lot consistency. During Phase I we will identify sites in angiostatin that can be modified without significantly affecting the protein?s in vitro bioactivity. During Phase II, we will manufacture sufficient quantities of the modified angiostatin-like proteins for testing in animal models of cancer. The improved characteristics of these novel proteins will allow for the rapid validation of efficacy in both pre-clinical and clinical studies for cancer.