LONG ACTING STABILIZED ENDOSTATIN FOR TREATING CANCER

内皮抑素是胶原样蛋白（胶原XVIII）的一个20kda的c端球状结构域，是血管生成和肿瘤生长的内源性抑制剂。通过抑制内皮细胞的增殖，内皮抑素可能通过限制血管形成的过程来控制癌症。重组人内皮抑素作为未折叠的悬浮液给予小鼠，抑制了人和小鼠肿瘤的生长，没有观察到毒性或耐药性。我们提出了一种改良的内皮抑素蛋白，它优于现有的重组内皮抑素。内皮抑素变体应具有更好的稳定性、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、更低的抗原性和批次间的一致性。在第一阶段，我们将确定内皮抑素中可以在不显著影响蛋白质体外生物活性的情况下进行修饰的位点。在第二阶段，我们将生产足够数量的改良内皮抑素蛋白用于癌症动物模型的测试。新型内皮抑素蛋白的改进特性将允许在癌症的临床前和临床研究中快速验证疗效。拟议的商业应用：内皮抑素是一种天然的抗血管生成蛋白，在动物模型中抑制癌性人类肿瘤的生长。全球癌症治疗市场估计超过68亿美元，随着预期寿命的增加和吸烟等风险因素的普遍存在，预计每年都会增长。改良的内皮抑素将提供一个稳定的，有效的形成，将加快临床前和临床试验。对癌症患者的额外好处可能包括减少给药频率，这将为患者节省大量成本，并增加仅在美国就有900多万癌症患者从抗衰老治疗中受益的药物可获得性。

Endostatin is a 20 kDa C-terminal globular domain of the collagen-like protein (collagen XVIII) and an endogenous inhibitor of angiogenesis and tumor growth. By inhibiting endothelial proliferation, endostatin presumably keeps cancers in check by restricting the process of blood vessel formation. Recombinant human endostatin administered to mice as an unfolded suspension inhibited the growth of both human and murine tumors with no observed toxicity or drug resistance. We propose to create modified endostatin proteins that are superior to the present preparations of recombinant endostatin. The endostatin variants 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 endostatin that can be modified without significantly affecting the protein's in vitro bioactivity. During Phase II, we will manufacture sufficient quantities of the modified endostatin proteins for testing in animal models of cancer. The improved characteristics of the novel endostatin proteins will allow for the rapid validation of efficacy in both pre-clinical and clinical studies for cancer. PROPOSED COMMERCIAL APPLICATIONS: Endostatin is a natural antiangiogenic protein that inhibits the growth of cancerous human tumors in animal models. The global market for cancer therapeutics is estimated to be in excess of $6.8 billion and expected to grow every year as life expectancies increase and risk factors such as smoking remain prevalent. The modified endostatin will provide a stable, potent formation that will expedite the preclinical and clinical trials. Additional benefits for cancer patients may include less frequent dosing which will provide significant cost savings to patients and increase drug availability for the more than 9 million cancer patients in the US alone that would benefit from antiagiogenic therapy.