Long-Acting IFN-gamma for Treating Ovarian Cancer

描述(申请人提供)：干扰素-伽马(干扰素-γ)是一种具有多种生理功能的T细胞和自然杀伤细胞产品。这种细胞因子是一种强大的免疫调节剂，也是巨噬细胞和其他免疫细胞的主要激活剂。干扰素-γ还具有抑制细胞生长的能力，在某些情况下会诱导细胞凋亡。对其抗增殖特性和刺激免疫系统能力的认识导致了对干扰素-γ在许多恶性肿瘤，特别是卵巢癌中的治疗活性的研究。在体外和体内研究表明，干扰素-γ对卵巢癌细胞具有直接毒性，并能刺激人体免疫系统，促进癌细胞的清除。干扰素-γ皮下注射后半衰期短(25-35分钟)，需要频繁给药并降低潜在疗效。我们建议创造新的聚合物修饰的干扰素-伽马蛋白，与现有的干扰素-伽马产品相比，这种蛋白可以更少的使用频率，但在体内具有更大的效力。在第一阶段，我们将确定干扰素-γ中可以在不影响蛋白质体外和体内生物活性的情况下进行修饰的位置。在第二阶段，我们将开发制造工艺，以生产足够数量的修改后的干扰素-伽马蛋白，用于在其他动物PK和肿瘤模型中进行测试。新型干扰素-伽马蛋白的改进特性应该会减少每个患者所需的干扰素-伽马量，提高疗效，降低毒性，改善患者的依从性和生活质量，并为患者和医疗保健提供者节省大量成本。干扰素-γ是一个结构相关的生长因子和细胞因子大家族的成员。从这些研究中获得的信息将有助于创建该基因家族其他成员的长效版本，用于治疗癌症、传染病和造血疾病。

DESCRIPTION (provided by applicant): Interferon-gamma (IFN-gamma) is a T-cell and natural killer cell product with diverse physiological functions. This cytokine is a potent immune modulator and a major activator of macrophages and other immune cells. IFN-gamma also has the ability to inhibit the growth of cells, in some cases inducing apoptosis. Recognition of its anti-proliferative properties and its ability to stimulate the immune system has led to the investigation of IFN-gamma's therapeutic activity in a number of malignant conditions, and in particular ovarian cancer. In vitro and in vivo studies, IFN-gamma has been shown to be directly toxic to ovarian cancer cells and to stimulate the body's immune system to enhance the removal of cancer cells. IFN-gamma has a short half-life after subcutaneous administration (25-35 min) that necessitates frequent administration and reduces potential efficacy. We propose to create novel polymer modified IFN-gamma proteins that can be administered less frequently, but with greater potency in vivo, than existing IFN-gamma products. During Phase I we will identify sites in IFN-gamma that can be modified without affecting the protein's in vitro and in vivo bioactivity. During Phase II, we will develop manufacturing processes to produce sufficient quantities of the modified IFN-gamma proteins for testing in additional animal PK and tumor models. The improved characteristics of the novel IFN-gamma proteins should reduce the amount of IFN-gamma required per patient, enhance efficacy, reduce toxicity, improve patient compliance and quality of life and result in considerable cost savings to patients and healthcare providers. IFN-gamma is a member of a large family of structurally related growth factors and cytokines. Information gained from these studies will aid in creating long-acting versions of other members of this gene family for use in treating cancer, infectious disease and hematopoietic disorders.