Long Acting IFN-gamma for Treating Immunodeficiencies

描述(申请人提供)：干扰素-γ是一种T细胞衍生的细胞因子，在许多细胞类型上表现出抗病毒和免疫调节作用。重组人干扰素-γ被批准用于治疗慢性肉芽肿性疾病和严重的恶性骨化症。目前正在进行的人体临床试验的其他适应症包括特发性肺纤维化、肝纤维化、丙型肝炎和卵巢癌。干扰素-伽玛在皮下给药后半衰期短，需要频繁给药并降低潜在疗效。我们建议创造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，这种蛋白给药频率较低，但效力更大。在第一阶段，我们确定了干扰素-γ中可以用聚乙二醇部分修饰的部位，而不会显着影响蛋白质的体外生物活性。此外，在大鼠身上进行了药代动力学研究，以证实添加惰性聚合物延长了干扰素伽马的循环半衰期。在第二阶段，我们将进行更广泛的PK研究，以评估不同的给药模式。我们将开发方法来生产足够数量的聚乙二醇化突变蛋白，以便进一步在动物模型中进行测试，并确定用于商业开发的最佳聚乙二醇化干扰素-γ半胱氨酸突变蛋白。

DESCRIPTION (provided by applicant): Interferon-gamma is a T cell-derived cytokine that exhibits anti-viral and immunomodulatory effects on many cell types. Recombinant human interferon-gamma is approved for the treatment of chronic granulomatous disease and severe malignant osteopetrosis. Other indications currently being investigated in human clinical trials include idiopathic pulmonary fibrosis, liver fibrosis, hepatitis C and ovarian cancer. Interferon-gamma has a short half-life after subcutaneous administration that necessitates frequent administration and reduces potential efficacy. We propose to create polymer modified interferon-gamma proteins that can be administered less frequently, but with greater potency, than existing interferon-gamma products. During Phase I we identified sites in interferon-gamma that can be modified with a polyethylene glycol moiety without significantly affecting the protein's in vitro bioactivity. In addition, pharmacokinetic studies were performed in rats to verify that the addition of an inert polymer extends the circulating half-life of interferon gamma. During the Phase II, we will perform more extensive PK studies that evaluate different modes of administration. We will develop methods to produce sufficient quantities of the PEGylated muteins for further testing in animal models and identify the optimum PEGylated interferon-gamma cysteine mutein for commercial development.