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，对许多细胞类型具有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硬化症。目前在人类临床试验中正在研究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-γ在皮下给药后半衰期短，需要频繁给药并降低潜在疗效。我们建议创建聚合物修饰的干扰素-γ蛋白，其可以比现有的干扰素-γ产品更少地施用，但具有更大的效力。在第一阶段，我们确定的网站干扰素-γ，可以修改与聚乙二醇部分，而不会显着影响蛋白质的体外生物活性。此外，在大鼠中进行药代动力学研究以验证添加惰性聚合物延长干扰素γ的循环半衰期。在II期研究期间，我们将进行更广泛的PK研究，以评价不同的给药模式。我们将开发方法来生产足够数量的聚乙二醇化突变蛋白，用于在动物模型中进行进一步测试，并确定最佳的聚乙二醇化干扰素-γ-半胱氨酸突变蛋白用于商业开发。

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.