LONG-ACTING GM-CSF PROTEINS FOR TREATING NEUTROPENIA

粒细胞-巨噬细胞集落刺激因子（GM-CSF）是刺激造血祖细胞增殖和分化的细胞因子。重组人GM-CSF用于刺激骨髓抑制化疗导致的中性粒细胞减少症患者的中性粒细胞生成。 1997年，重组人GM-CSF的全球销售额约为1亿美元，比1996年增长了20%。我们提出产生修饰的β-M-CSF蛋白，其在体内刺激粒细胞/单核细胞形成方面等于或上级于天然GM-CSF，但其需要较低频率的给药，大约每周一次或每隔一周一次。在I期，我们将鉴定GM-CSF中可以被修饰而不影响蛋白质的体外生物活性的位点。在第二阶段，我们将生产足够数量的修饰的GM-CSF蛋白，用于中性粒细胞减少症动物模型的测试。 新型GM-CSF蛋白质的改进的特性将减少每个患者所需的GM-CSF的量，改善患者依从性和生活质量，并为患者和医疗保健提供者节省大量成本。从这些研究中获得的信息将有助于创造用于治疗癌症、感染性疾病和造血障碍的结构相关细胞因子和生长因子的长效版本。拟议的商业应用：重组人GM-CSF用于恢复化疗或骨髓移植导致的中性粒细胞减少症患者的中性粒细胞生成。 1997年，重组GM-CSF的全球销售额超过1亿美元。正在开发中的修饰的GM-CSF蛋白将需要更少的剂量，为患者和医疗保健提供者提供显着的成本节约。其他潜在益处包括提高药物疗效和改善患者生活质量。

Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is a cytokine that stimulates proliferation and differentiation of hematopoietic progenitor cells. Recombinant human GM-CSF is used to stimulate neutrophil production in patients with neutropenia resulting from myelosuppressive chemotherapy. Recombinant human GM-CSF had world-wide sales of approximately $100 million during 1997, a 20% increase from 1996. We propose to create modified (3M-CSF proteins that are equal or superior to natural GM-CSF at stimulating granulocyte/monocyte formation in vivo, but which require less frequent dosing, on the order of once per week or once every other week. During Phase l we will identify sites in GM-CSF that can be modified without affecting the protein's in vitro bioactivity. During Phase II, we will manufacture sufficient quantities of the modified GM-CSF proteins for testing in animal models of neutropenia. The improved characteristics of the novel GM-CSF proteins will reduce the amount of GM-CSF required per patient, improve patient compliance and quality of life and result in considerable cost savings to patients and healthcare providers. Information gained from these studies will aid in creating long-acting versions of structurally related cytokines and growth factors for use in treating cancer, infectious disease and hematopoeitic disorders. PROPOSED COMMERCIAL APPLICATIONS: Recombinant human GM-CSF is used to restore neutrophil production in patients with neutropenia resulting from chemotherapy or bone marrow transplantation. Recombinant GM-CSF had world-wide sales in excess of $100 million in 1997. The modified GM-CSF proteins under development will require much less frequent dosing, providing significant cost savings to patients and healthcare providers. Additional potential benefits include improved drug efficacy and improved patient quality of life.