Development of Soluble FcR-Ig Fusion Proteins

描述(由申请人提供)：免疫复合体或含有致病自身抗体的调理细胞与效应细胞上的Fc受体相互作用，导致细胞耗竭、炎症和组织损伤，具体取决于抗体的目标。目前的建议是基于这样的假设，即可溶性FcGamma受体(SFCR)凭借其阻断这种相互作用的能力，可以用于预防或治疗以免疫复合物沉积或抗体介导的细胞耗竭为特征的疾病。这些SFCR分子将被制成与人铰链-Fc片段的融合蛋白，从而使SFCR具有高亲和力和长的血清半衰期。该项目的总体目标是基于FcGammaRIII(CD16)、FcGammaRIIb(CD32b)和FcGammaRIla(CD32a)的新型SFCR-Ig分子的产生，并在体外和在自身免疫衰竭和炎症的动物模型中对这些蛋白进行评估。在第一阶段结束时，作为第二阶段SBIR研究的一部分，这些蛋白质中的一种将被选择用于开发用于人类受试者的临床研究。特发性血小板减少性紫癜(ITP)是一种有吸引力的初始靶点，用于阻断免疫复合物和FCR之间的相互作用。我们认为，阻断FCR也可能在治疗自身免疫性溶血性贫血、狼疮、类风湿性关节炎、格林-巴利综合征和僵硬综合征方面有用。

DESCRIPTION (provided by applicant): The interaction of immune complexes or opsonized cells containing pathogenic autoantibodies with Fc-receptors on effector cells leads to cellular depletion, inflammation and tissue damage depending on the target of the antibody. The current proposal is based on the hypothesis that soluble Fcgamma-receptors (sFcR), by virtue of their ability to block this interaction, can be used to prevent or treat diseases characterized by immune complex deposition or antibody mediated cellular depletion. These sFcR molecules will be made as fusion proteins with a human hinge-Fc segment so that the sFcR will have high avidity and a long serum half-life. The overall aims of this project are the generation of novel sFcR-Ig molecules based on FcgammaRIII (CD16) FcgammaRIIb (CD32b) and FcgammaRIla (CD32a) and the evaluation of these proteins in vitro and in animal models of autoimmune depletion and inflammation. At the end of Phase I one of these proteins will be selected to develop for clinical studies in human subjects as part of Phase II SBIR studies. Idiopathic thrombocytopenic purpura (ITP) is an attractive initial target for an agent blocking the interaction between immune complexes and FcR. We believe that an FcR blockade would also be potentially useful in treating autoimmune hemolytic anemia, lupus, rheumatoid arthritis, Guillain-Barre syndrome and stiff man's syndrome.