FcRlll Blockade as a Treatment for Autoimmune Disease

FcRIII 阻断作为自身免疫性疾病的治疗方法

• 批准号: 6787891
• 负责人: L Syd Johnson
• 金额: $ 10万
• 依托单位: MACROGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787891
• 关键词: antibody receptor; autoantibody; autoimmune disorder; autoimmune hemolytic anemia; biotechnology; blocking antibody; drug design /synthesis /production; drug screening /evaluation; enzyme linked immunosorbent assay; fusion gene; genetically modified animals; human genetic material tag; immune complex; immunologic substance development /preparation; laboratory mouse; monoclonal antibody; radioimmunoassay; receptor binding; systemic lupus erythematosus; thrombocytopenic purpura

DESCRIPTION (provided by applicant): Recent studies have revealed the importance of Fc receptors, especially FcRIII in mediating the pathogenic effects of autoantibodies. Murine monoclonal antibodies against FcRIII have been demonstrated to be effective in blocking the interaction of this receptor with immune complexes. This blocking activity has potential as a treatment for autoimmune diseases such as idiopathic thrombocytopenia purpura (ITP) and systemic lupus erythrematosus (SLE). We propose to develop a humanized monoclonal antibody to FcRIII, which retains the ability to block the interaction of this receptor with immune complexes, but is minimally antigenic. In order to avoid unwanted cellular depletion and cytokine release we will modify the Fc portion of the humanized mAb to eliminate or modify FcR binding by this region. We will demonstrate and quantify the affinity of the humanized anti-FcRIII mAb for antigen and its inhibitory activity. Finally, we will test the molecule in vivo in a transgenic mouse model of ITP. The successful completion of the studies outlined in this application will provide the basis for expanded production, characterization and further safety and efficacy studies of this molecule in small animals and primates, ultimately leading to human clinical trials

描述（由申请人提供）：最近的研究揭示了Fc受体，尤其是FcRIII在介导自身抗体的致病作用中的重要性。针对 FcRIII 的鼠单克隆抗体已被证明可以有效阻断该受体与免疫复合物的相互作用。这种阻断活性具有治疗自身免疫性疾病的潜力，例如特发性血小板减少性紫癜（ITP）和系统性红斑狼疮（SLE）。我们建议开发一种针对 FcRIII 的人源化单克隆抗体，该抗体保留了阻断该受体与免疫复合物相互作用的能力，但抗原性最低。为了避免不必要的细胞耗竭和细胞因子释放，我们将修饰人源化 mAb 的 Fc 部分，以消除或修饰该区域的 FcR 结合。我们将证明并量化人源化抗 FcRIII mAb 对抗原的亲和力及其抑制活性。最后，我们将在 ITP 转基因小鼠模型中测试该分子的体内情况。本申请中概述的研究的成功完成将为该分子在小动物和灵长类动物中的扩大生产、表征以及进一步的安全性和有效性研究提供基础，最终导致人体临床试验