FcRlll Blockade as a Treatment for Autoimmune Disease

描述（由申请方提供）：最近的研究揭示了Fc受体，尤其是FcRIII在介导自身抗体致病作用中的重要性。已证明针对FcRIII的鼠单克隆抗体可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如特发性血小板减少性紫癜（ITP）和系统性红斑狼疮（SLE）的潜力。我们建议开发针对FcRIII的人源化单克隆抗体，其保留阻断该受体与免疫复合物的相互作用的能力，但具有最低限度的抗原性。为了避免不需要的细胞消耗和细胞因子释放，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。我们将证明并定量人源化抗FcRIII mAb对抗原的亲和力及其抑制活性。最后，我们将在ITP转基因小鼠模型中体内测试该分子。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、表征和进一步安全性和有效性研究提供基础，最终导致人类临床试验

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