Fc receptor targeted therapy for immune hemolytic anemia

自身免疫性溶血性贫血（AIHA）是由 吞噬细胞对自身抗体包被的RBC的破坏。许多研究表明，Fc？Rs 在吞噬细胞上表达的抗体在抗体包被的RBC的结合和吞噬作用中起重要作用。的 目前用于治疗AIHA的疗法，如类固醇，已经显示出通过非特异性地 抑制Fc的功能？Rs或吞噬细胞，并导致许多不必要的副作用。这 因此，需要开发基于引起AIHA的已知免疫机制的靶向疗法。 最近的研究强烈表明，阻断Fc？R介导的抗体包被的RBC的吞噬作用 可能是治疗AIHA的可行方法。虽然使用基于诱饵受体的阻断受体功能 治疗已被证明在临床上是成功的，存在高水平的循环IgG， 对重组Fc的使用提出了独特的挑战？Rs作为治疗分子。循环IgG 会立即中和高亲和力Fc？RS的管理，而低亲和力Fc？Rs是 在治疗可达到的浓度下无效。我们开发了一种新的Fc？低R二聚体 亲和力Fc？R，CD16Alg，其可以以高亲合力结合IC，而不显示与单体IgG的结合。 此外，我们的初步研究表明，CD16AIg二聚体可以阻断抗体包被的吞噬作用， 小鼠巨噬细胞体外红细胞和阻断中性粒细胞外渗， 在体内由IC诱导的炎症。在这项拨款申请中，我们建议探索以下可能性： 使用Fc？R二聚体作为阻断抗体包被的RBC通过 AIHA中的吞噬细胞。我们假设Fc？RIg二聚体可以结合抗体包被的RBC， 竞争性阻断吞噬Fc？体内携带R的吞噬细胞，并将恢复RBC计数 恢复到正常水平。具体目的是：1）确定巨噬细胞是否竞争性阻断 结合抗体包被的红细胞的重组Fc？RIg二聚体可阻止包被抗体的清除 循环中的红细胞2)确定是否竞争性阻断巨噬细胞结合 抗体包被的红细胞使用重组Fc？RIg二聚体预防由以下物质诱导的实验性AIHA： 不同同种型的自身抗体。3)确定是否给予重组低亲和力 FC？Rs二聚体可延缓或治愈幼年和老年NZB小鼠的自发性AIHA。获得的结果 从拟议的研究将证明是否竞争性阻断抗体包被红细胞， 吞噬细胞使用诱饵Fc？Rs二聚体对IgG诱导的免疫性溶血性贫血有保护作用 抗体的这些研究也将形成一个坚实的基础，为开发新的诱饵Fc？基于R的 用于治疗人类AIHA和其他抗体介导的自身免疫性疾病的疗法。

Autoimmune hemolytic anemia (AIHA) is caused by the destruction of autoantibody-coated RBCs by phagocytes. Many studies have shown that the Fc?Rs expressed on phagocytes play a vital role in binding and phagocytosis of antibody-coated RBCs. The current therapies used to treat AIHA, such as steroids, have been shown to act by non-specifically suppressing the function of Fc?Rs or phagocytes and result in many unwanted side effects. This warrants a need to develop targeted therapies based on known immune mechanisms that cause AIHA. Recent studies strongly suggest that blocking Fc?R- mediated phagocytosis of antibody-coated RBCs may be a viable approach for treating AIHA. Although blocking receptor functions using decoy receptorbased therapies have been proven clinically successful, the presence of high levels of circulating IgG pose a unique challenge to the use of recombinant Fc?Rs as therapeutic molecule. The circulating IgG will immediately neutralize if high affinity Fc?Rs are administered whereas low affinity Fc?Rs are ineffective at therapeutically achievable concentrations. We have developed a novel Fc?R dimer of low affinity Fc?R, CD16AIg, which can bind IC with high avidity while showing no binding to monomeric IgG. Further, our preliminary studies show that the CD16AIg dimer can block the phagocytosis of antibodycoated erythrocytes by mouse macrophages in vitro and block neutrophil extravasations and inflammation induced by ICs in vivo. In this grant application we propose to explore the possibility of using Fc?R dimers as a therapeutic modality to block the clearance of antibody-coated RBCs by phagocytes in AIHA. We hypothesize that Fc?RIg dimers can bind to antibody-coated RBC and competitively block phagocytosis by Fc?R-bearing phagocytic cells in vivo and will restore RBC counts to the normal level. The specific aims are: 1) Determine whether competitive blocking of macrophage binding to antibody-coated RBCs by recombinant Fc?RIg dimers could prevent clearance of antibodycoated erythrocytes from circulation. 2) Determine whether competitive blocking of macrophage binding to antibody-coated RBCs using recombinant Fc?RIg dimers prevent experimental AIHA induced by autoantibodies of different isotypes. 3) Determine whether administration of recombinant low affinity Fc?Rs dimers can delay or cure spontaneous AIHA in young and old NZB mice. The results obtained from the proposed studies will demonstrate whether competitively blocking antibody-coated RBCs to phagocytes by using decoy Fc?Rs dimers will attenuate immune hemolytic anemia induced by IgG antibodies. These studies will also form a solid foundation for the development of novel decoy Fc?Rbased therapies for treatment of AIHA and other antibody-mediated autoimmune disorders in humans.