Fc receptor targeted therapy for immune hemolytic anemia

描述（由申请方提供）：自身免疫性溶血性贫血（AIHA）由吞噬细胞破坏自身抗体包被的RBC引起。许多研究表明，Fc？在吞噬细胞上表达的Rs在抗体包被的RBC的结合和吞噬中起重要作用。目前用于治疗AIHA的疗法，如类固醇，已被证明是通过非特异性抑制Fc？Rs或吞噬细胞，并导致许多不必要的副作用。这就需要根据已知的导致AIHA的免疫机制开发靶向治疗。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。虽然阻断受体功能，使用诱饵受体为基础的治疗已被证明是成功的临床，高水平的循环IgG的存在下，使用重组Fc？Rs作为治疗分子。如果高亲和力Fc？RS的管理，而低亲和力Fc？Rs在治疗上可达到的浓度下是无效的。我们开发了一种新的Fc？R二聚体的低亲和力Fc？R，CD 16 Alg，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，CD 16 AIg二聚体可以在体外阻断小鼠巨噬细胞对抗体包被的红细胞的吞噬作用，并在体内阻断IC诱导的中性粒细胞外渗和炎症。在这项资助申请中，我们建议探索使用Fc？R二聚体作为阻断AIHA中吞噬细胞清除抗体包被的RBC的治疗方式。我们假设Fc？RIg二聚体可以结合抗体包被的红细胞和竞争性阻断吞噬Fc？R-承载吞噬细胞在体内，并将恢复红细胞计数到正常水平。具体目的是：1）确定重组Fc是否竞争性阻断巨噬细胞与抗体包被的红细胞的结合？RIg二聚体可阻止抗体包被的红细胞从循环中清除。2)确定是否使用重组Fc竞争性阻断巨噬细胞与抗体包被的RBC结合？RIg二聚体预防不同同种型自身抗体诱导的实验性AIHA。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。从拟议的研究中获得的结果将证明是否竞争性阻断抗体包被的红细胞吞噬细胞通过使用诱饵Fc？Rs二聚体将减弱IgG抗体诱导的免疫溶血性贫血。这些研究也将形成一个坚实的基础，为开发新的诱饵Fc？用于治疗人类AIHA和其他抗体介导的自身免疫性疾病的基于R的疗法。

DESCRIPTION (provided by applicant): 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 receptor-based 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 antibody-coated 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 antibody-coated 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?R-based therapies for treatment of AIHA and other antibody-mediated autoimmune disorders in humans.