Recombinant Fc receptor therapeutics for systemic lupus erythematosus

描述(申请人提供)：系统性红斑狼疮(SLE或狼疮)是一种影响多个器官的系统性自身免疫性疾病，在女性和非裔美国人中发病率较高。近90%的受影响人口是女性，在非裔美国人中发生的频率是女性的3倍。系统性红斑狼疮对人类是致命的，会导致重要器官损伤、残疾和死亡。在SLE中，自身抗体和自身抗原之间形成的免疫复合体(IC)与炎症细胞上的Fcγ受体(Fc3Rs)结合并触发它们，导致终末器官损害。狼疮易感小鼠Fc3Rs基因缺失导致狼疮小鼠对自发性狼疮的抵抗或减弱，这表明通过阻断IC与Fc3Rs的相互作用来治疗狼疮样疾病是可能的。到目前为止，基于Fc3R的治疗方法一直受到Fc3Rs低亲和力的阻碍，这就需要给药生理上无法达到的重组Fc受体水平。此外，即刻高水平的循环免疫球蛋白将中和高亲和力重组Fc受体的作用。我们实验室最近的研究表明，高亲和力的低亲和力Fc3Rs融合蛋白，如CD16AIg，通过将突变的IgG1的Fc结构域连接到Fc3Rs的胞外域而产生，与细胞表面的Fc3Rs竞争，并阻断巨噬细胞对抗体包裹的细胞的IC结合和吞噬。体内注射的CD16AIg二聚体不结合单体免疫球蛋白，但仍能稳定结合多价免疫球蛋白，阻断免疫球蛋白诱导的小鼠组织损伤、中性粒细胞迁移和肥大细胞脱颗粒。基于这些证据，我们推测，给予高亲和力的低亲和力Fc3Rs二聚体将有效地减轻或延缓狼疮的终末器官损害。我们建议：1)确定给予Fc3RIg二聚体是否可以预防、延迟或减轻抗体诱导的小鼠肾小球肾炎；2)通过使用狼疮易感NZB/NZW F1小鼠和CD32A转基因小鼠模型，研究通过给予诱骗Fc3RIg受体来中和IC对狼疮肾炎进展的影响；3)确定二聚体注射阻断IC与炎症细胞的结合是否导致狼疮易感小鼠炎症细胞因子的产生减少。从拟议的探索性研究中获得的知识将为设计和使用基于低亲和力的重组Fc3RIg二聚体治疗人类狼疮性肾炎提供重要信息。公共卫生相关性：系统性红斑狼疮(SLE或狼疮)是人类的一种慢性系统性自身免疫性疾病，影响多个器官，近90%的受影响人群是女性，在非裔美国人中发病率高出3倍。目前的提案计划开发和测试基于Fc3R的新的重组治疗策略，该策略将阻断表达在炎症细胞上的Fc3R自身抗体的相互作用。从拟议的临床前研究中获得的知识将对基于Fc3R的重组疗法的发展产生影响，以治疗人类系统性红斑狼疮。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE or lupus) is a systemic autoimmune disease that affects multiple organs and has a high incidence in women and African Americans. Nearly 90% of the affected populations are women, and it occurs 3 times more frequently in African Americans. SLE is fatal in humans and leads to vital organ damage, disability, and death. In SLE, the immune complexes (IC) formed between autoantibodies and self-antigens bind to Fc gamma receptors (Fc3Rs) on inflammatory cells and trigger them, resulting in end organ damage. Genetic deletion of Fc3Rs in lupus-prone mice results in resistance to or attenuation of spontaneous lupus in mice, which suggest that it is possible to treat lupus-like diseases by blocking the interaction of IC with Fc3Rs. So far, Fc3R-based therapeutic approaches have been hampered by the low affinity of Fc3Rs, which necessitates the administration of physiologically unattainable levels of recombinant Fc receptors. Furthermore, the high level of circulating IgG immediately will neutralize the action of high affinity recombinant Fc receptors. Recent studies from our laboratory show that high avidity dimeric forms of low affinity Fc3Rs fusion proteins like CD16AIg, created by attaching a mutated Fc domain of IgG1 to the extracellular domain of Fc3Rs, compete with cell surface Fc3Rs and block IC binding and phagocytosis of antibody-coated cells by macrophages. CD16AIg dimers administered in vivo do not bind monomeric IgG but are still available to bind multivalent IC stably and block IC-induced tissue damage, neutrophil emigration, and mast cell degranulation in mice. Based on such evidence, we hypothesize that the administration of high avidity dimers of low affinity Fc3Rs will effectively attenuate or delay the end-organ damage in lupus. We propose to: 1) Determine whether administration of Fc3RIg dimers can prevent, delay, or attenuate antibody-induced glomerulonephritis in mice; 2) Investigate the consequences of neutralizing IC by administering decoy Fc3RIg receptors on the progression of lupus nephritis using lupus-prone NZB/NZW F1 mice and CD32A transgenic mice models; 3) Determine whether blocking IC binding to inflammatory cells by dimer administration leads to decreased production of inflammatory cytokines in lupus prone mice. The knowledge obtained from the proposed exploratory studies will provide important information about the design and use of low affinity recombinant Fc3RIg dimer-based therapeutics to treat lupus-nephritis in humans. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus (SLE or lupus) is a chronic systemic autoimmune disease in humans that affects multiple organs with nearly 90% of the affected populations being women and occur 3 times more frequently in African Americans. The current proposal plans to develop and test novel recombinant Fc3R-based therapeutic strategy that will block the interaction of autoantibodies to Fc3R- expressed on inflammatory cells. The knowledge obtained from the proposed preclinical studies will have an impact on the development of recombinant Fc3R-based therapeutics to treat SLE in humans.