Recombinant Fc receptor therapeutics for systemic lupus erythematosus

描述（由申请人提供）：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，在女性和非洲裔美国人中发病率较高。近90%的受影响人群是女性，非裔美国人的发病率是女性的3倍。SLE在人类中是致命的，并导致重要器官损伤、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物（IC）与炎性细胞上的Fc γ受体（Fc 3R）结合并触发它们，导致终末器官损伤。在狼疮易感小鼠中Fc 3Rs的基因缺失导致小鼠对自发性狼疮的抵抗或减弱，这表明有可能通过阻断IC与Fc 3Rs的相互作用来治疗狼疮样疾病。到目前为止，基于Fc 3R的治疗方法受到Fc 3R的低亲和力的阻碍，这需要施用生理上无法达到的水平的重组Fc受体。此外，高水平的循环IgG将立即中和高亲和力重组Fc受体的作用。我们实验室最近的研究表明，通过将突变的IgG 1 Fc结构域连接到Fc 3 R的胞外结构域而产生的低亲和力Fc 3 R融合蛋白（如CD 16 AIg）的高亲合力二聚体形式与细胞表面Fc 3 R竞争，并阻断IC结合和巨噬细胞对抗体包被细胞的吞噬作用。体内施用的CD 16 Alg二聚体不结合单体IgG，但仍可用于稳定地结合多价IC并阻断小鼠中IC诱导的组织损伤、中性粒细胞移出和肥大细胞脱粒。基于这样的证据，我们假设施用低亲和力Fc 3R的高亲合力二聚体将有效地减弱或延迟狼疮中的终末器官损伤。我们建议：2）使用狼疮易感NZB/NZW F1小鼠和CD 32A转基因小鼠模型，研究通过施用诱饵Fc 3RIg受体中和IC对狼疮肾炎进展的影响; 3）确定通过二聚体施用阻断IC与炎性细胞的结合是否导致狼疮易感小鼠中炎性细胞因子的产生减少。从所提出的探索性研究中获得的知识将提供关于设计和使用基于低亲和力重组Fc 3RIg二聚体的治疗剂来治疗人类狼疮肾炎的重要信息。公共卫生相关性：系统性红斑狼疮（SLE或狼疮）是一种慢性全身性自身免疫性疾病，影响多个器官，近90%的受影响人群为女性，在非裔美国人中的发生频率是女性的3倍。目前的建议计划开发和测试新的重组Fc 3R为基础的治疗策略，将阻止自身抗体的相互作用，Fc 3R-表达的炎症细胞。从拟议的临床前研究中获得的知识将对开发基于Fc 3 R的重组疗法治疗人类SLE产生影响。

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.