Mechanistic studies of FcRn inhibitors for the treatment of IgG-mediated diseases

FcRn抑制剂治疗IgG介导疾病的机制研究

• 批准号: 8274344
• 负责人: ELIZABETH SALLY WARD
• 金额: $ 21.23万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-08 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274344
• 关键词: Address; Adverse effects; Animal Model; Antibodies; Autoimmune Diseases; Autoimmunity; Binding; Cells; Chronic; Clinical; Competitive Binding; Complex; Disease; Early Endosome; Engineering; Enhancing Antibodies; Fc Immunoglobulins; Fc Receptor; Funding; Generations; Goals; Graft Rejection; Half-Life; Health; Homeostasis; Humoral Immunities; Immunoglobulin G; Immunosuppressive Agents; In Vitro; Investigation; Knowledge; Life; Longevity; MHC Class I Genes; Mediating; Modeling; Molecular; Mus; Mutagenesis; Mutate; Mutation; Nature; Parents; Pathogenesis; Pharmaceutical Preparations; Play; Process; Property; Reagent; Regulation; Research; Rheumatoid Arthritis; Role; Site; System; Systemic Lupus Erythematosus; Testing; Therapeutic; Toxin; antibody engineering; design; effective therapy; human disease; in vivo; in vivo Model; inhibitor/antagonist; insight; interest; model design; mouse model; neonatal Fc receptor; receptor; research study

DESCRIPTION (provided by applicant): The regulation of immunoglobulin G (IgG) levels in vivo represents a fundamental aspect of humoral immunity. A central player in this process is the non-classical Fc receptor, FcRn, that transports IgGs within and across cells and salvages them from lysosomal degradation. The current application is directed towards mechanistic studies of engineered antibodies that are designed to inhibit the salvage function of FcRn. Our approach is to engineer Fc fragments so that they competitively inhibit the binding of wild type IgGs to FcRn and thereby enhance their degradation. Such engineered antibodies, or Abdegs (for `antibodies that enhance IgG degradation'), can be used to lower IgG levels in mice. As such, Abdegs hold promise as therapeutics for the clearance of IgGs in antibody-mediated diseases and in inducing the elimination of IgG-drug or IgG-toxin complexes. However, to date, the mechanisms and properties of Abdeg activity are poorly characterized. For example, it is not well understood how the biophysical nature of Abdeg-FcRn interactions correlates with inhibitory activity. The efficacy of Abdegs in the treatment of IgG-mediated autoimmunity has also not been analyzed. Our experiments are designed to address these and other questions, and will involve the use of in vitro and in vivo murine systems. The Specific aims of the current study are: 1. To understand how Fc-FcRn interaction properties impact FcRn function using in vitro systems; 2. To analyze the effects of potential Abdegs with distinct properties on endogenous IgG levels; 3. To analyze the effects of Abdegs in murine models of rheumatoid arthritis. This comprehensive mechanistic study in animal models constitutes a crucial component of our longer term research goal, which is to use Abdegs for the treatment of human disease. In addition, this project should provide valuable insight into the molecular mechanisms that regulate the transport and dynamics of IgGs in vivo. PUBLIC HEALTH RELEVANCE The current application is directed towards the generation and characterization of a class of engineered antibodies that can be used to lower the levels of immunoglobulin G (IgG). Such engineered antibodies would have applications in many clinical situations, such as for the treatment of IgG-mediated autoimmunity (e.g. rheumatoid arthritis and systemic lupus erythematosus) and the clearance of toxins or drugs from the body. We seek funds to carry out mechanistic and efficacy studies in mouse models that are a prerequisite to the use of these reagents to treat human disease.

描述（由申请人提供）：体内免疫球蛋白 G (IgG) 水平的调节代表体液免疫的基本方面。这一过程中的核心角色是非经典 Fc 受体 FcRn，它在细胞内和细胞间运输 IgG，并将其从溶酶体降解中拯救出来。目前的申请针对旨在抑制 FcRn 挽救功能的工程化抗体的机制研究。我们的方法是改造 Fc 片段，使其竞争性抑制野生型 IgG 与 FcRn 的结合，从而增强其降解。这种工程抗体或 Abdegs（“增强 IgG 降解的抗体”）可用于降低小鼠的 IgG 水平。因此，Abdegs 有望成为抗体介导疾病中 IgG 清除以及诱导 IgG-药物或 IgG-毒素复合物消除的治疗药物。然而，迄今为止，Abdeg 活性的机制和特性尚不清楚。例如，目前尚不清楚 Abdeg-FcRn 相互作用的生物物理性质如何与抑制活性相关。 Abdegs 在治疗 IgG 介导的自身免疫性疾病中的功效也尚未得到分析。我们的实验旨在解决这些和其他问题，并将涉及体外和体内小鼠系统的使用。当前研究的具体目标是： 1. 利用体外系统了解 Fc-FcRn 相互作用特性如何影响 FcRn 功能； 2. 分析具有不同特性的潜在Abdegs对内源性IgG水平的影响； 3. 分析Abdegs在类风湿关节炎小鼠模型中的作用。这项动物模型综合机制研究构成了我们长期研究目标的重要组成部分，即利用 Abdegs 治疗人类疾病。此外，该项目应该为调节体内 IgG 运输和动力学的分子机制提供有价值的见解。公共卫生相关性当前的申请针对一类可用于降低免疫球蛋白 G (IgG) 水平的工程化抗体的生成和表征。这种工程抗体将在许多临床情况下得到应用，例如用于治疗 IgG 介导的自身免疫（例如类风湿性关节炎和系统性红斑狼疮）以及清除体内的毒素或药物。我们寻求资金在小鼠模型中进行机制和功效研究，这是使用这些试剂治疗人类疾病的先决条件。