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: 7656698
• 负责人: ELIZABETH SALLY WARD
• 金额: $ 34.54万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656698
• 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; 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; public health relevance; 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）水平的调节代表了体液免疫的基本方面。在此过程中的核心参与者是非经典FC受体FCRN，它在细胞内和跨细胞内运输IgG，并从溶酶体降解中挽救它们。当前的应用针对工程抗体的机械研究，这些抗体旨在抑制FCRN的打捞功能。我们的方法是设计FC碎片，以便它们有竞争力抑制野生型IgG与FCRN的结合，从而增强其降解。这种工程化的抗体或Abdegs（对于增强IgG降解的抗体）可用于降低小鼠的IgG水平。因此，阿卜杜勒（Abdegs）作为抗体介导的疾病中IgG的治疗疗法有希望，并诱导消除IgG-drug或IgG-Toxoxin复合物。但是，迄今为止，Abdeg活性的机制和特性的表征很差。例如，尚不清楚Abdeg-FCRN相互作用的生物物理性质与抑制活性相关。尚未分析Abdegs治疗IgG介导的自身免疫性的功效。我们的实验旨在解决这些问题和其他问题，并将涉及体外和体内鼠系统的使用。当前研究的具体目的是：1。了解FC-FCRN相互作用如何使用体外系统影响FCRN功能； 2。分析具有不同特性对内源性IgG水平的潜在abdegs的影响； 3。分析阿卜杜勒在类风湿关节炎的鼠模型中的影响。这项在动物模型中的全面机械研究构成了我们长期研究目标的关键组成部分，即使用Abdegs治疗人类疾病。此外，该项目应对调节体内IgG的运输和动力学的分子机制提供宝贵的见解。公共卫生相关性目前的应用是针对一类工程抗体的生成和表征，这些抗体可用于降低免疫球蛋白G（IgG）的水平。这种工程的抗体将在许多临床情况下应用，例如治疗IgG介导的自身免疫性（例如类风湿关节炎和全身性红斑狼疮），以及从体内清除毒素或药物。我们寻求资金在小鼠模型中进行机械和功效研究，这是使用这些试剂治疗人类疾病的先决条件。