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

描述(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一个基本方面。这一过程的核心是非经典的Fc受体，FcRN，它在细胞内和细胞之间运输IgG，并从溶酶体的降解中挽救它们。目前的应用是针对工程抗体的机制研究，这些抗体旨在抑制FcRN的挽救功能。我们的方法是设计Fc片段，使它们竞争性地抑制野生型IgG与FcRN的结合，从而增强它们的降解。这类工程抗体或Abdegs(即“增强免疫球蛋白降解的抗体”)可用于降低小鼠的免疫球蛋白水平。因此，Abdegs有望作为治疗药物，清除抗体介导的疾病中的IgG，并诱导消除免疫球蛋白药物或免疫球蛋白毒素复合体。然而，到目前为止，Abdeg活动的机制和性质还没有得到很好的描述。例如，Abdeg-FcRN相互作用的生物物理性质如何与抑制活性相关尚不清楚。Abdegs在治疗免疫球蛋白介导的自身免疫方面的疗效也没有得到分析。我们的实验旨在解决这些和其他问题，并将涉及使用体外和体内小鼠系统。本研究的具体目的是：1.利用体外系统了解Fc-FcRN相互作用对FcRN功能的影响；2.分析具有不同性质的潜在Abdegs对内源性免疫球蛋白水平的影响；3.分析Abdegs在类风湿关节炎小鼠模型中的作用。这项在动物模型中进行的全面机制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，该项目将为调节免疫球蛋白在体内的转运和动力学的分子机制提供有价值的见解。公共卫生相关性目前的应用是针对一类可用于降低免疫球蛋白G(IgG)水平的工程抗体的产生和表征。这种工程抗体将在许多临床情况下得到应用，例如用于治疗免疫球蛋白介导的自身免疫(如类风湿性关节炎和系统性红斑狼疮)和清除体内的毒素或药物。我们寻求资金在小鼠模型上进行机制和疗效研究，这是使用这些试剂治疗人类疾病的先决条件。

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.