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

描述（由申请人提供）：体内免疫球蛋白G （IgG）水平的调节是体液免疫的一个基本方面。在这一过程中，非经典Fc受体FcRn发挥了核心作用，它在细胞内和细胞间运输igg，并将它们从溶酶体降解中拯救出来。目前的应用是针对工程抗体的机制研究，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。这种工程抗体，或称为Abdegs（“增强IgG降解的抗体”），可用于降低小鼠体内的IgG水平。因此，abdeg有望成为清除抗体介导疾病中igg的治疗药物，并诱导消除igg -药物或igg -毒素复合物。然而，到目前为止，Abdeg活性的机制和性质尚不清楚。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介导的自身免疫中的疗效也未被分析。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小鼠系统的使用。本研究的具体目的是：1.研究目标：了解在体外系统中Fc-FcRn相互作用特性如何影响FcRn功能；2. 分析不同性质的潜在Abdegs对内源性IgG水平的影响；3. 目的：分析Abdegs在小鼠类风湿关节炎模型中的作用。这项在动物模型中进行的全面机制研究是我们长期研究目标的关键组成部分，该目标是使用Abdegs治疗人类疾病。此外，该项目将为体内调节igg转运和动力学的分子机制提供有价值的见解。目前的应用是针对一类工程抗体的产生和表征，可用于降低免疫球蛋白G （IgG）的水平。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（例如类风湿关节炎和系统性红斑狼疮）和清除体内毒素或药物。我们寻求资金在小鼠模型中开展机制和功效研究，这是使用这些试剂治疗人类疾病的先决条件。

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.