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

描述（由申请人提供）：本申请代表了一种跨学科的方法，用于模拟体内工程抗体的行为。在母基金中，我们提出通过改变与Fc受体FcRn的结合来产生工程抗体，可以降低体内内源性免疫球蛋白G（IgG）水平。因此，这些抗体（称为“Abdegs”，用于增强IgG降解的抗体）具有治疗抗体介导的自身免疫性疾病如关节炎的潜力。该基金会计划在关节炎小鼠模型中测试对FcRn具有不同结合特性的Abdegs的功效。数学模型的Abdeg活动承诺提供重要的新的见解和援助的评估和设计的Abdegs与改进的性能。这些模型在使用Abdegs设计治疗策略时也是非常宝贵的。总体目标是开发和验证数学模型，该模型允许基于Abdeg-FcRn相互作用的动力学常数预测内源性IgG水平。这些模型将被开发和广泛验证的基础上，将在母公司补助金和本补充产生的实验数据。我们这项研究的研究建议涉及一个新的合作分子免疫学家（E。Sally Ward）和生物工程师Leonidas Bleris。Bleris博士是生物系统建模方面的专家，包括药物输送和基因网络领域。他最近加入了UT达拉斯电气工程系的生物工程单元，并对与UT西南部的教师进行互动非常感兴趣。因此，我们认为这个项目是一个令人兴奋的，协同的风险，将有利于沃德和Bleris实验室。总之，这项研究因此代表了一个高度跨学科的合作，以产生体内抗体行为的预测模型，这反过来又与抗体在治疗中的成功使用直接相关。 公共卫生相关性：这项拟议的研究有望揭示设计潜在的新治疗药物治疗自身免疫性疾病的重要见解。这种方法的跨学科性质有可能带来新的方法，从而大大改进设计过程。

DESCRIPTION (provided by applicant): This application represents an interdisciplinary approach towards modeling the behavior of engineered antibodies in vivo. In the parent grant we propose to generate engineered antibodies that through alterations in binding to the Fc receptor, FcRn, can lower endogenous immunoglobulin G (IgG) levels in vivo. As such, these antibodies (called 'Abdegs', for antibodies that enhance IgG degradation) have potential for the treatment of antibody-mediated autoimmune diseases such as arthritis. The parent grant plans to test the efficacy of Abdegs that have different binding properties for FcRn in mouse models of arthritis. Mathematical models of Abdeg activity promise to provide significant new insights and aid in the evaluation and design of Abdegs with improved properties. Such models can also be invaluable in designing treatment strategies using Abdegs. The overall goal is to develop and validate mathematical models that allow the prediction of endogenous IgG levels based on the kinetic constants of the Abdeg-FcRn interaction. These models will be developed and extensively validated based on the experimental data that will be generated in the parent grant and this supplement. Our research proposal for this study involves a new collaboration between a molecular immunologist (E. Sally Ward) and a bioengineer (Leonidas Bleris). Dr. Bleris is an expert in the modeling of biological systems, including in the areas of drug delivery and gene networks. He recently joined the Bioengineering unit in the Department of Electrical Engineering at UT Dallas and is very interested in developing interactions with faculty at UT Southwestern. We therefore see this project as an exciting, synergistic venture that will benefit both the Ward and Bleris laboratories. In summary, this study therefore represents a highly interdisciplinary collaboration towards the generation of predictive models for antibody behavior in vivo which in turn has direct relevance to the successful use of antibodies in therapy. PUBLIC HEALTH RELEVANCE: The proposed study promises to reveal important insights into the design of potential new therapeutic agents for the treatment of autoimmune diseases. The interdisciplinary nature of the approach has the potential to bring out new methodologies that will result in significant improvements in the design process.