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

描述（由申请人提供）：该申请代表了一种跨学科的方法来模拟体内工程抗体的行为。在母体研究中，我们提出通过改变与Fc受体（FcRn）的结合来产生工程化抗体，从而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。该基金计划在关节炎小鼠模型中测试具有不同FcRn结合特性的Abdegs的功效。Abdeg活性的数学模型有望提供重要的新见解，并有助于评估和设计具有改进性能的Abdeg。这些模型在设计使用Abdegs的治疗策略时也具有不可估量的价值。总体目标是开发和验证基于Abdeg-FcRn相互作用动力学常数的内源性IgG水平预测的数学模型。这些模型将根据将在家长拨款和本补充中产生的实验数据进行开发和广泛验证。我们的研究计划涉及分子免疫学家（E. Sally Ward）和生物工程师（Leonidas Bleris）之间的新合作。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。他最近加入了德州大学达拉斯分校电气工程系的生物工程部门，并对与德州大学西南分校的教师发展互动非常感兴趣。因此，我们认为这个项目是一个令人兴奋的，协同的冒险，将有利于沃德和Bleris实验室。总之，这项研究代表了一种高度跨学科的合作，旨在建立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。

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.