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

Ut Southwestern Medical Center, Dallas TX

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Abstract

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.