Design of Fc-conjugated protein therapeutics using computational modeling of protein-protein interaction energetics

Abstract

Summary form only given. The long-term goal of this research is to combine computational structural biology with quantitative cell biology to rationally develop therapeutic proteins with increased half-lives. Therapeutic proteins with increased half-lives should decrease the frequency of injections and allow the administration of low and potentially non-toxic concentrations of protein. Our approach for addressing this challenge is to conjugate a therapeutic protein to a protein fragment with a long half-life. The Fc fragment of immunoglobulin G (IgG) has a long half-life due to its propensity for being recycled in the vascular endothelium. Specifically, when IgG enters the endosomes of these epithelial cells, the neonatal Fc receptor, FcRn, binds to the Fc fragment of IgG. This binding of FcRn to Fc has been experimentally found to enhance the recycling of IgG back to the cell surface, which decreases the amount of IgG that is degraded in the lysosomes. Since there is potential for engineering Fc fragments with even longer halflives, we want to develop guidelines for identifying appropriate mutations. The interaction between Fc and FcRn must therefore be fundamentally understood, and theoretical models for studying this interaction will be validated in this presentation by comparing theoretical predictions with available experimental data.