An Engineered Human Follistatin Variant: Insights into the Pharmacokinetic and Pharmocodynamic Relationships of a Novel Molecule with Broad Therapeutic Potential

摘要: Human follistatin is a regulatory glycoprotein with widespread biological functions including anti-inflammatory activities, wound healing properties and muscle stimulating effects. The role of in wide range activities shows promise for potential clinical application, which has prompted considerable interest the investigation protein as disease modifying agent. In spite this potential, development a broad use biotherapeutic been severely hindered by poor understanding characterization its pharmacokinetic pharmacodynamic (PK/PD) relationships. Therefore, to better define these relationships, we performed in-depth analyses PK/PD relationships native follistatin-315. Our data indicates that intrinsic native follistatin-315 are poorly suited acting parentally administered broad systemic Herein, leveraged engineering modify PK characteristics molecule fusing follistatin-315 murine IgG1 Fc removing heparan sulfate binding activity follistatin. engineered variant had ~100- ~1600-fold improvements terminal half-life exposure, respectively. contrast follistatin-315, showed robust, dose-dependent pharmacological effect when subcutaneously on weekly basis mouse models atrophy degeneration. These studies highlight underappreciated critical relationship between optimizing multiple physical chemical overall profile. Moreover, our findings provide first documented strategy towards a follistatin therapeutic utility patients affected skeletal diseases.