A Therapeutic Uricase with Reduced Immunogenicity and Improved Pharmacokinetics

Thesis (Master's)--University of Washington, 2020Due to the lack of uricase, humans are not capable of oxidizing uric acid in their bodies. High level of uric acid in serum may cause crystallization in joints and acute inflammation with severe pain, known as gout. Uricase is a protein of the promising therapeutic value for patients with gout, but it still meets several challenges, such as the short blood-circulation life, instability and inherent immunogenicity of an exogenous enzyme. Chemical conjugation of poly (ethylene glycol) (PEG) is one of the methods to address this issue, but pre-existing and induced PEGspecific antibodies can cause adverse side effects. Here, we reported a novel hydrophilic polypeptide for uricase modification. We studied the thermal stability and in Vivo pharmacokinetics of this polypeptide-protein conjugates. Results show improved thermal stability and prolonged in vivo half-life circulation and a feasible method for highly immunogenic therapeutic proteins