Engineering polynorbornene based uricase conjugates for gout therapy

Protein-polymer conjugation improves pharmacokinetics and pharmacodynamics and has successfully been used to improve the therapeutic value of proteins. Polyethylene glycol (PEG) has been considered as the golden standard in protein-polymer conjugation since the pioneering discovery by Abuchowski et.al in 1977. There are more than 24 FDA-approved PEGylated protein therapeutics for health conditions ranging from anemia to acute lymphoblastic leukemia. On the other hand, anti-PEG antibodies were found soon after the discovery of protein PEGylation. An alarming 42% of healthy humans have anti-PEG antibodies as reported by Yang et. al in 2015. Therefore, PEGylated version of uricase enzyme, used for the treatment of gout called Pegloticase was met with 38% of patients eliciting anti-PEG antibodies in Phase I and 89% patients in the Phase III trials leading to a loss of treatment response, increased drug clearance, and risk of infusion reactions and adverse events in at least 90% of the patients.

So evidently, the presence of anti-PEG antibodies could potentially lead to a loss of treatment response and adverse reactions in any PEG-based therapeutics and thus demands us to engineer an alternative for PEG. Towards this goal, we are studying the potential of ROMP-derived water-soluble polynorbornene polymers and their potential to reduce the immunogenicity of native uricase enzyme. The uricase enzyme was modified by random conjugation mediated by lysine residues. The conjugates were purified by FPLC and ELISA test will be done for immunogenicity studies.

Scheme 1: Synthesis of Uricase conjugates