Non-Immunogenic PEG-like Conjugates of Uricase

ABSTRACT Covalent conjugation of therapeutic peptides and proteins with the “stealth” polymer poly(ethylene glycol) (PEG), termed PEGylation, is a widely used approach to increase the circulation half-life and stability of “biologics” —peptide, protein and oligonucleotide drugs— and to reduce their immunogenicity. However, recent studies show that PEG is itself immunogenic, as anti-PEG antibodies have been induced in patients treated with some PEGylated drugs, and circulating anti-PEG antibodies have also been found in individuals naïve to PEGylated therapeutics, possibly induced by chronic exposure to PEGs present in consumer products. Motivated by this compelling clinical need and commercial opportunity, the overall objective of this STTR proposal is to develop biologic conjugates of a novel PEG-like polymer — poly(oligoethyene glycol methyl methacrylate) (POEGMA), wherein the PEG chain is distributed as short oligoethylene glycol (OEG) oligomers along a polymer backbone (Fig. 1) — to eliminate PEGandapos;s immunogenicity while preserving its ability to prolong plasma half life. The outcome of this project, if successful, will be the identification of a POEGMA conjugate with the same or better activity as the linear PEG conjugate, but with minimal PEG antigenicity and reduced overall immunogenicity, thereby providing a next-generation technology that is superior to PEGylation.PROJECT NARRATIVE PEGylation —the conjugation of polyethylene glycol (PEG) to biologics— is commonly used to overcome the short plasma half-life of peptide and protein drugs. However, PEG is now known to be immunogenic, and anti-PEG antibodies are present in ~50% of the US population, likely due to the ubiquitous use of PEG in common consumer products. Anti-PEG antibodies have led to the early termination of a Phase III clinical trial of a PEGylated drug candidate and have caused several PEGylated drugs to be withdrawn from the market because of severe allergic reactions in some patients. This application proposes to eliminate the negative interaction of PEGylated therapeutics with anti-PEG antibodies by developing “PEG-like” POEGMA conjugates that do not interact with anti- PEG antibodies.