Engineering a Potent Immune-evading Uricase

Abstract The accumulation of uric acid in the urinary tract, blood stream, or tissues causes a pathological condition known as hyperuricemia, which leads to a variety of acute and chronic diseases including gout. Gout alone afflicts more than 8 million Americans, causing acute pain and potentially even chronic functional impairment. While a number of drugs have been developed to treat symptoms and to limit production or increase excretion of uric acid, these drugs do not suffice for the majority of gout patients. A powerful alternative therapeutic approach is to directly attack uric acid deposits, using the enzyme uricase to degrade uric acid into products that are readily excreted. Unfortunately, while one uricase variant (pegloticase, or Krystexxa®) has been approved for treatment of chronic refractory gout, it suffers from severe immunogenicity-associated problems. In particular it carries black box warnings for anaphylaxis and other detrimental outcomes, along with a fairly short period of therapeutic efficacy for many patients, who have to discontinue treatment due to the development of antidrug antibodies. Stealth Biologics® has developed a leading-edge immuno engineering platform, integrating computational protein design, high-throughput protein engineering, and exquisitely sensitive immunoassays. We have a proven track record of using this platform to render non-human enzymes (among other types of proteins) “stealth”y, evading immune recognition while still maintaining potent therapeutic function. We propose here to systematically overcome uricase’s immunogenicity problems by addressing the root sources of immune recognition, using our platform to develop a high-function, low-immunogenicity candidate. This molecule will then serve as the basis for a phase II project to further advance the lead candidate towards IND-enabling studies and ultimately an effective treatment for gout and other hyperuricemia-associated diseases.Project Narrative: The enzymatic function of uricase, degrading uric acid, is potentially very beneficial in the treatment of gout and other diseases that stem from uric acid accumulation. However, due to its non-human nature, uricase can trigger immune reactions; consequently, approved uricase-based therapeutics have immunogenicity-associated black box warnings, and many patients cannot remain on therapy for long due to the development of detrimental antidrug antibodies. Here, Stealth Biologics® will use its powerful immune engineering platform, proven to render proteins “stealth”y with regard to immune surveillance, in order to develop a functionally deimmunized lead uricase variant that evades the immune response while maintaining a potent ability to degrade uric acid.