Research Project
10267479
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 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 a water soluble metabolic that is 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 an AI-driven immune-engineering platform, integrating computational protein design, high-throughput protein engineering, and exquisitely sensitive immunoassays. We have used our platform technology to engineered deimmunized uricase variants under a Phase I SBIR program, and several of the deimmunized enzymes from our pipeline exceed all the performance specifications of the Phase I grant. Here, we propose to execute advanced preclinical development of our lead candidate deimmunized uricase. Studies will include large scale testing with human primary immune cells to validate reduced immunogenicity risk across genetically diverse patient populations, functional and stability analysis in human serum, development of a scalable commercial production system and associated drug substance release assays, in vivo immunological and efficacy testing in humanized HLA transgenic mice (the preferred preclinical model for assessing antidrug antibody responses against T cell epitope engineered biotherapeutics), and toxicokinetic analysis in standard rodent and non-rodent preclinical models. We have assembled a top-talent team to ensure the success of the proposed development program, including the physician-scientist who led clinical translation of one of the two FDA-approved uricase biotherapies that are currently on the market. The combined results of this Phase II SBIR will yield a Target Product Profile and will position our deimmunized uricase for subsequent IND-enabling studies and clinical translation. Ultimately, our innovative immune-evading uricase promises to be breakthrough therapy for the 100+ million sufferers of gout and hyperuricemia world-wide.
