Uricases as Therapeutic Agents to Treat Refractory Gout: Current States and Future Directions

Abstract

Treatment of refractory gout remains a challenge on drug development. While pegloticase, a recombinant mammalian uricase modified with monomethoxyl-poly(ethylene glycol) (mPEG) is effective in treating refractory gout, after continued treatment for three months biweekly at a therapeutic dose of 0.14 mg/kg body weight, it elicits an immune response against mPEG in nearly 20% of patients. For continued treatment of refractory gout PEGylated uricases at monthly therapeutic doses below 4 μg/kg body weight have promise. To formulate uricases to achieve monthly therapeutic regimens requires pharmacodynamics simulation and experimentation including: (a) molecular engineering of uricases based on rational design and evolution biotechnology in combination to improve their inherent catalytic efficiency, thermostability and selectivity for urate over xanthine and; (b) optimization of the number and distribution of accessible reactive amino acid residues in native uricases for site-specific PEGylation with PEG derivatives with lower of immunogenicity than mPEG to retain activity, minimize immunogenicity and enhance the pharmacokinetics of the PEGylated uricase. These issues are briefly reviewed as a means to stimulate the development of safer uricase formulations for continued treatment of refractory gout.

Evolutionary history and metabolic insights of ancient mammalian uricases

“…The buildup of serum urate in the blood (hyperuricemia) can have severe consequences for human health. As such, the medical community has a strong interest in developing a recombinant "human-like" uricase to treat gout, prevent tumor lysis syndrome, and control hyperuricemia in general (27). The difficulties in developing a therapeutic uricase are many-fold, but mostly rely on a compromise between activity, stability, and immunoreactivity in human patients.…”

PharmGKB summary

“…Allopurinol and its metabolite oxypurinol are analogues of hypoxanthine and xanthine, respectively, and work by binding to and inhibiting xanthine dehydrogenase (XDH), preventing the formation of uric acid (Figure 1) [1–5]. Hypoxanthine and xanthine are cleared in the urine or reutilized in the synthesis of nucleotides and nucleic acids [1, 6].…”

“…probenecid, benzbromarone, sulfinpyrazone) inhibit reabsorption of uric acid in the renal proximal tubule by targeting transporters (Figure 3) [2, 5]. Probenecid is recommended by the ACR as an alternative first line therapy in patients with gout in whom allopurinol/febuxostat are contraindicated [22].…”

“…Probenecid prevents the reabsorption of organic anions such as uric acid from the renal proximal tubule predominantly by inhibiting URAT1 ( SLC22A12 ) transporter protein activity [5, 66, 74, 75, 84]. It may also act upon OAT1 (SLC22A6), OAT4 (SLC22A11) and OAT10 [83–85].…”

Production and Optimization of Site-Specific monoPEGylated Uricase Conjugates Using mPEG-Maleimide Through RP–HPLC Methodology

“…Uricase is widely used to treat hyperuricemia and gout. Uricolytic therapy is fast-acting, highly effective and unveils less drug-drug interactions [5]. Uricases derived from natural sources possess lower thermostability, lower solubility, and higher sensitivity towards xanthine and are recognized as foreign antigens by the human body immune system [6,7].…”