Uricase Formulated with Polyethylene Glycol (Uricase-PEG 20): Biochemical Rationale and Preclinical Studies

JOHN S. BOMALASKI, FREDERICK W. HOLTSBERG, C. MARK ENSOR, and MIKE A. CLARK

ABSTRACT.

Objective. Humans have a non-sense codon inserted into the 5 prime end of the open reading frame of urate oxidase, and thus express an enzymatically inactive fragment of this enzyme; and consequently are unable to metabolize uric acid into allantoin and are prone to develop hyperuricemia and gout. Various urate oxidases (uricase) from mammals and microorganisms have been administered to humans with hyperuricemia and gout. Although successful in lowering plasma uric acid, these therapies have had limited application due to undesirable biochemical properties of the enzymes used, the short circulating half-life, and inherent antigenicity of these preparations.

Methods. We compared urate oxidase from a variety of sources for specific enzyme activity, pH optimum, affinity, and retention of enzyme activity under physiological conditions. A variety of polyethylene glycols (PEG) were tested to formulate uricase.

Results. Urate oxidase from Candida utilis had more favorable enzymatic properties and PEG of 20,000 MW (termed uricase-PEG 20) had greatly reduced antigenicity and increased circulating half-life as compared to those previously described.

Conclusion. It is anticipated that uricase-PEG 20 may have utility as a treatment for hyperuricemia and gout. (J Rheumatol 2002;29:1942-9)

Key Indexing Terms:

URICASE
URIC ACID
GOUT
URATE OXIDASE

---

From the Department of Biology, University of Kentucky, and Phoenix Pharmacologies, Inc., Lexington, Kentucky, USA.

Supported by US National Institutes of Health R43 CA85023-01A and R44 CA78028-02A1.

J.S. Bomalaski, MD, Professor; F.W. Holtsberg, PhD, Assistant Professor; C.M. Ensor, PhD, Assistant Professor; M.A. Clark, PhD, Professor.

Address reprint requests to Dr. M.A. Clark, Department of Biology, University of Kentucky, Lexington, KY 40506. E-mail: mclark@phoenixpharm.org

Submitted November 14, 2001; revision accepted February 7, 2002.

---