Uricase formulated with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies.
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.


CONCLUSIONS
It is anticipated that uricase-PEG 20 may have utility as a treatment for hyperuricemia and gout.
Bomalaski
John S
JS
Department of Biology, University of Kentucky, Lexington 40506, USA.
Holtsberg
Frederick W
FW
Ensor
C Mark
CM
Clark
Mike A
MA
D000818:Animals; D001682:Biological Availability; D002175:Candida; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D033461:Hyperuricemia / Q000503:physiopathology*; D007273:Injections, Intramuscular; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011995:Recombination, Genetic; D012680:Sensitivity and Specificity; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013552:Swine; D014503:Urate Oxidase / Q000494:pharmacology*; D014527:Uric Acid / Q000378:metabolism*
D014527:Uric Acid; D011092:Polyethylene Glycols; D014503:Urate Oxidase