AGalactosidase urate oxidase and laronidase

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Recombinant a-galactosidase, urate oxidase and laronidase represent additional biopharmaceuti-cals recently approved for general medical use. a-Galactosidase is approved for long-term enzyme replacement therapy in patients with Fabry disease. Like Gaucher's disease, Fabry disease is a genetic disease of lipid metabolism. Sufferers display little or no liposomal a-galactosidase-A activity. This results in the progressive accumulation of glycosphingolipids in several body cell types. Resultant clinical manifestations are complex, affecting the nervous system, vascular en-dothelial cells and major organs. Although the condition is rare (500-1000 patients within the EU), untreated sufferers usually die in their 40s or 50s.

Two recombinant a-galactosidases are now on the market (Fabrazyme, produced by Genzyme and Replagal, produced by TKT Europe). Fabrazyme is produced in an engineered CHO cell line, and downstream processing entails a combination of five chromatographic purification steps followed by concentration and diafiltration. Excipients added include mannitol and sodium phosphate buffering agents, and the final product is freeze-dried after filling into glass vials. Replagal is produced in a continuous human cell line and is also purified by a combination of five chroma-tographic purification steps, although it is marketed as a liquid solution.

Human a-galactosidase is a 100 kDa homodimeric glycoprotein. Each 398 amino acid monomer displays a molecular mass of 45.3 kDa (excluding the glycocomponent) and is glycosylated at three positions (asparagines 108, 161 and 184). After administration (usually every second week by a 40 min infusion), the enzyme is taken up by various body cell types and directed to the lysosomes. This cellular uptake and delivery process appear to be mediated by mannose-

6-phosphate residues present in the oligosaccharide side-chains of the enzyme. Mannose-6-phos-phate receptors are found on the surfaces of various cell types, and also intracellularly, associated with the golgi complex, which then directs the enzyme to the lysosomes.

The enzyme urate oxidase has also found medical application for the treatment of acute hype-ruricaemia (elevated plasma uric acid levels), associated with various tumours, particularly during their treatment with chemotherapy.

Uric acid is the end-product of purine metabolism in humans, other primates, birds and reptiles. It is produced in the liver by the oxidation of xanthine and hypoxanthine (Figure 12.16),

Purine nucleotides GMP/AMP

Purine nucleotides GMP/AMP

(Excreted by many primates, birds, reptiles and insects)

Urate oxidase

(Excreted by amphibians and some fish)

(Excreted by amphibians and some fish)

Urate oxidase

0

H

nh2

C"

N H

H

Allantoin

(Excreted by most mammals)

(Excreted by most mammals)

ammonium ion

(Excreted by marine invertebrates)

NH4+

Figure 12.16 Summary overview of purine metabolism and is excreted via the kidneys. Owing to its relatively low solubility, an increase in serum uric acid levels often triggers the formation and precipitation of uric acid crystals, typically resulting in conditions such as gout or urate stones in the urinary tract. Significantly elevated serum uric acid concentrations can also be associated with rapidly proliferating cancers or, in particular, with onset of chemotherapy. In the former instance, rapid cellular turnover results in increased rates of nucleic acid catabolism and, hence, uric acid production. In the latter case, chemotheraphy-in-duced cellular lysis results in the release of intracellular contents, including free purines and pu-rine-containing nucleic acids, into the bloodstream. The increased associated purine metabolism then triggers hyperuricaemia. The elevated uric acid concentrations often trigger crystal formation in the renal tubules, and hence renal failure.

Purine metabolism in some mammals is characterized by a further oxidation of uric acid to al-lantoin by the enzyme urate oxidase. Allantoin is significantly more water soluble than uric acid and is also freely excreted via the renal route.

Administration of urate oxidase to humans suffering from hyperuricaemia results in the reduction of serum uric acid levels through its conversion to allantoin. Urate oxidase purified directly

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