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Development of PEGylated mammalian urate oxidase as a therapy for patients with refractory gout

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PEGylated Protein Drugs: Basic Science and Clinical Applications

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

Gout is a form of arthritis caused by inflammatory crystals of monosodium urate, which deposit in joints when the plasma concentration of uric acid chronically exceeds the limit of solubility, ∼7 mg/dL (0.42 mM). The human species is predisposed to hyperuricemia and gout by mutation of the urate oxi dase gene during evolution. Urate oxidases from various sources have been used as a model to inves tigate the effects of PEGylation in animals. More than 15 years ago we initiated a project to develop a PEGylated recombinant mammalian urate oxidase as an Orphan Drug for treating patients with refractory gout. Clinical testing of this PEG-uricase, now called pegloticase, began in 2001. Pegloticase was found to have a half-life in plasma of about two weeks, and when infused at 2–4 week intervals to rapidly correct hyperuricemia. PEGylation was effective in limiting immune recognition of the recombinant uricase protein, but antibodies to PEG develop in some patients, resulting in the rapid clearance of pegloticase and loss of efficacy. However, in many patients with refractory gout, treatment with pegloticase maintains plasma urate at well below saturating concentrations, leading to elimination of tissue urate deposits and control of disease.

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Author information

Authors and Affiliations

  1. Duke University Medical Center, Box 3049, 418 Sands Building, Durham, NC, 27710, USA

    Michael S. Hershfield, John S. Sundy, Nancy J. Ganson & Susan J. Kelly

Authors
  1. Michael S. Hershfield
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  2. John S. Sundy
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  3. Nancy J. Ganson
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  4. Susan J. Kelly
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Editors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Padova, 35131, Padova, Italy

    Francesco M. Veronese

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© 2009 Birkhäuser Verlag/Switzerland

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Hershfield, M.S., Sundy, J.S., Ganson, N.J., Kelly, S.J. (2009). Development of PEGylated mammalian urate oxidase as a therapy for patients with refractory gout. In: Veronese, F.M. (eds) PEGylated Protein Drugs: Basic Science and Clinical Applications. Milestones in Drug Therapy. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8679-5_13

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