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Open Access Research article

Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout

Peter E Lipsky1*, Leonard H Calabrese2, Arthur Kavanaugh3, John S Sundy4, David Wright5, Marsha Wolfson6 and Michael A Becker7

Author Affiliations

1 1545 London Road, Charlottesville, VA 22901, USA

2 Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA

3 University of California San Diego, La Jolla, CA, USA

4 Duke University Medical Center, Durham, NC, USA

5 Savient Pharmaceuticals Inc., Bridgewater, NJ, USA

6 Formerly of Savient Pharmaceuticals Inc., East Brunswick, NJ, USA

7 Rheumatology Section, University of Chicago, Chicago, IL, USA

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Arthritis Research & Therapy 2014, 16:R60  doi:10.1186/ar4497

Published: 4 March 2014

Abstract

Introduction

The efficacy of pegloticase, a polyethylene glycol (PEG)-conjugated mammalian recombinant uricase, approved for chronic refractory gout, can be limited by the development of antibodies (Ab). Analyses from 2 replicate, 6-month, randomized controlled trials were performed to characterize Ab responses to pegloticase.

Methods

Anti-pegloticase, anti-PEG, and anti-uricase Ab were determined by validated enzyme-linked immunosorbent assays. Ab titers were analyzed for possible relationships with serum pegloticase concentrations, serum uric acid (sUA) lowering, and risk of infusion reactions (IRs).

Results

Sixty-nine (41%) of 169 patients receiving pegloticase developed high titer anti-pegloticase Ab (> 1:2430) and 40% (67/169) developed anti-PEG Ab; 1 patient receiving placebo developed high titer anti-pegloticase Ab. Only 14% (24/169) of patients developed anti-uricase Ab, usually at low titer. In responders, patients showing sustained UA lowering, mean anti-pegloticase titers at week 25 (1:837 ± 1687 with biweekly and 1:2025 ± 4506 with monthly dosing) were markedly lower than in nonresponders (1:34,528 ± 42,228 and 1:89,658 ± 297,797, respectively). Nonresponder status was associated with reduced serum pegloticase concentrations. Baseline anti-pegloticase Ab, evident in 15% (31/212) of patients, did not predict subsequent loss of urate-lowering response. Loss of sUA response preceded IRs in 44 of 56 (79%) pegloticase-treated patients.

Conclusions

Loss of responsiveness to pegloticase is associated with the development of high titer anti-pegloticase Ab that increase clearance of pegloticase and are associated with a loss of the sUA lowering effect and increased IR risk. Pre-infusion sUA can be used as a surrogate for the presence of deleterious anti-pegloticase Ab.

Trial registration

NCT00325195. Registered 10 May 2006, NCT01356498. Registered 27 October 2008.