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

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.

Figure 1

Mean serum uric acid (sUA) levels in responders (top panel) and nonresponders (bottom panel). Values for placebo-treated patients are shown in the graph of nonresponders.

Figure 2

Mean anti-pegloticase Ab titers over time among serum uric acid (sUA) responders and nonresponders (and placebo-treated patients) receiving biweekly (top panel) and monthly (bottom panel) pegloticase.

Figure 3

Percentage of patients with immunoglobulin (Ig)M and/or IgG anti-pegloticase antibodies (Ab) over time for responders and nonresponders receiving biweekly and monthly pegloticase.

Figure 4

Mean serum pegloticase concentrations in responders and nonresponders receiving pegloticase biweekly (top panel) or monthly (bottom panel).

Figure 5

Anti-pegloticase antibody (Ab) titer when serum uric acid (sUA) first exceeded 6 mg/dL and the highest titer subsequently detected during the randomized controlled trial. Both sUA and Ab titers were measured in the same samples from patients defined as nonresponders.