title: Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout.
abstract: BACKGROUND
  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.
  
  
  BACKGROUND
  NCT00325195. Registered 10 May 2006, NCT01356498. Registered 27 October 2008.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lipsky
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Calabrese
authors.forename: Arthur
authors.initials: A
authors.lastname: Kavanaugh
authors.forename: John S
authors.initials: JS
authors.lastname: Sundy
authors.forename: David
authors.initials: D
authors.lastname: Wright
authors.forename: Marsha
authors.initials: M
authors.lastname: Wolfson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Becker
mesh_terms: D000906:Antibodies / Q000097:blood; D002908:Chronic Disease; D004797:Enzyme-Linked Immunosorbent Assay; D006073:Gout / Q000188:drug therapy*; D006801:Humans; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D014503:Urate Oxidase / Q000276:immunology* / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D011092:Polyethylene Glycols; D014503:Urate Oxidase; C031545:Pegloticase