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

Abstract

IntroductionThe 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.MethodsAnti-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).ResultsSixty-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.ConclusionsLoss 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 registrationNCT00325195. Registered 10 May 2006, NCT01356498. Registered 27 October 2008.

Zwitterionic gel encapsulation promotes protein stability, enhances pharmacokinetics, and reduces immunogenicity

“…In contrast, neither anti-uricase IgG nor IgM were detected in the rat group treated with uricase-PCBX. Our results here are consistent with clinical findings, showing that PEGylation cannot completely prevent the generation of anti-protein antibodies, at least for highly immunogenic uricase (9). This finding supports our hypothesis that comprehensive surface coverage of a protein with a stealth polymer network can effectively render the protein "invisible" to the immune system and thus mitigate antibody induction.…”

“…The haptenic character of PEG is considered the main culprit in the therapeutic efficacy loss of PEGylated products. Recent clinical studies of Pegloticase (PEGylated uricase) in refractory chronic gout patients unequivocally demonstrated that anti-PEG antibodies correlate with a reduction in drug effectiveness-Pegloticase loses efficacy in more than 40% of patients, and the presence of anti-PEG antibodies doubles the risk of infusion reactions (8,9). Similar results have also been observed for other PEGylated proteins in clinical use, including PEG-asparaginase (10) and Peginterferon alfa (11).…”

Pre-existing Antibody: Biotherapeutic Modality-Based Review

“…In the case of PEGylated interferon, a high prevalence of anti-PEG pre-Abs was not associated with impaired response to PEG-interferon in hepatitis C patients (16). In the case of Pegloticase ™ , a recombinant pegylated porcine uricase, low titer predominately IgM isotype pre-Abs with presumed anti-PEG specificity were detected in 15% of patients and did not predict subsequent impact on the drug effect (63). In a separate study, pre-existing anti-Pegloticase ™ antibodies with specificity to the PEG moiety found in 19% of drug-naïve patients partially contributed to the increased clearance and reduced efficacy of the drug (64).…”

“…Overall, the prevalence and impact of the anti-PEG preAbs varies with specific products and study populations (16,(62)(63)(64)(65)(66) (Table II). High incidences of treatment induced anti-PEG antibodies have been documented only for the large conjugates of highly immunogenic proteins, such as Pegloticase ™ (Table II).…”

Updated Eular Guidelines for the Management of Gout. Comments on Certain Items

“…Назначение препарата позволяет дос-тичь целевого уровня МК у 42% пациентов, но широкое его применение ограничено из-за частых аллегрических реакций и высокой стоимости [120,121]. В Российской Федерации препарат не зарегистрирован.…”