Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients

Abstract

IntroductionPegloticase, a PEGylated recombinant porcine uricase, is approved for treating refractory gout at a dose of 8 mg intravenous (IV) every 2 weeks. However, during phase 1 testing, pharmacokinetics supported less frequent dosing. Also, single doses of pegloticase unexpectedly induced antibodies (Ab) that bound to polyethylene glycol (PEG). We have conducted a phase 2 trial to evaluate every 3-week dosing, and to further define the Ab response to pegloticase. Organ transplant recipients were included, as they are prone to severe gout that is difficult to manage, and because treatment to prevent graft rejection might influence the immune response to pegloticase.MethodsPlasma uricase activity (pUox), urate concentration (pUA), and clinical response were monitored during up to 5 infusions in 30 patients, including 7 organ transplant recipients. Depending on whether pUA <6 mg/dL was achieved and maintained, patients were classified as non (NR), persistent (PR), or transient (TR) responders. Ab to pegloticase and 10 kDa mPEG were monitored by enzyme linked immunosorbent assay and specificity was further defined.ResultsWe observed 17 PR, 12 TR, and 1 NR; 21 patients (16 PR, 5 TR) received all 5 infusions. Over the 15-week trial, pUA in PR averaged 1.0 ± 0.4 mg/dL; T½ for pUox was approximately 13 days, and area under the curve after dose 5 was approximately 30% higher than after dose 1. PR showed clinical benefit and in some, tophi resolved. In 11 of 12 TR, pUox fell rapidly and hyperuricemia recurred before dose 2. In all TR and NR, loss of response to pegloticase was accompanied by Ab to PEG, which was pre-existing in half of those who had no prior exposure to pegloticase. No PR, and 1 one out of 7 organ transplant recipients, had a sustained Ab response to pegloticase.ConclusionsEvery 3-week dosing is effective and may enhance the utility of pegloticase for treating refractory gout. Ab to PEG, which were pre-existing or induced by treatment, caused rapid loss of efficacy and increased the risk of infusion reactions. Organ transplant recipients can benefit from pegloticase, and may be less prone than non-recipients to developing anti-PEG Ab. Investigation of immunosuppressive strategies to minimize anti-PEG Ab is warranted.Trial registrationClincalTrials.gov identifier: NCT00111657

PEGylated Biopharmaceuticals

“…Historically, most PEGylated biopharmaceuticals have proven to be safe and efficacious and have not been associated with the development of anti-PEG antibodies. Recently, a number of reports have documented the development of anti-PEG antibodies following treatment with PEGylated therapeutics, which have been associated with reduced efficacy and hypersensitivity (Ganson et al 2006;Judge et al 2006;Armstrong et al 2007;Hershfield et al 2014). Some of these reports have evoked controversial discussion (Schellekens, Hennink, and Brinks 2013).…”

“…T cell-independent mechanisms might also be responsible for the induction of anti-PEG antibodies observed in patients Ganson et al 2006;Armstrong et al 2007;Hershfield et al 2014). Krystexxa is a PEGylated mammalian enzyme used for the treatment of chronic refractory gout (Kelly et al 2001;Ganson et al 2006;Sundy et al 2011).…”

Synthesis and characterization of heparosan-granulocyte-colony stimulating factor conjugates: a natural sugar-based drug delivery system to treat neutropenia

“…Studies correlate the existence of pre-existing or induced anti-PEG with poor or non-responsiveness to some PEGylated drugs. A significant percentage (~22-25%) of normal blood donors show evidence of anti-PEG antibodies (Richter and Akerblom 1984), while this number was only 0.2% about two decades earlier (Hershfield et al 2014), suggesting that anti-PEG antibodies may result from exposure of "free" PEG which has been used evermore as excipients or ingredients in cosmetics, toothpaste, laxatives, and other over-the-counter products. Recently, a phase III clinical study testing a PEG-aptamer was halted because one patient died from an anaphylactic reaction.…”

“…PEG lacks a natural, efficient degradation system and thus has been associated with the accumulation of intracellular vacuoles in animals (Bendele et al 1998;Rudmann et al 2013), which could become a concern for long-term pediatric or genetic disease treatments. PEG has also been reported to induce anti-PEG antibodies (Armstrong et al 2007;Hershfield et al 2014;Garay et al 2012;Richter and Akerblom 1984;Ganson et al 2015;Veronese 2001). Studies correlate the existence of pre-existing or induced anti-PEG with poor or non-responsiveness to some PEGylated drugs.…”

Development of a Generic Anti-PEG Antibody Assay Using BioScale’s Acoustic Membrane MicroParticle Technology

“…This recommendation has proven to be a tall order, as developing and validating assays to detect antibodies against a PEG moiety is a major challenge. In a review paper by Schellekens et al (3), the authors concluded that most, if not all, assays used for detecting anti-PEG antibodies are flawed due to the lack of specificity as well as poor characterization of positive controls (3,4). Until recently, traditional bridge immunoassay format assays have been able to detect anti-PEG IgM antibodies but have struggled to detect IgG isotype antibodies with sufficient sensitivity in human matrix (5,6), suggesting that the type of PEG and/or protein therapeutic may play a role.…”