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

Peter E Lipsky, Leonard H Calabrese, Arthur Kavanaugh, John S Sundy, David Wright, Marsha Wolfson, Michael A Becker, Peter E Lipsky, Leonard H Calabrese, Arthur Kavanaugh, John S Sundy, David Wright, Marsha Wolfson, Michael A Becker

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.

Figures

Figure 1
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
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
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
Figure 4
Mean serum pegloticase concentrations in responders and nonresponders receiving pegloticase biweekly (top panel) or monthly (bottom panel).
Figure 5
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.

References

    1. Mandell BF. Clinical manifestations of hyperuricemia and gout. Cleve Clin J Med. 2008;75:S5–S8.
    1. Garay RP, El-Gewely R, Armstrong JK, Garratty G, Richette P. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin Drug Deliv. 2012;9:1319–1323. doi: 10.1517/17425247.2012.720969.
    1. Hudson PB, London M. Purification and properties of solubilized uricase. Biochim Biophys Acta. 1956;21:290–298. doi: 10.1016/0006-3002(56)90010-5.
    1. Sherman MR, Saifer MG, Perez-Ruiz F. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv Drug Deliv Rev. 2008;60:59–68. doi: 10.1016/j.addr.2007.06.011.
    1. Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs. 2008;22:315–329. doi: 10.2165/00063030-200822050-00004.
    1. Krystexxa (pegloticase) prescribing information. Bridgewater, NJ: Savient Pharmaceuticals, Inc; 2012.
    1. European Medicines Agency. Krystexxa summary of product characteristics. .
    1. Sundy JS, Baraf HS, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, Vázquez-Mellado J, White WB, Lipsky PE, Horowitz Z, Huang W, Maroli AN, Waltrip RW 2nd, Hamburger SA, Becker MA. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306:711–720.
    1. Baraf HSB, Matsumoto AK. Pegloticase: a new biologic for treating advanced gout. Int J Clin Rheumatol. 2012;7:143–154. doi: 10.2217/ijr.11.79.
    1. Cammalleri L, Malaguarnera M. Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout. Int J Med Sci. 2007;4:83–93.
    1. Armstrong JK, Hempel G, Koling S, Chan LS, Fisher T, Meiselman HJ, Garratty G. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer. 2007;110:103–111. doi: 10.1002/cncr.22739.
    1. Sundy JS, Ganson NJ, Kelly SJ, Scarlett EL, Rehrig CD, Huang W, Hershfield MS. Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum. 2007;56:1021–1028. doi: 10.1002/art.22403.
    1. Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther. 2006;8:R12. doi: 10.1186/ar1861.
    1. Wang X, Ishida T, Kiwada H. Anti-PEG IgM elicited by injection of liposomes is involved in the enhanced blood clearance of a subsequent dose of PEGylated liposomes. J Control Release. 2007;119:236–244. doi: 10.1016/j.jconrel.2007.02.010.
    1. Ishida T, Kiwada H. Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes. Int J Pharm. 2008;354:56–62. doi: 10.1016/j.ijpharm.2007.11.005.
    1. Ishihara T, Takeda M, Sakamoto H, Kimoto A, Kobayashi C, Takasaki N, Yuki K, Tanaka K, Takenaga M, Igarashi R, Maeda T, Yamakawa N, Okamoto Y, Otsuka M, Ishida T, Kiwada H, Mizushima Y, Mizushima T. Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles. Pharm Res. 2009;26:2270–2279. doi: 10.1007/s11095-009-9943-x.
    1. Janeway CA, Jr, Travers P, Walport M, Shlomchik M. Immunobiology: The Immune System in Health and Disease. 5. New York: Garland Publishing; 2001.
    1. Richter AW, Akerblom E. Polyethylene glycol reactive antibodies in man: titer distribution in allergic patients treated with monomethoxy polyethylene glycol modified allergens or placebo, and in healthy blood donors. Int Arch Allergy Appl Immunol. 1984;74:36–39. doi: 10.1159/000233512.
    1. Liu Y, Reidler H, Pan J, Milunic D, Qin D, Chen D, Vallejo YR, Yin R. A double antigen bridging immunogenicity ELISA for the detection of antibodies to polyethylene glycol polymers. J Pharmacol Toxicol Methods. 2011;64:238–245. doi: 10.1016/j.vascn.2011.07.003.
    1. Belsey JD, Geraint M, Dixon TA. Systematic review and meta analysis: polyethylene glycol in adults with non-organic constipation. Int J Clin Pract. 2010;64:944–955. doi: 10.1111/j.1742-1241.2010.02397.x.
    1. Pisal DS, Kosloski MP, Balu-Iyer SV. Delivery of therapeutic proteins. J Pharm Sci. 2010;99:2557–2575. doi: 10.1002/jps.22054.
    1. Tang YC, Thoman M, Linton PJ, Deisseroth A. Use of CD40L immunoconjugates to overcome the defective immune response to vaccines for infections and cancer in the aged. Cancer Immunol Immunother. 2009;58:1949–1957. doi: 10.1007/s00262-009-0718-3.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever