Anti-PEG Immunity: Emergence, Characteristics, and Unaddressed Questions

Overview

Journal Wiley Interdiscip Rev Nanomed Nanobiotechnol

Specialty Biotechnology

Date 2015 Feb 25

PMID 25707913

Citations 198

Authors

Qi Yang

Samuel K Lai

Affiliations

Soon will be listed here.

Abstract

The modification of protein and nanoparticle therapeutics with polyethylene glycol (PEG), a flexible, uncharged, and highly hydrophilic polymer, is a widely adopted approach to reduce RES clearance, extend circulation time, and improve drug efficacy. Nevertheless, an emerging body of literature, generated by numerous research groups, demonstrates that the immune system can produce antibodies that specifically bind PEG, which can lead to the 'accelerated blood clearance' of PEGylated therapeutics. In animals, anti-PEG immunity is typically robust but short-lived and consists of a predominantly anti-PEG IgM response. Rodent studies suggest that the induction of anti-PEG antibodies (α-PEG Abs) primarily occurs through a type 2 T-cell independent mechanism. Although anti-PEG immunity is less well-studied in humans, the presence of α-PEG Abs has been correlated with reduced efficacy of PEGylated therapeutics in clinical trials. The prevalence of anti-PEG IgG and reports of memory immune responses, as well as the existence of α-PEG Abs in healthy untreated individuals, suggests that the mechanism(s) and features of human anti-PEG immune responses may differ from those of animal models. Many questions, including the incidence rate of pre-existing α-PEG Abs and immunological mechanism(s) of α-PEG Ab formation in humans, must be answered in order to fully address the potential complications of anti-PEG immunity.

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References

Dams E, Laverman P, Oyen W, Storm G, Scherphof G, van der Meer J . Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J Pharmacol Exp Ther. 2000; 292(3):1071-9. View

Ganson N, Kelly S, Scarlett E, Sundy J, Hershfield M . 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. 2005; 8(1):R12. PMC: 1526556. DOI: 10.1186/ar1861. View

Soshee A, Zurcher S, Spencer N, Halperin A, Nizak C . General in vitro method to analyze the interactions of synthetic polymers with human antibody repertoires. Biomacromolecules. 2013; 15(1):113-21. DOI: 10.1021/bm401360y. View

Kawanishi M, Hashimoto Y, Shimizu T, Sagawa I, Ishida T, Kiwada H . Comprehensive analysis of PEGylated liposome-associated proteins relating to the accelerated blood clearance phenomenon by combination with shotgun analysis and conventional methods. Biotechnol Appl Biochem. 2014; 62(4):547-55. DOI: 10.1002/bab.1291. View

Needham D, McIntosh T, Lasic D . Repulsive interactions and mechanical stability of polymer-grafted lipid membranes. Biochim Biophys Acta. 1992; 1108(1):40-8. DOI: 10.1016/0005-2736(92)90112-y. View

Cerutti A, Cols M, Puga I . Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol. 2013; 13(2):118-32. PMC: 3652659. DOI: 10.1038/nri3383. View

Judge A, McClintock K, Phelps J, MacLachlan I . Hypersensitivity and loss of disease site targeting caused by antibody responses to PEGylated liposomes. Mol Ther. 2005; 13(2):328-37. DOI: 10.1016/j.ymthe.2005.09.014. View

Ishida T, Wang X, Shimizu T, Nawata K, Kiwada H . PEGylated liposomes elicit an anti-PEG IgM response in a T cell-independent manner. J Control Release. 2007; 122(3):349-55. DOI: 10.1016/j.jconrel.2007.05.015. View

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(2):236-44. DOI: 10.1016/j.jconrel.2007.02.010. View

10.

Owens 3rd D, Peppas N . Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2005; 307(1):93-102. DOI: 10.1016/j.ijpharm.2005.10.010. View

11.

Ishihara T, Maeda T, Sakamoto H, Takasaki N, Shigyo M, Ishida T . Evasion of the accelerated blood clearance phenomenon by coating of nanoparticles with various hydrophilic polymers. Biomacromolecules. 2010; 11(10):2700-6. DOI: 10.1021/bm100754e. View

12.

Veronese F, Pasut G . PEGylation, successful approach to drug delivery. Drug Discov Today. 2005; 10(21):1451-8. DOI: 10.1016/S1359-6446(05)03575-0. View

13.

Vonarbourg A, Passirani C, Saulnier P, Benoit J . Parameters influencing the stealthiness of colloidal drug delivery systems. Biomaterials. 2006; 27(24):4356-73. DOI: 10.1016/j.biomaterials.2006.03.039. View

14.

Taguchi K, Urata Y, Anraku M, Watanabe H, Kadowaki D, Sakai H . Hemoglobin vesicles, polyethylene glycol (PEG)ylated liposomes developed as a red blood cell substitute, do not induce the accelerated blood clearance phenomenon in mice. Drug Metab Dispos. 2009; 37(11):2197-203. DOI: 10.1124/dmd.109.028852. View

15.

Tagami T, Nakamura K, Shimizu T, Yamazaki N, Ishida T, Kiwada H . CpG motifs in pDNA-sequences increase anti-PEG IgM production induced by PEG-coated pDNA-lipoplexes. J Control Release. 2009; 142(2):160-6. DOI: 10.1016/j.jconrel.2009.10.017. View

16.

Ishihara T, Takeda M, Sakamoto H, Kimoto A, Kobayashi C, Takasaki N . Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles. Pharm Res. 2009; 26(10):2270-9. DOI: 10.1007/s11095-009-9943-x. View

17.

Laverman P, Carstens M, Boerman O, Dams E, Oyen W, van Rooijen N . Factors affecting the accelerated blood clearance of polyethylene glycol-liposomes upon repeated injection. J Pharmacol Exp Ther. 2001; 298(2):607-12. View

18.

Ishida T, Masuda K, Ichikawa T, Ichihara M, Irimura K, Kiwada H . Accelerated clearance of a second injection of PEGylated liposomes in mice. Int J Pharm. 2003; 255(1-2):167-74. DOI: 10.1016/s0378-5173(03)00085-1. View

19.

Harris J, Chess R . Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov. 2003; 2(3):214-21. DOI: 10.1038/nrd1033. View

20.

Balazs M, Martin F, Zhou T, Kearney J . Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses. Immunity. 2002; 17(3):341-52. DOI: 10.1016/s1074-7613(02)00389-8. View