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01.09.2008 | Drug Development

The Impact of PEGylation on Biological Therapies

verfasst von: Prof. Francesco M. Veronese, Anna Mero

Erschienen in: BioDrugs | Ausgabe 5/2008

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Abstract

The term PEGylation describes the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer, and is used as a strategy to overcome disadvantages associated with some biopharmaceuticals. PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug. In general, PEGylation improves drug solubility and decreases immunogenicity. PEGylation also increases drug stability and the retention time of the conjugates in blood, and reduces proteolysis and renal excretion, thereby allowing a reduced dosing frequency. In order to benefit from these favorable pharmacokinetic consequences, a variety of therapeutic proteins, peptides, and antibody fragments, as well as small molecule drugs, have been PEGylated.

This paper reviews the chemical procedures and the conditions that have been used thus far to achieve PEGylation of biomedical molecules. It also discusses the importance of structure and size of PEGs, as well as the behavior of linear and branched PEGs. A number of properties of the PEG polymer — e.g. mass, number of linking chains, the molecular site of PEG attachment — have been shown to affect the biological activity and bioavailability of the PEGylated product. Releasable PEGs have been designed to slowly release the native protein from the conjugates into the blood, aiming at avoiding any loss of efficacy that may occur with stable covalent PEGylation.

Since the first PEGylated drug was developed in the 1970s, PEGylation of therapeutic proteins has significantly improved the treatment of several chronic diseases, including hepatitis C, leukemia, severe combined immunodeficiency disease, rheumatoid arthritis, and Crohn disease. The most important PEGylated drugs, including pegademase bovine, pegaspargase, pegfilgrastim, interferons, pegvisomant, pegaptanib, certolizumab pegol, and some of the PEGylated products presently in an advanced stage of development, such as PEG-uricase and PEGylated hemoglobin, are reviewed. The adaptations and applications of PEGylation will undoubtedly prove useful for the treatment of many previously difficult-to-treat conditions.

The use of trade names is for product identification purposes only and does not imply endorsement.

Maeda H. SMANCS and polymer conjugated macromolecular drags: advances in cancer therapeutics. Adv Drag Del Rev 1991; 6: 181–202CrossRef

Torchilin VP. Immobilised enzymes as drugs. Adv Drag Del Rev 1987; 1: 41–86CrossRef

Abuchowski A, Van E, Palczuk NC, et al. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J Biol Chem 1977; 252: 3578–81PubMed

Israelachvili J. The different faces of poly(ethylene glycol). Proc Natl Acad Sci U S A 1997; 94: 8378–9PubMedCrossRef

Harris JM, Chess RB. Effect of PEGylation on pharmaceuticals. Nat Rev Drag Discov 2003; 2: 214–21CrossRef

Kinstler OB, Brems DN, Lauren SL, et al. Characterization and stability of N-terminally PEGylated rhG-CSF. Pharm Res 1996; 13: 996–1002PubMedCrossRef

Veronese FM, Saccà B, Polverino de Laureto P, et al. New PEGs for peptide and protein modification, suitable for identification of the PEGylation site. Bioconjug Chem 2001; 12: 62–70PubMedCrossRef

Veronese FM. Peptide and protein PEGylation: a review of problems and solutions. Biomaterials 2001; 22: 405–17PubMedCrossRef

Sato H, Ikea M, Suzuki K, et al. Site-specific modification of interleukin-2 by the combined use of genetic engineering techniques and transglutaminase. Biochemistry 1996; 35: 13072–80PubMedCrossRef

10.

Balan S, Choi JW, Godwin A, et al. Site-specific PEGylation of protein disulfide bonds using a three-carbon bridge. Bioconjug Chem 2007; 18: 61–76PubMedCrossRef

11.

Zhao H, Yang K, Martinez A, et al. Linear and branched bicine linkers for releasable PEGylation of macromolecules: controlled release in vivo and in vitro from mono- and multi-PEGylated proteins. Bioconjug Chem 2006; 17: 341–51PubMedCrossRef

12.

Roberts MJ, Bentley MD, Harris JM. Chemistry for peptide and protein PEGylation. Adv Drag Del Rev 2002; 54: 459–76CrossRef

13.

Levy Y, Hershfield MS, Fernandez-Mejia C, et al. Adenosine deaminase deficiency with late onset or recurrent infections: response to treatment with poly(ethylene glycol) modified adenosine deaminase. J Pediatr 1988; 113: 312–7PubMedCrossRef

14.

Graham LM. Pegasparaginase: a review of clinical studies. Adv Drag Del Rev 2003; 10: 1293–302CrossRef

15.

Hak LJ, Relling MV, Cheng C, et al. Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia. Leukemia 2004; 18: 1072–7PubMedCrossRef

16.

Wang YS, Youngster S, Grace M, et al. Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications. Adv Drag Deliv Rev 2002; 54: 547–70CrossRef

17.

Monkarsh SP, Ma Y, Aglione A, et al. Positional isomers of mono-pegylated interferon α-2a: isolation, characterization, and biological activity. Anal Biochem 1997; 247: 434–40PubMedCrossRef

18.

Roelfsema F, Biermasz NR, Pereira AM, et al. Nanomedicines in the treatment of acromegaly: focus on pegvisomant. Int J Nanomedicine 2006; 1: 385–98PubMedCrossRef

19.

Pasut G, Veronese FM. Polymer-drug conjugation, recent achievements and general strategies. Prog Polym Sci 2007; 32: 933–61CrossRef

20.

Blick S, Curran M. Certolizumab pegol. Biodrugs 2007; 21: 196–201CrossRef

21.

Inada Y, Takahashi K, Yoshimoto T, et al. Application of PEG-enzyme and magnetite-PEG-enzyme conjugates for biotechnological processes. Trends Biotechnol 1988; 6: 131–4CrossRef

22.

Harris JM. Polyethylene glycol chemistry, biochemical and biochemical applications. New York: Plenum Press, 1992

23.

Harris JM, Zalipsky S, editors. Polyethylene glycol, chemistry and biological applications. Washington, DC: American Chemical Society, 1997

24.

Veronese FM, Harris JM. Peptide and protein PEGylation III: advances in chemistry and clinical applications. Adv Drag Deliv Rev 2008; 60(1): 1–2CrossRef

25.

Greenwald RB. PEG drags: an overview. J Control Release 2001; 74: 159–71PubMedCrossRef

26.

Pasut G, Guiotto A, Veronese FM. Protein, peptide and non-peptide drug PEGylation for therapeutic application. Exp Opin Ther Pat 2004; 14: 859–94CrossRef

27.

Banci L, Bertini I, Caliceti P, et al. Spectroscopic characterization of polyethylene glycol Superoxide dismutase: 1H-NMR studies on its Cu₂2CO₂ derivative. J Inorg Biochem 1990; 39: 149–59PubMedCrossRef

28.

Greenwald RB, Choe YH, McGuire J, et al. Effective drag delivery by PEGylated drug conjugates. Adv Drag Deliv Rev 2003; 55: 217–50CrossRef

29.

Harris JM, Sedaghat-Herati MR. Preparation and use of polyethylene glycol propionaldehyde [US patent 5252714; online]. Available from URL: http://patft.uspto.gov/netahtml/PTO/srchnum.htm [Accessed 2008 Aug 26]

30.

Takakura Y, Fujita T, Hashida M, et al. Disposition of macromolecules in tumor bearing mice. Pharm Res 1990; 7: 339–46PubMedCrossRef

31.

Sartore L, Caliceti P, Schiavon O, et al. Accurate evaluation method of the polymer content in monomethoxy(polyethylene glycol) modified proteins based on amino acid analysis. Applied Biochem Biotechnol 1991; 31: 213–22CrossRef

32.

Miron T, Wilchek M. A simplified method for the preparation of succinimidyl carbonate polyethylene glycol for coupling to proteins. Bioconjug Chem 1993; 4: 568–9PubMedCrossRef

33.

Veronese FM, Largajolli R, Boccu E, et al. Activation of monomethoxy(poly-ethylene glycol) by phenylchloroformiate and modification of ribonuclease and Superoxide dismutase. Appl Biochem Biotechnol 1985; 11: 141–52PubMedCrossRef

34.

Lee S, McNemar C. Substantially pure histidine-linked protein polymer conjugates [US patent 5985263; online]. Available from URL: http://patft.uspto.gov/netahtml/PTO/srchnum.htm [Accessed 2008 Aug 26]

35.

Morpurgo M, Veronese FM, Kachensky D, et al. Preparation and characterization of polyethylene glycol vinyl sulfone. Bioconjug Chem 1996; 7: 2417–24CrossRef

36.

Woghiren C, Sharma B, Stein S. Protected thiol-polyethylene glycol: a new activated polymer for reversible protein modification. Bioconjug Chem 1993; 4: 314–8PubMedCrossRef

37.

Veronese FM, Mero A, Caboi F, et al. Site-specific PEGylation of G-CSF by reversible denaturation. Bioconjug Chem 2007; 18: 1824–30PubMedCrossRef

38.

Kopchick JJ, Parkinson C, Stevens EC, et al. Growth hormone receptor antagonist: discovery, development, and use in patients with acromegaly. Endocr Rev 2002; 23: 623–46PubMedCrossRef

39.

Zalipsky S, Meno-Rudolph S. Hydrazide derivatives of polyethylene glycol and their bioconjugates, in polyethylene glycol chemistry and biological applications. In: Harris JM, Zalipsky S, editors. ACS Symposium Series 1997; 680: 318–41

40.

Tayar E, Zhao X, Bentley MD. PEG-LHRH analog conjugates [world patent publication no. WO/1999/055376; online]. Available from URL: http://www.wipo.int/pctdb/en/ [Accessed 2008 Aug 26]

41.

Orsatti L, Veronese FM. An unusual coupling of poly(ethylene glycol) to tyrosine residues in epidermal growth factor. J Bioac Comp Polymer 1999; 14: 429–36

42.

DeFrees S, Wang ZG, Xing R, et al. GlycoPEGylation of recombinant therapeutic proteins produced in Escherichia coll. Glycobiology 2006; 16: 833–43PubMedCrossRef

43.

Gaertner HF, Puigserver AJ. Increased activity and stability of poly(ethylene glycol)-modified trypsin. Enzyme Microb Technol 1992; 14: 150–5PubMedCrossRef

44.

Fontana A, Spolaore B, Mero A, et al. Site-specific modification and PEGylation of pharmaceutical proteins mediated by transglutaminase. Adv Drug Del Rev 2008; 60: 13–28CrossRef

45.

Messersmith PB, Hu B-H, Ritter Jones M. Injectable and bioadhesive polymeric hydrogels as well as related methods of enzymatic preparation [US patent 7208171; online]. Available from URL: http://patft.uspto.gov/netahtml/PTO/srchnum.htm [Accessed 2008 Aug 26]

46.

Monfardini C, Schiavon O, Caliceti P, et al. A branched monomethoxypoly-(ethylene glycol) for protein modification. Bioconjug Chem 1995; 6: 62–9PubMedCrossRef

47.

Veronese FM, Caliceti P, Schiavon O. Branched and linear poly(ethylene glycol): influence of the polymer structure on enzymological, pharmacokinetic, and immunological properties of protein conjugates. J Bioact Comp Polym 1997; 12: 196–207

48.

Srividhya M, Preethi S, Gnanamani A, et al. Sustained release of protein from polyethylene glycol incorporated amphiphilic comb like polymers. Int J Pharm 2006; 326: 119–27PubMedCrossRef

49.

Bailon P, Palleroni A, Schaffer CA, et al. Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated interferon alpha-2a for the treatment of hepatitis C. Bioconjug Chem 2001; 12: 195–202PubMedCrossRef

50.

Delgado C, Francis GE, Fisher D. The uses and properties of PEG-linked proteins. Crit Rev Ther Drug Carrier Syst 1992; 9: 249–304PubMed

51.

Caliceti P, Schiavon O, Veronese FM. Immunological properties of uricase conjugated to neutral soluble polymers. Bioconjug Chem 2001; 12: 515–22PubMedCrossRef

52.

Morpurgo M, Veronese FM. Conjugates of peptides and proteins to polyethylene glycols. Methods Mol Biol 2004; 283: 45–70PubMed

53.

Federico R, Cona A, Caliceti P, et al. Histaminase PEGylation: preparation and characterization of a new bioconjugate for therapeutic application. J Control Release 2006; 115: 168–74PubMedCrossRef

54.

Visentin R, Pasut G, Veronese FM, et al. Highly efficient technetium-99m labeling procedure based on the conjugation of N-[N-(3-diphenylphosphinopropionyl) glycil] cysteine ligand with poly(ethylene glycol). Bioconjug Chem 2004; 15: 1046–54PubMedCrossRef

55.

Pradhananga S, Wilkinson I, Ross RJ. Pegvisomant: structure and function. J Mol Endocrinol 2002; 29: 11–4PubMedCrossRef

56.

Bell EA, Wall GC. Pediatric constipation therapy using guidelines and polyethylene glycol 3350. Ann Pharmacother 2004; 38: 686–93PubMedCrossRef

57.

Pashankar DS, Loening-Baucke V, Bishop WP. Polyethylene glycol 3350 without electrolytes: a new safe, effective, and palatable bowel preparation for colonoscopy in children. J Pediatr 2004; 144: 358–62PubMedCrossRef

58.

Yamaoka T, Tabata Y, Ikada Y. Distribution and tissue uptake of polyethylene glycol with different molecular weights after intravenous administration to mice. J Pharm Sci 1994; 83: 601–6PubMedCrossRef

59.

Kawai F. Microbial degradations of polyethers. Appl Microbiol Biotechnol 2002; 58: 30–8PubMedCrossRef

60.

Beranova M, Wasserbauer R, Vancurova D, et al. Effect of cytochrome P-450 inhibition and stimulation on intensity of polyethylene degradation in microsomal fraction of mouse and rat livers. Biomaterials 1990; 11: 521–4PubMedCrossRef

61.

Working PK, Newman MS, Johnson J, et al. Safety of poly(ethylene glycol) and poly(ethylene glycol) derivatives. In: Harris JM, Zalipsky S, editors. Polyethylene glycol chemistry and biological applications. ACS Symposium Series 1997; 680: 45–57CrossRef

62.

Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine 2006; 1: 297–315PubMedCrossRef

63.

Bendele A, Seely J, Richey C, et al. Short communication: renal tubular vacuolation in animals treated with poly(ethylene glycol)-conjugated proteins. Toxicol Sci 1999; 42: 152–7CrossRef

64.

Webster R, Didier E, Harris P, et al. Pegylated proteins: evaluation of their safety in the absence of definitive metabolism studies. Drug Metabol Dis 2007; 35: 9–16CrossRef

65.

Fibbe WE, Daha MR, Hiemstra PS, et al. Interleukin-1 and poly(rI)-poly(rC) induce production of granulocyte CSF, macrophage CSF and granulocyte-macrophage CSF by human endothelial cells. Exp Hematol 1989; 17: 229–34PubMed

66.

Weite K, Platzer E, Lu L, et al. Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor. Proc Natl Acad Sci U S A 1985; 82: 1526–30CrossRef

67.

Lu HS, Clogston CL, Narhi LO, et al. Folding and oxidation of recombinant human granulocyte colony stimulating factor produced in Escherichia coli: characterization of the disulfide-reduced intermediates and cysteine-serine analogs. J Biol Chem 1992; 267: 8770–7PubMed

68.

Kinstler O, Molineaux G, Treuheit M, et al. Mono-N-terminal poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 2002; 54: 477–86PubMedCrossRef

69.

Molineaux G. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des 2004; 10: 1235–44CrossRef

70.

Piedmonte DM, Treuheit MJ. Formulation of Neulasta® (pegfilgrastim). Adv Drug Del Rev 2008; 60: 50–8CrossRef

71.

Luxon BA, Grace M, Brassard D, et al. Pegylated interferons for the treatment of chronic hepatitis C infection. Clin Ther 2002; 24: 1363–83PubMedCrossRef

72.

Foster GR. Pegylated interferons: chemical and clinical differences. Aliment Pharmacol Ther 2004; 20: 825–30PubMedCrossRef

73.

Hinds KD, Kim SW. Effect of PEG conjugation on insulin properties. Adv Drug Deliv Rev 2002; 54: 505–30CrossRef

74.

Hershfield MS, Chaffee S, Koro-Johnson L, et al. Use of site-directed mutagenesis to enhance the epitope-shielding effect of covalent modification of proteins with polyethylene glycol. Pro Natl Acad Sci U S A 1991; 88: 7185–9CrossRef

75.

Fishburn CS. The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. J Pharm Sci Epub 2008 Jan 15

76.

Parkinson C, Scarlett JA, Trainer PJ. Pegvisomant in the treatment of acromegaly. Adv Drug Deliv Rev 2003; 55: 1303–14PubMedCrossRef

77.

Ng EWM, Shima DT, Calias P, et al. A targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Dis 2006; 5: 123–32CrossRef

78.

Chapman AP. PEGylated antibodies and antibody fragments for improved therapy: a review. Adv Drug Del Rev 2002; 54: 531–45CrossRef

79.

Chapman AP, Antoniw P, Spitali M, et al. Therapeutic antibody fragments with prolonged in vivo half-lives. Nat Biotechnol 1999; 17: 780–3PubMedCrossRef

80.

Melmed GY, Targan SR, Yasothan U, et al. Certolizumab pegol. Nat Rev Drug Discov 2008; 7: 641–2PubMedCrossRef

81.

Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. PRECISE 1 Study Investigators. N Engl J Med 2007; 357: 228–38PubMedCrossRef

82.

Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. PRECISE 2 Study Investigators. N Engl J Med 2007; 357: 239–50PubMedCrossRef

83.

Fleischmann R, Mason D, Cohen S. Efficacy and safety of certolizumab pegol monotherapy in patients with rheumatoid arthritis failing previous DMARD therapy [abstract]. Ann Rheum Dis 2007; 66Suppl. II: 169

84.

Smolen J, Brzezicki J, Mason D, et al. Efficacy and safety of certolizumab pegol in combination with methotrexate (MTX) in patients with active rheumatoid arthritis despite MTX therapy: results from the RAPID 2 study [abstract]. Ann Rheum Dis 2007; 66Suppl. II: 187

85.

Reich K, Tasset C, Ortonne J. Efficacy and safety of certolizumab pegol in patients with chronic plaque psoriasis: preliminary results of a randomised, double-blind, placebo-controlled trial [abstract]. Ann Rheum Dis 2007; 66Suppl. II: 251

86.

Edwards C. PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases. Ann Rheum Dis 1999; 58: 173–81CrossRef

87.

Paz K, Zhu Z. Development of angiogenesis inhibitors to vascular endothelial growth factor receptor 2: current status and future perspective. Front Biosci 2005; 10: 1415–39PubMedCrossRef

88.

Nishimura H, Ashihara Y, Matsushima A, et al. Modification of yeast uricase with poly(ethylene glycol): disappearance of binding ability towards anti-uricase serum. Enzyme 1979; 24: 261–4PubMed

89.

Abuchowski A, Karp D, Davis FF. Reduction of plasma urate levels in the cockerel with poly(ethylene glycol)-uricase. J Pharmacol Exp Ther 1981; 219: 352–4PubMed

90.

Caliceti P, Morpurgo M, Schiavon O, et al. Preservation of thrombolytic activity of urokinase modified with monomethoxypoly(ethylene glycol). J Bioact Comp Polym 1999; 4: 252–66

91.

Chua CC, Greenberg ML, Viau AT, et al. Use of poly(ethylene glycol)-modified uricase (PEG-uricase) to treat hyperuricemia in a patient with non-Hodgkin lymphoma. Ann Intern Med 1988; 109: 114–7PubMed

92.

Coiffier B, Mounier N, Bologna S, et al. Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin’s lymphoma: results of the GRAAL1 (Groupe d’Etude des Lymphomes de l’Adulte Trial on Rasburicase Activity in Adult Lymphoma) study. J Clin Oncol 2003; 21: 4402–6PubMedCrossRef

93.

Sherman MR, Saifer MGP, Perez-Ruiz F. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv Drug Del Rev 2008; 60: 59–68CrossRef

94.

Sundy JS, Ganson NJ, Kelly SJ, et al. Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum 2007; 56: 1021–8PubMedCrossRef

95.

Ganson NJ, Kelly SJ, Scarlett E, et al. Control of hyperuricemia in subjects with refractory gout, and induction of antibody poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther 2006; 8(1): R12PubMedCrossRef

96.

Richter AW, Akerblom E. Antibodies against polyethylene glycol produced in animals by immunization with monomethoxy polyethylene glycol modified proteins. Int Arch Allergy Appl Immunol 1983; 74: 124–31CrossRef

97.

Fisher TC, Armstrong JK, Wenby RW, et al. Isolation and identification of a human antibody to poly(ethylene glycol) [abstract]. Blood 2003; 102: 559

98.

Hess JR, Macdonald VM, Brinkley WW. Systemic and pulmonary hypertension after resuscitation with cell free hemoglobin. J Appl Physiol 1993; 74: 1769–78PubMed

99.

Nho K, Zalipsky S, Davis F. Chemically modified hemoglobin as an effective, stable, non-immunogenic red blood cell substitute [US patent 5386014; online]. Available from URL: http://patft.uspto.gov/netahtml/PTO/srchnum.htm [Accessed 2008 Aug 26]

100.

Manjula BN, Tsai A, Upadhya R, et al. Site-specific PEGylation of hemoglobin at Cys-93β: correlation between the colligative properties of the PEGylated protein and the length of the conjugated PEG chain. Bioconjug Chem 2003; 14: 464–72PubMedCrossRef

101.

Hu T, Prabhakaran M, Acharya S, et al. Influence of the chemistry of conjugation of polyethylene glycol to Hb on the oxygen-binding and solution properties of the PEG-Hb conjugate. Biochem J 2005; 392: 555–64PubMedCrossRef

102.

Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov 2003; 2: 347–60PubMedCrossRef

103.

Zhao H, Rubio B, Sapra P, et al. Novel prodrugs of SN38 using multiarm poly(ethylene glycol) linkers. Bioconjug Chem 2008; 19: 849–59PubMedCrossRef

Titel: The Impact of PEGylation on Biological Therapies
verfasst von: Prof. Francesco M. Veronese
Anna Mero
Publikationsdatum: 01.09.2008
Verlag: Springer International Publishing
Erschienen in: BioDrugs / Ausgabe 5/2008
Print ISSN: 1173-8804
Elektronische ISSN: 1179-190X
DOI: https://doi.org/10.2165/00063030-200822050-00004

Springer Medizin

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