Advances in the development of PEG derivatives and pegylated protein drugs

ZHANG Yu; LIAN Zhiguo; XU Mingbo; FENG Fang

doi:10.3969/j.issn.1006-0111.2018.04.004

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2018 > 36(4): 301-306,328

ZHANG Yu, LIAN Zhiguo, XU Mingbo, FENG Fang. Advances in the development of PEG derivatives and pegylated protein drugs[J]. Journal of Pharmaceutical Practice and Service, 2018, 36(4): 301-306,328. doi: 10.3969/j.issn.1006-0111.2018.04.004

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ZHANG Yu, LIAN Zhiguo, XU Mingbo, FENG Fang. Advances in the development of PEG derivatives and pegylated protein drugs[J]. Journal of Pharmaceutical Practice and Service, 2018, 36(4): 301-306,328. doi: 10.3969/j.issn.1006-0111.2018.04.004

Advances in the development of PEG derivatives and pegylated protein drugs

doi: 10.3969/j.issn.1006-0111.2018.04.004

1.
China Pharmaceutical University, Nanjing 210009, China;Beijing SL Pharmaceutical Co., Ltd., Beijing 100041, China
2.
Beijing SL Pharmaceutical Co., Ltd., Beijing 100041, China
3.
China Pharmaceutical University, Nanjing 210009, China

Received Date: 2017-11-23
Rev Recd Date: 2018-03-30

Abstract

Polyethylene glycol and its derivatives are widely used in protein drug modification due to the excellent hydrophilicity, biocompatibility and bioinertia. The pegylation makes it possible that protein has lower immunogenicity and longer half-life. PEG derivatives had undergone three generations, from random modifications, to site-specific and functional modifications, and then branched structures. The application of PEG derivatives also extends to biosensing and drug delivery. Advances in the development of PEG derivatives and pegylated protein drugs were reviewed in this paper.
- PEG derivatives,
- pegylation,
- protein drugs,
- long-acting

References

[1]	LAWRENCE P B, PRICE J L. How PEGylation influences protein conformational stability[J]. Curr Opin Chem Biol, 2016, 34:88-94.
[2]	PFISTER D, BOURGEAUX E, MORBIDELLI M. Kinetic modeling of protein PEGylation[J]. Chem Engin Sci, 2015, 137:816-827.
[3]	YANG Z, WANG J, LU Q, et al. PEGylation confers greatly extended half-life and attenuated immunogenicity to recombinant methioninase in primates[J]. Cancer Res, 2004, 64(18):6673-6678.
[4]	RODR GUEZMART NEZ JA, RIVERARIVERA I, SOL RJ, et al. Enzymatic activity and thermal stability of PEG-α-chymotrypsin conjugates[J]. Biotechnol Lett, 2009, 31(6):883-887.
[5]	姜忠义, 许松伟, 王艳强. 蛋白质和肽类分子的聚乙二醇化化学[J]. 有机化学, 2003, 23(12):1340-1347.
[6]	ZALIPSKY S, SELTZER R, MENONRUDOLPH S. Evaluation of a new reagent for covalent attachment of polyethylene glycol to proteins[J]. Biotechnol Appl Biochem, 1992, 15(1):100-114.
[7]	MIRON T, WILCHEK M. A simplified method for the preparation of succinimidyl carbonate polyethylene glycol for coupling to proteins[J]. Bioconjug Chem, 1993, 4(6):568-569.
[8]	ABUCHOWSKI A, KAZO GM, JR VC, et al. Cancer therapy with chemically modified enzymes. I. Antitumor properties of polyethylene glycol-asparaginase conjugates[J]. Cancer Biochem Biophys, 1984, 7(2):175-186.
[9]	ABUCHOWSKI A,VAN ES T,PALCZUK NC,et al. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol[J]. J Biol Chem,1977,252(11):3578-3581.
[10]	GAIS H J, RUPPERT S. Modification and immobilization of proteins with polyethylene glycol tresylates and polysaccharide tresylates:Evidence suggesting a revision of the coupling mechanism and the structure of the polymer-polymer linkage[J]. Tetrahedron Lett, 1995, 36(22):3837-3838.
[11]	ZALIPSKY S, LEE C. Use of functionalized poly(ethylene glycol)s for modification of polypeptides[M]//Poly(Ethylene Glycol) Chemistry. Springer US, 1992:1-15.
[12]	WANG J, HU T, LIU Y, et al. Kinetic and stoichiometric analysis of the modification process for N-terminal PEGylation of staphylokinase[J]. Anal Biochem, 2011, 412(1):114-116.
[13]	KINSTLER OB, BREMS DN, LAUREN SL, et al. Characterization and stability of N-terminally PEGylated rhG-CSF[J]. Pharm Res, 1996, 13(7):996-1002.
[14]	KINSTLER OB, GABRIEL NE, FARRAR CE, et al. N-terminally chemically modified protein-compositions and method:, DE 69509628 D1[P]. 1999.
[15]	FEE C J, DAMODARAN VB. Production of PEGylated proteins[M]//Biopharmaceutical Production Technology. 2012:199-222.
[16]	BROCCHINI S, GODWIN A, BALAN S, et al. Disulfide bridge based PEGylation of proteins[J]. Adv Drug Deliv Rev, 2008, 60(1):3-12.
[17]	TSUTSUMI Y, ONDA M, NAGATA S, et al. Site-specific chemical modification with polyethylene glycol of recombinant immunotoxin anti-Tac(Fv)-PE38(LMB-2) improves antitumor activity and reduces animal toxicity and immunogenicity[J]. Proc Natl Acad Sci USA, 2000, 97(15):8548-8553.
[18]	BANGALORE S, KUMAR S, FUSARO M, et al. Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus:mixed treatment comparison analysis of 22844 patient years of follow-up from randomised trials[J]. BMJ, 2012, 345:e5170.
[19]	PASUT G, VERONESE FM. State of the art in PEGylation:The great versatility achieved after forty years of research[J]. J Control Release, 2012, 161(2):461-472.
[20]	MORGENSTERN J, BAUMANN P, BRUNNER C, et al. Effect of PEG molecular weight and PEGylation degree on the physical stability of PEGylated lysozyme[J]. Int J Pharm, 2017, 519(1-2):408-417.
[21]	ROBERTS MJ, HARRIS JM. Attachment of degradable poly(ethylene glycol) to proteins has the potential to increase therapeutic efficacy[J]. J Pharm Sci, 1998, 87(11):1440-1445.
[22]	ANDREW J. GARMAN S,BARRET KALINDJIAN. The preparation and properties of novel reversible polymer-protein conjugates 2-ω-Methoxypolyethylene (5000) glycoxymethylene-3-methylmaleyl conjugates of plasminogen activators[J]. Febs Lett, 1987, 223(2):361-365.
[23]	田浤, 金宇灏, 陈阳建,等. 聚乙二醇氨基酸衍生物的合成及其对紫杉醇的修饰[J]. 中国药科大学学报, 2011, 42(1):78-82.
[24]	KIZILEL S, SCAVONE A, LIU X, et al. Encapsulation of pancreatic islets within nano-thin functional polyethylene glycol coatings for enhanced insulin secretion[J]. Tissue Engin Part A, 2010, 16(7):2217.
[25]	YOO MK, PARK IK, LIM HT, et al. Folate PEG superparamagnetic iron oxide nanoparticles for lung cancer imaging[J]. Acta Biomater, 2012, 8(8):3005-3013.
[26]	ZHANG C, YANG XL, YUAN YH, et al. Site-specific PEGylation of therapeutic proteins via optimization of both accessible reactive amino acid residues and PEG derivatives[J]. Biodrugs, 2012, 26(4):209. 209-215.
[27]	RYAN SIN AD M, MANTOVANI GIUSEPPE, WANG XUEXUAN, et al. Advances in PEGylation of important biotech molecules:delivery aspects[J]. Expert Opin Drug Deliv,2008,5(4):371-383.
[28]	VUGMEYSTER Y,ENTRICAN C A,JOYCE AP,et al.Pharmacokinetic,biodistribution and biophysical profiles of TNF nanobodies conjugated to linear or branched poly (ethylene glycol)[J].Bioconjug Chem,2012,23(7):1452-1462.
[29]	DAVIS, FF.The origin of pegnology[J]. Adv Drug Deliv Rev,2002,54(4):457-458.
[30]	DAVIS FF, VAN EST, PALCZUK NC. Non-immunogenic polypeptides:US, US 4179337 A[P]. 1979.
[31]	ABUCHOWSKI A,MCCOY JR,PALCZUK NC,et al. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase[J]. J Biol Chem,1977,252(11):3582-3586.
[32]	LEE CR,MCKENZIE CA,WEBSTER KD,et al. Pegademase bovine:replacement therapy for severe combined immunodeficiency disease[J]. DICP, 1991, 25(10):1092-1095
[33]	"Amgen 2016 Annual Report to Stockholders"[www.amgen.com/~/media/amgen/full/www-amgen-com/downloads/investors/2016-annual-report-letter-and-10k_restrict.ashx?la=en] 2016-annual-report-letter-and-10.pdf, 2017, p. 55
[34]	DE GRAAF AJ, KOOIJMAN M, HENNINK WE, et al. Nonnatural amino acids for site-specific protein conjugation[J]. Bioconjug Chem, 2009, 20(7):1281.
[35]	YANG BB, KIDO MA, MS MMS, et al. Pharmacokinetics and pharmacodynamics of pegfilgrastim in subjects with various degrees of renal function[J]. J Clin Pharmacol, 2011, 50(5):295-306.
[36]	TURECEK PL, BOSSARD MJ, GRANINGER M,et al. BAX 855, a PEGylated rFVⅢ product with prolonged half-life. Development, functional and structural characterisation[J]. Hamostaseologie, 2012, 32(Suppl 1):S29-S38.
[37]	WORLD HEALTH ORGANIZATION. WHO Guidelines on the Quality, Safety, and Efficacy of Biological Medicinal Products Prepared by Recombinant DNA Technology. Switzerland:WHO Press, 2013. 91-92.
[38]	LI XL, LIU L, GAO JP, et al. Methods for identification of conjugation site on PEGylated protein[J]. Pharmaceutical Biotechnology, 2013.
[39]	YU W, YU C, WU L, et al. PEGylated recombinant human interferon-ω as a long-acting antiviral agent:structure, antiviral activity and pharmacokinetics[J]. Antiviral Res, 2014, 108:142-147.
[40]	JOHN B, SWAPAN C, JOHNSTON D. Characterization of poly(ethylene glycol)-modified superoxide dismutase:Comparison of capillary electrophoresis and matrix-assisted laser desorption/ionization mass spectrometry[J]. Analytical Chemistry, 1996, 68(18):3258-3264.
[41]	李晶, 何辉, 程速远,等. 荧光胺衍生化法测定3种聚乙二醇化重组人生长激素的平均修饰率[J]. 药物分析杂志, 2014(8):1368-1373.

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通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

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Advances in the development of PEG derivatives and pegylated protein drugs

1. China Pharmaceutical University, Nanjing 210009, China;Beijing SL Pharmaceutical Co., Ltd., Beijing 100041, China

2. Beijing SL Pharmaceutical Co., Ltd., Beijing 100041, China

3. China Pharmaceutical University, Nanjing 210009, China

Received Date: 2017-11-23

Rev Recd Date: 2018-03-30

Key words:

Abstract: Polyethylene glycol and its derivatives are widely used in protein drug modification due to the excellent hydrophilicity, biocompatibility and bioinertia. The pegylation makes it possible that protein has lower immunogenicity and longer half-life. PEG derivatives had undergone three generations, from random modifications, to site-specific and functional modifications, and then branched structures. The application of PEG derivatives also extends to biosensing and drug delivery. Advances in the development of PEG derivatives and pegylated protein drugs were reviewed in this paper.

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Reference (41)

[1]	LAWRENCE P B, PRICE J L. How PEGylation influences protein conformational stability[J]. Curr Opin Chem Biol, 2016, 34:88-94.
[2]	PFISTER D, BOURGEAUX E, MORBIDELLI M. Kinetic modeling of protein PEGylation[J]. Chem Engin Sci, 2015, 137:816-827.
[3]	YANG Z, WANG J, LU Q, et al. PEGylation confers greatly extended half-life and attenuated immunogenicity to recombinant methioninase in primates[J]. Cancer Res, 2004, 64(18):6673-6678.
[4]	RODR GUEZMART NEZ JA, RIVERARIVERA I, SOL RJ, et al. Enzymatic activity and thermal stability of PEG-α-chymotrypsin conjugates[J]. Biotechnol Lett, 2009, 31(6):883-887.
[5]	姜忠义, 许松伟, 王艳强. 蛋白质和肽类分子的聚乙二醇化化学[J]. 有机化学, 2003, 23(12):1340-1347.
[6]	ZALIPSKY S, SELTZER R, MENONRUDOLPH S. Evaluation of a new reagent for covalent attachment of polyethylene glycol to proteins[J]. Biotechnol Appl Biochem, 1992, 15(1):100-114.
[7]	MIRON T, WILCHEK M. A simplified method for the preparation of succinimidyl carbonate polyethylene glycol for coupling to proteins[J]. Bioconjug Chem, 1993, 4(6):568-569.
[8]	ABUCHOWSKI A, KAZO GM, JR VC, et al. Cancer therapy with chemically modified enzymes. I. Antitumor properties of polyethylene glycol-asparaginase conjugates[J]. Cancer Biochem Biophys, 1984, 7(2):175-186.
[9]	ABUCHOWSKI A,VAN ES T,PALCZUK NC,et al. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol[J]. J Biol Chem,1977,252(11):3578-3581.
[10]	GAIS H J, RUPPERT S. Modification and immobilization of proteins with polyethylene glycol tresylates and polysaccharide tresylates:Evidence suggesting a revision of the coupling mechanism and the structure of the polymer-polymer linkage[J]. Tetrahedron Lett, 1995, 36(22):3837-3838.
[11]	ZALIPSKY S, LEE C. Use of functionalized poly(ethylene glycol)s for modification of polypeptides[M]//Poly(Ethylene Glycol) Chemistry. Springer US, 1992:1-15.
[12]	WANG J, HU T, LIU Y, et al. Kinetic and stoichiometric analysis of the modification process for N-terminal PEGylation of staphylokinase[J]. Anal Biochem, 2011, 412(1):114-116.
[13]	KINSTLER OB, BREMS DN, LAUREN SL, et al. Characterization and stability of N-terminally PEGylated rhG-CSF[J]. Pharm Res, 1996, 13(7):996-1002.
[14]	KINSTLER OB, GABRIEL NE, FARRAR CE, et al. N-terminally chemically modified protein-compositions and method:, DE 69509628 D1[P]. 1999.
[15]	FEE C J, DAMODARAN VB. Production of PEGylated proteins[M]//Biopharmaceutical Production Technology. 2012:199-222.
[16]	BROCCHINI S, GODWIN A, BALAN S, et al. Disulfide bridge based PEGylation of proteins[J]. Adv Drug Deliv Rev, 2008, 60(1):3-12.
[17]	TSUTSUMI Y, ONDA M, NAGATA S, et al. Site-specific chemical modification with polyethylene glycol of recombinant immunotoxin anti-Tac(Fv)-PE38(LMB-2) improves antitumor activity and reduces animal toxicity and immunogenicity[J]. Proc Natl Acad Sci USA, 2000, 97(15):8548-8553.
[18]	BANGALORE S, KUMAR S, FUSARO M, et al. Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus:mixed treatment comparison analysis of 22844 patient years of follow-up from randomised trials[J]. BMJ, 2012, 345:e5170.
[19]	PASUT G, VERONESE FM. State of the art in PEGylation:The great versatility achieved after forty years of research[J]. J Control Release, 2012, 161(2):461-472.
[20]	MORGENSTERN J, BAUMANN P, BRUNNER C, et al. Effect of PEG molecular weight and PEGylation degree on the physical stability of PEGylated lysozyme[J]. Int J Pharm, 2017, 519(1-2):408-417.
[21]	ROBERTS MJ, HARRIS JM. Attachment of degradable poly(ethylene glycol) to proteins has the potential to increase therapeutic efficacy[J]. J Pharm Sci, 1998, 87(11):1440-1445.
[22]	ANDREW J. GARMAN S,BARRET KALINDJIAN. The preparation and properties of novel reversible polymer-protein conjugates 2-ω-Methoxypolyethylene (5000) glycoxymethylene-3-methylmaleyl conjugates of plasminogen activators[J]. Febs Lett, 1987, 223(2):361-365.
[23]	田浤, 金宇灏, 陈阳建,等. 聚乙二醇氨基酸衍生物的合成及其对紫杉醇的修饰[J]. 中国药科大学学报, 2011, 42(1):78-82.
[24]	KIZILEL S, SCAVONE A, LIU X, et al. Encapsulation of pancreatic islets within nano-thin functional polyethylene glycol coatings for enhanced insulin secretion[J]. Tissue Engin Part A, 2010, 16(7):2217.
[25]	YOO MK, PARK IK, LIM HT, et al. Folate PEG superparamagnetic iron oxide nanoparticles for lung cancer imaging[J]. Acta Biomater, 2012, 8(8):3005-3013.
[26]	ZHANG C, YANG XL, YUAN YH, et al. Site-specific PEGylation of therapeutic proteins via optimization of both accessible reactive amino acid residues and PEG derivatives[J]. Biodrugs, 2012, 26(4):209. 209-215.
[27]	RYAN SIN AD M, MANTOVANI GIUSEPPE, WANG XUEXUAN, et al. Advances in PEGylation of important biotech molecules:delivery aspects[J]. Expert Opin Drug Deliv,2008,5(4):371-383.
[28]	VUGMEYSTER Y,ENTRICAN C A,JOYCE AP,et al.Pharmacokinetic,biodistribution and biophysical profiles of TNF nanobodies conjugated to linear or branched poly (ethylene glycol)[J].Bioconjug Chem,2012,23(7):1452-1462.
[29]	DAVIS, FF.The origin of pegnology[J]. Adv Drug Deliv Rev,2002,54(4):457-458.
[30]	DAVIS FF, VAN EST, PALCZUK NC. Non-immunogenic polypeptides:US, US 4179337 A[P]. 1979.
[31]	ABUCHOWSKI A,MCCOY JR,PALCZUK NC,et al. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase[J]. J Biol Chem,1977,252(11):3582-3586.
[32]	LEE CR,MCKENZIE CA,WEBSTER KD,et al. Pegademase bovine:replacement therapy for severe combined immunodeficiency disease[J]. DICP, 1991, 25(10):1092-1095
[33]	"Amgen 2016 Annual Report to Stockholders"[www.amgen.com/~/media/amgen/full/www-amgen-com/downloads/investors/2016-annual-report-letter-and-10k_restrict.ashx?la=en] 2016-annual-report-letter-and-10.pdf, 2017, p. 55
[34]	DE GRAAF AJ, KOOIJMAN M, HENNINK WE, et al. Nonnatural amino acids for site-specific protein conjugation[J]. Bioconjug Chem, 2009, 20(7):1281.
[35]	YANG BB, KIDO MA, MS MMS, et al. Pharmacokinetics and pharmacodynamics of pegfilgrastim in subjects with various degrees of renal function[J]. J Clin Pharmacol, 2011, 50(5):295-306.
[36]	TURECEK PL, BOSSARD MJ, GRANINGER M,et al. BAX 855, a PEGylated rFVⅢ product with prolonged half-life. Development, functional and structural characterisation[J]. Hamostaseologie, 2012, 32(Suppl 1):S29-S38.
[37]	WORLD HEALTH ORGANIZATION. WHO Guidelines on the Quality, Safety, and Efficacy of Biological Medicinal Products Prepared by Recombinant DNA Technology. Switzerland:WHO Press, 2013. 91-92.
[38]	LI XL, LIU L, GAO JP, et al. Methods for identification of conjugation site on PEGylated protein[J]. Pharmaceutical Biotechnology, 2013.
[39]	YU W, YU C, WU L, et al. PEGylated recombinant human interferon-ω as a long-acting antiviral agent:structure, antiviral activity and pharmacokinetics[J]. Antiviral Res, 2014, 108:142-147.
[40]	JOHN B, SWAPAN C, JOHNSTON D. Characterization of poly(ethylene glycol)-modified superoxide dismutase:Comparison of capillary electrophoresis and matrix-assisted laser desorption/ionization mass spectrometry[J]. Analytical Chemistry, 1996, 68(18):3258-3264.
[41]	李晶, 何辉, 程速远,等. 荧光胺衍生化法测定3种聚乙二醇化重组人生长激素的平均修饰率[J]. 药物分析杂志, 2014(8):1368-1373.

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Advances in the development of PEG derivatives and pegylated protein drugs

doi: 10.3969/j.issn.1006-0111.2018.04.004

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References

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通讯作者: 陈斌, bchen63@163.com

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