Пэгилирование как метод создания пролонгированных форм биофармацевтических препаратов (на примере пэгилированного гранулоцитарного колониестимулирующего фактора)

В настоящее время пэгилирование биологически активных молекул, в том числе белков, с помощью инертного гидрофильного полимера полиэтиленгликоля (ПЭГ) представляет собой важное направление в создании нового поколения фармацевтических препаратов пролонгирован-ного действия. Конъюгированные молекулы, как правило, имеют улучшенный фармакокинетический профиль, в том числе пониженный почечный клиренс, дополнительную защиту от действия протео-литических ферментов и низкую иммуногенность, что позволяет сохранить активность in vivo нативного препарата в человеческом организме в течение более продолжительного времени. Данный обзор дает возможность ознакомиться с современными методиками пэгилирования биофармацев-тических молекул, препаратами на основе конъюгатов с ПЭГ и рассматривает, как пример, пэгилирование рекомбинантного человеческого гранулоцитарного колониестимулирующего фактора (рчГ-КСФ). Также в обзоре представлены различные виды модифицированных ПЭГ-реагентов для направленного присоединения к биологическим молекулам и обсуждаются их преимущества и недостатки.

полиэтиленгликоль (ПЭГ), биофармацевтические препараты, рекомбинантный человеческий гранулоцитарный колониестимулирующий фактор (рчГ-КСФ), модификация, цитокины, фармакокинетический профиль

1. Freyer G., Ligneau B., Trillet-Lenoir V. Colony-stimulating factors in the prevention of solid tumors induced by chemotherapy in patients with febrile neutropenia // Int. J. Antimicrob. Agents. 1998. V. 10. P. 3-9.

2. Morstyn G., Burgess A.W. Hemopoietic growth factors: A review // Cancer Res. 1988. V. 48. P. 5624-5637.

3. Molineux G. Granulocyte colony-stimulating factors // Cancer Treatment & Res. 2011. V. 157. P. 33-53.

4. Asano S. Human granulocyte colony-stimulating factor: Its basic aspects and clinical applications // Am. J. Pediatr. Hematol. Oncol. 1991. V. 13. P. 400-413.

5. Herman A.C., Boone T.C., Lu H.S. Characterization, formulation, and stability of Neupogen (Filgrastim), a recombinant human granulocyte-colony stimulating factor // Pharm. Biotechnol. 1996. V. 9. P. 303-328.

6. Khalilzadeh R., Mohammadian-Mosaabadi J., Bahrami A., Nazak-Tabbar A., Nasiri-Khalili M.A., Amouheidari A. Process development for production of human granulocyte-colony stimulating factor by high cell density cultivation of recombinant Escherichia coli // J. Ind. Microbiol. Biotechnol. 2008. V. 35. P. 1643-1650.

7. Molineux G. Granulocyte colony-stimulating factor / In: Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics / Ed. G. Morstyn, M. Foote, G. J. Lieschke. N.Y., Totowa: Humana Press Inc., 2004. P. 83-97.

8. Vanz A.L., Renard G., Palma M.S., Chies J.M., Dalmora S.L., Basso L.A., Santos D.S. Human granulocyte colony stimulating factor (hG-CSF): Cloning, overexpression, purification and characterization // Microb. Cell Fact. 2008. V. 7. P. 1-12.

9. Gervais V., Zerial A., Oschkinat H. NMR investigations of the role of the sugar moiety in glycosylated recombinant human granulocyte-colony-stimulating factor // Eur. J. Biochem. 1997. V. 247. P. 386-395.

10. Wingfield P., Benedict R., Turcatti G., Allet B., Mermod J.-J., DeLamarter J., Simona M.G., Rose K. Characterization of recombinant-derived granulocyte-colony stimulating factor (G-CSF) // Biochem. J. 1988. V. 256. P. 213-218.

11. Hill C.P., Osslund T.D., Eisenberg D. The structure of granulocyte-colony-stimulating factor and its relationship to other growth factors // Proc. Natl. Acad. Sci. USA. 1993. V. 90. P. 5167-5171.

12. Molineux G. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta) // Curr. Pharm. Des. 2004. V. 10. P. 1235-1244.

13. Wadhwa M., Thorpe R. Haematopoietic growth factors and their therapeutic use // Thromb. Haemost. 2008. V. 99. P. 863-873.

14. Heuser M., Ganser A. Colony-stimulating factors in the management of neutropenia and its complications // Ann. Hematol. 2005. V. 84. P. 697-708.

15. van de Geijn G.J.M., Aarts L.H.J., Erkeland S.J., Prasher J.M., Touw I.P. Granulocyte colony-stimulating factor and its receptor in normal hematopoietic cell development and myeloid disease // Rev. Physiol. Biochem. Pharmacol. 2003. V. 149. P. 53-71.

16. Zalipsky S. Functionalized poly(ethylene glycol) for preparation of biologically relevant conjugates // Bioconjug. Chem. 1995. V. 6. P. 150-165.

17. Veronese F.M., 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. Compat. Polym. 1997. V. 12. P. 196-207.

18. Herman S., Hooftman G., Schacht E. Poly(ethylene glycol) with reactive endgroups: I. Modification of proteins // J. Bioact. Compat. Polym. 1995. V. 10. P. 145-186.

19. Knop K., Hoogenboom R., Fischer D., Schubert U.S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives // Angew. Chem. Int. Ed. Engl. 2010. V. 49. P. 6288-6308.

20. Morpurgo M., Veronese F.M. Conjugates of peptides and proteins to polyethylene glycols / In: Methods in Molecular Biology: Bioconjugation Protocols: Strategies and Methods / Ed. C.M. Niemeyer. N.Y, Totowa: Humana Press Inc., 2004. V. 283. P. 45-70.

21. Kang J.S., Deluca P.P., Lee K.C. Emerging PEGylated drugs // Expert Opin. Emerg. Drugs. 2009. V. 14. P. 363-380.

22. Jevsevar S., Kunstelj M., Porekar V.G. PEGylation of therapeutic proteins // Biotechnol. J. 2010. V. 5. P. 113-128.

23. Milla P., Dosio F., Cattel L. PEGylation of proteins and liposomes: A powerful and flexible strategy to improve the drug delivery // Curr. Drug Metab. 2012. V. 13. P. 105-119.

24. Scholz M., Engel C., Apt D., Sankar S.L., Goldstein E., Loeffler M. Pharmacokinetic and pharmacodynamic modelling of the novel human granulocyte colony-stimulating factor derivative Maxy-G34 and pegfilgrastim in rats // Cell Prolif. 2009. V. 42. P. 823-837.

25. Ljung R., Karim F.A., Saxena K., Suzuki T. [et al.]. 40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics, and preliminary efficacy in hemophilia patients with inhibitors // J. Thromb. Haemost. 2013. V. 11. P. 1260-1268.

26. Tiede A., Brand B., Fischer R., Kavakli K. [et al.]. Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A // J. Thromb. Haemost. 2013. V. 11. P. 670-678.

27. Collins P.W., Møss J., Knobe K., Groth A., Colberg T., Watson E. Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX // J. Thromb. Haemost. 2012. V. 10. P. 2305-2312.

28. Sarkissian C.N., Kang T.S., Gámez A., Scriver C.R., Stevens R.C. Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of phenylketonuria // Mol. Genet. Metab. 2011. V. 104. P. 249-254.

29. Jacobetz M.A., Chan D.S., Neesse A., Bapiro T.E., Cook N., Frese K.K., Feig C., Nakagawa T. [et al.]. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer // Gut. 2013. V. 62. P. 112-120.

30. Skerra A. Engineered protein scaffolds for molecular recognition // J. Mol. Recognit. 2000. V. 13. P. 167-187.

31. Gebauer M., Skerra A. Engineered protein scaffolds as next-generation antibody therapeutics // Curr. Opin. Chem. Biol. 2009. V. 13. P. 245-255.

32. Ackermann M., Morse B.A., Delventhal V., Carvajal I.M., Konerding M.A. Anti-VEGFR2 and anti-IGF-1R-Adnectins inhibit Ewing's sarcoma A673-xenograft growth and normalize tumor vascular architecture // Angiogenesis. 2012. V. 15. P. 685-695.

33. Cong Y., Pawlisz E., Bryant P., Balan S., Laurine E., Tommasi R. [et al.]. Site-specific PEGylation at histidine tags // Bioconjug. Chem. 2012. V. 23. P. 248-263.

34. Schoonooghe S., Laoui D., Van Ginderachter J.A., Devoogdt N., Lahoutte T., De Baetselier P., Raes G. Novel applications of nanobodies for in vivo bio-imaging of inflamed tissues in inflammatory diseases and cancer // Immunobiology. 2012. V. 217. P. 1266-1272.

35. Huang L., Muyldermans S., Saerens D. Nanobodies®: Proficient tools in diagnostics // Expert Rev. Mol. Diagn. 2010. V. 10. P. 777-785.

36. Sadeqzadeh E., Rahbarizadeh F., Ahmadvand D., Rasaee M.J. [et al.]. Combined MUC1-specific nanobody-tagged PEG-polyethylenimine polyplex targeting and transcriptional targeting of tBid transgene for directed killing of MUC1 over-expressing tumour cells // J. Control. Release. 2011. V. 156. P. 85-91.

37. Vugmeyster Y., Entrican C.A., Joyce A.P., Lawrence-Henderson R.F. [et al.]. Pharmacokinetic, biodistribution, and biophysical profiles of TNF nanobodies conjugated to linear or branched poly(ethylene glycol) // Bioconjug. Chem. 2012. V. 23. P. 1452-1462.

38. Sabar M.F., Kausar S., Zafar A.U. PEG-interferon conjugates: Effects of length and structure of linker // Pak. J. Pharm. Sci. 2013. V. 26. P. 425-430.

39. Onoue S., Matsui T., Kato M., Mizumoto T., Liu B., Liu L. [et al.]. Chemical synthesis and formulation design of a PEGylated vasoactive intestinal peptide derivative with improved metabolic stability // Eur. J. Pharm. Sci. 2013. V. 49. P. 382-389.

40. Mezo A.R., Low S.C., Hoehn T., Palmieri H. PEGylation enhances the therapeutic potential of peptide antagonists of the neonatal Fc receptor, FcRn // Bioorg. Med. Chem. Lett. 2011. V. 21. P. 6332-6335.

41. Kunstelj M., Fidler K., Skrajnar S., Kenig M. [et al]. Cysteine-specific PEGylation of rhG-CSF via selenylsulfide bond // Bioconjug. Chem. 2013. V. 24. P. 889-896.

42. da Silva Freitas D., Mero A., Pasut G. Chemical and enzymatic site specific PEGylation of hGH // Bioconjug. Chem. 2013. V. 24. P. 456-463.

43. Mattos A., de Jager-Krikken A., de Haan M., Beljaars L., Poelstra K. PEGylation of interleukin-10 improves the pharmacokinetic profile and enhances the antifibrotic effectivity in CCl₄-induced fibrogenesis in mice // J. Control. Release. 2012. V. 162. P. 84-91.

44. Tsiourvas D., Sideratou Z., Sterioti N., Papadopoulos A., Nounesis G., Paleos C.M. Insulin complexes with PEGylated basic oligopeptides // J. Colloid. Interface Sci. 2012. V. 384. P. 61-72.

45. Lee L.S., Conover C., Shi C., Whitlow M., Filpula D. Prolonged circulating lives of single-chain Fv proteins conjugated with polyethylene glycol: A comparison of conjugation chemistries and compounds // Bioconjug. Chem. 1999. V. 10. P. 973-981.

46. Mohs A.M., Zong Y., Guo J., Parker D.L., Lu Z.R. PEG-g-poly(GdDTPA-co-L-cystine): Effect of PEG chain length on in vivo contrast enhancement in MRI // Biomacromolecules. 2005. V. 6. P. 2305-2311.

47. Kaminskas L.M., Boyd B.J., Karellas P., Krippner G.Y., Lessene R., Kelly B., Porter C.J. The impact of molecular weight and PEG chain length on the systemic pharmacokinetics of PEGylated poly L-lysine dendrimers // Mol. Pharm. 2008. V. 5. P. 449-463.

48. Pasut G., Veronese F.M. PEG conjugates in clinical development or use as anticancer agents: An overview // Adv. Drug Deliv. Rev. 2009. V. 61. P. 1177-1188.

49. Caliceti P., Veronese F.M. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates // Adv. Drug Deliv. Rev. 2003. V. 55. P. 1261-1277.

50. Noureddin M., Ghany M.G. Pharmacokinetics and pharmacodynamics of peginterferon and ribavirin: Implications for clinical efficacy in the treatment of chronic hepatitis C // Gastroenterol. Clin. North Am. 2010. V. 39. P. 649-658.

51. Harris J.M., Martin N.E., Modi M. Pegylation: A novel process for modifying pharmacokinetics // Clin. Pharmacokinet. 2001. V. 40. P. 539-551.

52. González-Valdez J., Rito-Palomares M., Benavides J. Advances and trends in the design, analysis, and characterization of polymer-protein conjugates for "PEGylaided" bioprocesses // Anal. Bioanal. Chem. 2012. V. 403. P. 2225-2235.

53. Nojima Y., Suzuki Y., Yoshida K., Abe F., Shiga T., Takeuchi T. [et al]. Lactoferrin conjugated with 40-kDa branched poly(ethylene glycol) has an improved circulating half-life // Pharm. Res. 2009. V. 26. P. 2125-2132.

54. Veronese F.M., Mero A. The impact of PEGylation on biological therapies // BioDrugs. 2008. V. 22. P. 315-329.

55. Fee C.J. Size comparison between proteins PEGylated with branched and linear poly(ethylene glycol) molecules // Biotechnol. Bioeng. 2007. V. 98. P. 725-731.

56. Hamidi M., Azadi A., Rafiei P. Pharmacokinetic consequences of pegylation // Drug Deliv. 2006. V. 13. P. 399-409.

57. Gokarn Y.R., McLean M., Laue T.M. Effect of PEGylation on protein hydrodynamics // Mol. Pharm. 2012. V. 9. P. 762-773.

58. Gaberc-Porekar V., Zore I., Podobnik B., Menart V. Obstacles and pitfalls in the PEGylation of therapeutic proteins // Curr. Opin. Drug Discov. Devel. 2008. V. 11. P. 242-250.

59. Bailon P., Won C.Y. PEG-modified biopharmaceuticals // Expert Opin. Drug Deliv. 2009. V. 6. P. 1-16.

60. Fee C.J., Van Alstine J.M. PEG-proteins: Reaction engineering and separation issues // Chem. Eng. Sci. 2006. V. 61. P. 924-939.

61. Roberts M.J., Harris J.M. Attachment of degradable poly(ethylene glycol) to proteins has the potential to increase therapeutic efficacy // J. Pharm. Sci. 1998. V. 87. P. 1440-1445.

62. Fishburn C.S. The pharmacology of PEGylation: Balancing PD with PK to generate novel therapeutics // J. Pharm. Sci. 2008. V. 97. P. 4167-4183.

63. Pasut G., Veronese F.M. PEGylation for improving the effectiveness of therapeutic biomolecules // Drugs Today (Barc.). 2009. V. 45. P. 687-695.

64. Harris J.M., Chess R.B. Effect of pegylation on pharmaceuticals // Nat. Rev. Drug Discov. 2003. V. 2. P. 214-221.

65. Bailon P., Berthold W. Polyethylene glycol-conjugated pharmaceutical proteins // Pharm. Sci. Technol. Today. 1998. V. 1. P. 352-356.

66. Zhang C., Yang X.L., Yuan Y.H., Pu J., Liao F. Site-specific PEGylation of therapeutic proteins via optimization of both accessible reactive amino acid residues and PEG derivatives // BioDrugs. 2012. V. 26. P. 209-215.

67. Larson R.S., Menard V., Jacobs H., Kim S.W. Physicochemical characterization of poly(ethylene glycol)-modified anti-GAD antibodies // Bioconjug. Chem. 2001. V. 12. P. 861-869.

68. Bonora G.M., Drioli S. Reactive PEGs for protein conjugation // In: PEGylated Protein Drugs: Basic Science and Clinical Applications / Ed. F.M. Veronese. Switzeland: Birkhäuser Verlag, 2009. P. 33-45.

69. Hooftman G., Herman S., Schacht E. Poly(ethylene glycol)s with reactive endgroups. II. Practical consideration for the preparation of protein-PEG conjugates // J. Bioact. Compat. Polym. 1996. V. 11. P. 135-159.

70. Fee C.J., Van Alstine J.M. Purification of pegylated proteins // Methods Biochem. Anal. 2011. V. 54. P. 339-362.

71. Hershfield M.S., Chaffee S., Koro-Johnson L., Mary A., Smith A.A., Short S.A. Use of site-directed mutagenesis to enhance the epitope-shielding effect of covalent modification of proteins with polyethylene glycol // Proc. Natl. Acad. Sci. USA. 1991. V. 88. P. 7185-7189.

72. Wylie D.C., Voloch M., Lee S., Liu Y.H., Cannon-Carlson S., Cutler C. [et al.]. Carboxy-alkylated histidine is a pH-dependent product of pegylation with SC-PEG // Pharm. Res. 2001. V. 18. P. 1354-1360.

73. Lee J.I., Eisenberg S.P., Rosendahl M.S., Chlipala E.A., Brown J.D. [et al.]. Site-specific PEGylation enhances the pharmacokinetic properties and antitumor activity of interferon Beta-1b // J. Interferon Cytokine Res. 2013. V. 33. P. 769-777.

74. Pasut G., Veronese F.M. State of the art in PEGylation: The great versatility achieved after forty years of research // J. Control. Release. 2012. V. 161. P. 461-472.

75. Bell S.J., Fam C.M., Chlipala E.A., Carlson S.J., Lee J.I. [et al.]. Enhanced circulating half-life and antitumor activity of a site-specific pegylated interferon-alpha protein therapeutic // Bioconjug. Chem. 2008. V. 19. P. 299-305.

76. Gaertner H.F., Offord R.E. Site-specific attachment of functionalized poly(ethylene glycol) to the amino terminus of proteins // Bioconjug. Chem. 1996. V. 7. P. 38-44.

77. Wu H., Li J., Zhang Q., Yan X., Guo L. [et al]. A novel small Odorranalectin-bearing cubosomes: Preparation, brain delivery and pharmacodynamic study on amyloid-β₂₅₋₃₅-treated rats following intranasal administration // Eur. J. Pharm. Biopharm. 2012. V. 80. P. 368-378.

78. Goodson R.J., Katre N.V. Site-directed pegylation of recombinant interleukin-2 at its glycosylation site // Biotechnology. 1990. V. 8. P. 343-346.

79. Woghiren C., Sharma B., Stein S. Protected thiol-polyethylene glycol: A new activated polymer for reversible protein modification // Bioconjug. Chem. 1993. V. 4. P. 314-318.

80. Pepinsky R.B., Shapiro R.I., Wang S., Chakraborty A. Long-acting forms of Sonic hedgehog with improved pharmacokinetic and pharmacodynamic properties are efficacious in a nerve injury model // J. Pharm. Sci. 2002. V. 91. P. 371-387.

81. Morpurgo M., Veronese F.M., Kachensky D., Harris J.M. Preparation and characterization of poly(ethylene glycol) vinyl sulfone // Bioconjug. Chem. 1996. V. 7. P. 363-368.

82. Balan S., Choi J.W., Godwin A., Teo I. [et al]. Site-specific PEGylation of protein disulfide bonds using a three-carbon bridge // Bioconjug. Chem. 2007. V. 18. P. 61-76.

83. Brocchini S., Godwin A., Balan S. [et al.]. Disulfide bridge based PEGylation of proteins // Adv. Drug Deliv. Rev. 2008. V. 60. P. 3-12.

84. Scaramuzza S., Tonon G., Olianas A., Messana I., Schrepfer R. [et al.]. A new site-specific monoPEGylated filgrastim derivative prepared by enzymatic conjugation: Production and physicochemical characterization // J. Control. Release. 2012. V. 164. P. 355-363.

85. Zhao X., Shaw A.C., Wang J., Chang C.C., Deng J., Su J. A novel high-throughput screening method for microbial transglutaminases with high specificity toward Gln141 of human growth hormone // J. Biomol. Screen. 2010. V. 15. P. 206-212.

86. Sato H., Yamamoto K., Hayashi E., Takahara Y. Transglutaminase-mediated dual and site-specific incorporation of poly(ethylene glycol) derivatives into a chimeric interleukin-2 // Bioconjug. Chem. 2000. V. 11. P. 502-509.

87. Wang Y.J., Liu Y.D., Chen J., Hao S.J., Hu T. et al. Efficient preparation and PEGylation of recombinant human non-glycosylated erythropoietin expressed as inclusion body in E. coli // Int. J. Pharm. 2010. V. 386. P. 156-164.

88. Orsatti L., Veronese F.M. An unusual coupling of poly(ethylene glycol) to tyrosine residues in epidermal growth factor // Journal Bioact. Compat. Polym. 1999. V. 14. P. 429-436.

89. Wang Y.S., Youngster S., Bausch J., Zhang R., McNemar C., Wyss D.F. Identification of the major positional isomer of pegylated interferon alpha-2b // Biochemistry. 2000. V. 39. P. 10634-10640.

90. Riordan J.F., Vallee B.L. O-Acetyl tyrosine // Methods of Enzymology. 1972. 1972. P. 500-506.

91. Zalipsky S. Menon-Rudolph S. Hydrazide derivatives of polyethylene glycols and their bio-conjugates / In: Poly(ethylene glycol) Chemistry and Biological Applications / Ed. J.M. Harris, S. Zalipsky. Washington: ACS, 1997. V. 680. P. 318-341.

92. Francis G.E., Fisher D., Delgado C., Malik F., Gardiner A., Neale D. PEGylation of cytokines and other therapeutic proteins and peptides: The importance of biological optimisation of coupling techniques // Int. J. Hematol. 1998. V. 68. P. 1-18.

93. Sakane T., Pardridge W.M. Carboxyl-directed pegylation of brain-derived neurotrophic factor markedly reduces systemic clearance with minimal loss of biologic activity // Pharm. Res. 1997. V. 14. P. 1085-1091.

94. Wysocka M., Lesner A., Popow J., Legowska M., Rolka K. Pegylated fluorescent peptides as substrates of proteolytic enzymes // Protein Pept. Lett. 2012. V. 19. P. 1237-1244.

95. Veronese F.M. Peptide and protein PEGylation: A review of problems and solutions // Biomaterials. 2001. V. 22. P. 405-417.

96. Youn Y.S., Lee K.C. Site-specific PEGylation for high-yield preparation of Lys(21)-amine PEGylated growth hormone-releasing factor (GRF) (1-29) using a GRF(1-29) derivative FMOC-protected at Tyr(1) and Lys(12) // Bioconjug. Chem. 2007. V. 18. P. 500-506.

97. Herold D.A., Keil K., Bruns D.E. Oxidation of polyethylene glycols by alcohol dehydrogenase // Biochem. Pharmacol. 1989. V. 38. P. 73-76.

98. Kawai F. Microbial degradation of polyethers // Appl. Microbiol. Biotechnol. 2002. V. 58. P. 30-38.

99. Eliason J.F. Pegylated cytokines: Potential application in immunotherapy of cancer // BioDrugs. 2001. V. 15. P. 705-711.

100. Veronese F.M., Morpurgo M. Bioconjugation in pharmaceutical chemistry // Il Farmaco. 1999. V. 54. P. 497-516.

101. Giorgi M.E., Ratier L., Agusti R., Frasch A.C., de Lederkremer R.M. Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol // Glycobiology. 2012. V. 22. P. 1363-1373.

102. Miyaji Y., Kasuya Y., Furuta Y., Kurihara A., Takahashi M. [et al.]. Novel comb-shaped PEG modification enhances the osteoclastic inhibitory effect and bone delivery of osteoprotegerin after intravenous administration in ovariectomized rats // Pharm. Res. 2012. V. 29. P. 3143-3155.

103. Ouchi M., Terashima T., Sawamoto M. Transition metal-catalyzed living radical polymerization: toward perfection in catalysis and precision polymer synthesis // Chem. Rev. 2009. V. 109. P. 4963-5050.

104. Filpula D., Zhao H. Releasable PEGylation of proteins with customized linkers // Adv. Drug Deliv. Rev. 2008. V. 60. P. 29-49.

105. Zhao H., Yang K., Martinez A. [et al.]. Linear and branched bicin linkers for releasable PEGylation of macromolecules: Controlled release in vivo and in vitro from mono- and multi-PEGylated proteins // Bioconjug. Chem. 2006. V. 17. P. 341-351.

106. Lee S., Greenwald R.B., McGuire J., Yang K., Shi C. Drug delivery systems employing 1,6-elimination: Releasable poly(ethylene glycol) conjugates of proteins // Bioconjug. Chem. 2001. V. 12. P. 163-169.

107. Filpula D., Yang K., Basu A., Hassan R., Xiang L. [et al.]. Releasable PEGylation of mesothelin targeted immunotoxin SS1P achieves single dosage complete regression of a human carcinoma in mice // Bioconjug. Chem. 2007. V. 18. P. 773-784.

108. Zalipsky S., Qazen M., Walker J.A. 2nd, Mullah N. [et al.]. New detachable poly(ethylene glycol) conjugates: Cysteine-cleavable lipopolymers regenerating natural phospholipid, diacyl phos-phatidylethanolamine // Bioconjug. Chem. 1999. V. 10. P. 703-707.

109. Greenwald R.B., Yang K., Zhao H., Conover C.D., Lee S., Filpula D. Controlled release of proteins from their poly(ethylene glycol) conjugates: Drug delivery systems employing 1,6-elimination // Bioconjug. Chem. 2003. V. 14. P. 395-403.

110. Greenwald R.B., Zhao H., Yang K., Reddy P., Martinez A. A new aliphatic amino prodrug system for the delivery of small molecules and proteins utilizing novel PEG derivatives // J. Med. Chem. 2004. V. 47. P. 726-734.

111. Falchi A., Taddei M. PEG-dichlorotriazine (PEG-DCT): A new soluble polymer-supported scavenger for alcohols, thiols, phosphines, and phosphine oxides // Org. Lett. 2000. V. 2. P. 3429-3431.

112. Srichana T., Suwandecha T. Polyethylene glycol in glinical application and PEGylated drugs / In: Biodegradable Polymers in Clinical Use and Clinical Development / Ed. A.J. Domb, N. Kumar, A. Ezra. John Wiley & Sons, Inc., 2011. P. 451-493.

113. Ross E.A., Branham M.L., Tebbett I.R. High mass clearance of autoantibodies from a murine model of lupus nephritis by immunoadsorption using star-configured polyethylene glycols // J. Biomed. Mater. Res. 2001. V. 55. P. 114-120.

114. Hsu C.W., Olabisi R.M., Olmsted-Davis E.A., Davis A.R., West J.L. Cathepsin K-sensitive poly(ethylene glycol) hydrogels for degradation in response to bone resorption // J. Biomed. Mater. Res. A. 2011. V. 98. P. 53-62.

115. Zalipsky S., Seltzer R., Menon-Rudolph S. Evaluation of a new reagent for covalent attachment of polyethylene glycol to proteins // Biotechnol. Appl. Biochem. 1992. V. 15. P. 100-114.

116. Zhang G., Wang X., Wang Z., Zhang J., Suggs L. A PEGylated fibrin patch for mesenchymal stem cell delivery // Tissue Eng. 2006. V. 12. P. 9-19.

117. Woodward C.A., Kaufman E.N. Enzymatic catalysis in organic solvents: Polyethylene glycol modified hydrogenase retains sulfhydrogenase activity in toluene // Biotechnol. Bioeng. 1996. V. 52. P. 423-428.

118. Vasudev S.S., Ahmad S., Parveen R., Ahmad F.J. [et al]. Formulation of PEG-ylated L-asparaginase loaded poly (lactide-co-glycolide) nanoparticles: Influence of pegylation on enzyme loading, activity and in vitro release // Pharmazie. 2011. V. 66. P. 956-960.

119. Abuchowski A.,Vanes T., Palczuk N.C., Davis F.F. Alteration of immunological properties of bovine serum-albumin by covalent attachment of polyethylene-glycol // J. Biol. Chem. 1977. V. 252. P. 3578-3581.

120. Abuchowski A., McCoy J.R., Palczuk N.C., van Es T., Davis F.F. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase // J. Biol. Chem. 1977. V. 252. P. 3582-3586.

121. Roberts M.J., Bentley M.D., Harris J.M. Chemistry for peptide and protein PEGylation // Adv. Drug Deliv. Rev. 2002. V. 54. P. 459-476.

122. Kaul G., Amiji M. Long-circulating poly(ethylene glycol)-modified gelatin nanoparticles for intracellular delivery // Pharm. Res. 2002. V. 19. P. 1061-1067.

123. Bergström K., Holmberg K., Safranj A., Hoffman A.S. [et al.]. Reduction of fibrinogen adsorption on PEG-coated polystyrene surfaces // J. Biomed. Mater. Res. 1992. V. 26. P. 779-790.

124. Chen A., Kozak D., Battersby B.J., Forrest R.M. [et al.]. Antifouling surface layers for improved signal-to-noise of particle-based immunoassays // Langmuir. 2009. V. 25. P. 13510-13515.

125. Chamow S.M., Kogan T.P., Venuti M., Gadek T. Modification of CD4 immunoadhesin with mono-methoxypoly(ethylene glycol) aldehyde via reductive alkylation // Bioconjug. Chem. 1994. V. 5. P. 133-140.

126. Kinstler O.B., Brems D.N., Lauren S.L., Paige A.G., Hamburger J.B., Treuheit M.J. Characterization and stability of N-terminally PEGylated rhG-CSF // Pharm. Res. 1996. V. 13. P. 996-1002.

127. Abello N., Kerstjens H.A., Postma D.S., Bischoff R. Selective acylation of primary amines in peptides and proteins // J. Proteome Res. 2007. V. 6. P. 4770-4776.

128. Abuchowski A., Kazo G.M., Verhoest C.R.Jr.,Van Es T. [et al.]. Cancer therapy with chemically modified enzymes. I. Antitumor properties of polyethylene glycol-asparaginase conjugates // Cancer Biochem. Biophys. 1984. V. 7. P. 175-186.

129. Santos L.F., Iglesias A.H., Gozzo F.C. Fragmentation features of intermolecular cross-linked peptides using N-hydroxy- succinimide esters by MALDI- and ESI-MS/MS for use in structural proteomics // J. Mass Spectrom. 2011. V. 46. P. 742-750.

130. Zimmermann J.L., Nicolaus T., Neuert G., Blank K. Thiol-based, site-specific and covalent immobilization of biomolecules for single-molecule experiments // Nat. Protoc. 2010. V. 5. P. 975-985.

131. Schlapak R., Pammer P., Armitage D., Zhu R. [et al.]. Glass surfaces grafted with high-density poly(ethylene glycol) as substrates for DNA oligonucleotide microarrays // Langmuir. 2006. V. 22. P. 277-285.

132. Nathan A., Zalipsky S., Ertel S.I., Agathos S.N. [et al]. Copolymers of lysine and polyethylene glycol: a new family of functionalized drug carriers // Bioconjug. Chem. 1993. V. 4. P. 54-62.

133. Zavareh S., Samandari G. Polyethylene glycol as an epoxy modifier with extremely high toughening effect: Formation of nanoblend morphology // Polymer Engineering & Science. 2013. (http://onlinelibrary.wiley.com/doi/10.1002/pen.23733/abstract).

134. Geoghegan K.F. Modification of amino groups / In: Current Protocols in Protein Science. 2001. Chapter 15. Unit 15.2. (http://onlinelibrary.wiley.com/doi/10.1002/0471140864.ps1502s04/abstract).

135. Ikegawa S., Kinoshita J., Shimizu M., Tohma M. Radioimmunological characterization of anti lithocholic acid antisera elicited by [C-6] carboxylic acid N-succinimidyl esters as haptenic derivatives // Yakugaku Zasshi: J. Pharmaceut. Soc. Japan. 1989. V. 109. P. 306-311.

136. Kinstler O., Molineux G., Treuheit M., Ladd D. [et al]. Mono-N-terminal poly(ethylene glycol)-protein conjugates // Adv. Drug Deliv. Rev. 2002. V. 54. P. 477-485.

137. Xu H., Kaar J.L., Russell A.J., Wagner W.R. Characterizing the modification of surface proteins with poly(ethylene glycol) to interrupt platelet adhesion // Biomaterials. 2006. V. 27. P. 3125-3135.

138. Harris J.M., Kozlowski A. Polyethylene glycol and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications : US Patent. 1997. 5672662 A (http://www.google.es/patents/US5672662).

139. Sartore L., Caliceti P., Schiavon O., Veronese F.M. Enzyme modification by MPEG with an amino acid or peptide as spacer arms // Appl. Biochem. & Biotechnol. 1991. V. 27. P. 45-54.

140. Veronese F.M., Sacca B., De Laureto P.P., Sergi M., Caliceti P., Schiavon O. [et al.]. New PEGs for peptide and protein modification, suitable for identification of the PEGylation site // Bioconjug. Chem. 2001. V. 12. P. 62-70.

141. Veronese F.M., Pasut G. PEGylation, successful approach to drug delivery // Drug Discov. Today. 2005. V. 10. P. 1451-1458.

142. Bentley M.D., Roberts M.J., Harris J.M. Reductive amination using poly(ethylene glycol) acetaldehyde hydrate generated in situ: Applications to chitosan and lysozyme // J. Pharm. Sci. 1998. V. 87. P. 1446-1449.

143. Bentley M.D., Harris J.M., Kozlowski A. Heterobifunctional poly(ethylene glycol) derivatives and methods for their preparation :1999. US Patent. US 6448369 B1. PCT US99/23536. (http://www.google.com/patents/US6448369).

144. Ryan S.M., Mantovani G., Wang X., Haddleton D.M. [et al.]. Advances in PEGylation of important biotech molecules: Delivery aspects // Expert Opin. Drug Deliv. 2008. V. 5. P. 371-383.

145. Veronese F.M., Mero A., Caboi F., Sergi M. [et al.]. Site-specific pegylation of G-CSF by reversible denaturation // Bioconjug. Chem. 2007. V. 18. P. 1824-1830.

146. Doherty D.H., Rosendahl M.S., Smith D.J., Hughes J.M. [et al.]. Site-specific PEGylation of engineered cysteine analogues of recombinant human granulocyte-macrophage colony-stimulating factor // Bioconjug. Chem. 2005. V. 16. P. 1291-1298.

147. Rosendahl M.S., Doherty D.H., Smith D.J., Carlson S.J. [et al]. A long-acting, highly potent interferon alpha-2 conjugate created using site-specific PEGylation // Bioconjug. Chem. 2005. V. 16. P. 200-207.

148. Pasut G., Guiotto A., Veronese F.M. Protein, peptide and non-peptide drug PEGylation for therapeutic application // Expert Opin. Ther. Pat. 2004. V. 14. P. 859-894.

149. Shaunak S., Godwin A., Choi J.W., Balan S. [et al.]. Site-specific PEGylation of native disulfide bonds in therapeutic proteins // Nat. Chem. Biol. 2006. V. 2. P. 312-313.

150. Li X.Q., Lei J.D., Su Z.G. [et al]. Comparison of bioactivities of monopegylated rhG-CSF with branched and linear mPEG // Proc. Biochem. 2007. V. 42. P. 1625-1631.

151. Monfardini C., Schiavon O., Caliceti P., Morpurgo M., Harris J.M., Veronese F.M. A branched monomethoxypoly(ethylene glycol) for protein modification // Bioconjug. Chem. 1995. V. 6. P. 62-69.

152. Kamigaito M., Ando T., Sawamoto M. Metal-catalyzed living radical polymerization // Chem. Rev. 2001. V. 101. P. 3689-3746.

153. Lecolley F., Tao L., Mantovani G., Durkin I. A new approach to bioconjugates for proteins and peptides («pegylation») utilising living radical polymerization // Chem. Commun. (Camb.). 2004. V. 18. P. 2026-2027.

154. Jones M.W., Strickland R.A., Schumacher F.F., Caddick S. [et al.]. Polymeric dibromo-maleimides as extremely efficient disulfide bridging bioconjugation and pegylation agents // J. Am. Chem. Soc. 2012. V. 134. P. 1847-1852.

155. Fan X., Lin L., Messersmith P.B. Cell fouling resistance of polymer brushes grafted from ti substrates by surface-initiated polymerization: Effect of ethylene glycol side chain length // Biomacro-molecules. 2006. V. 7. P. 2443-2448.

156. Mantovani G., Lecolley F., Tao L. [et al.]. Design and synthesis of N-maleimido-functionalized hydrophilic polymers via copper-mediated living radical polymerization: A suitable alternative to PEGylation chemistry // J. Am. Chem. Soc. 2005. V. 127. P. 2966-2973.

157. Asayama S., Nogawa M., Takei Y., Akaike T., Maruyama A. Synthesis of novel polyampholyte comb-type copolymers consisting of a poly(L-lysine) backbone and hyaluronic acid side chains for a DNA carrier // Bioconjug. Chem. 1998. V. 9. P. 476-481.

158. Miyaji Y., Kasuya Y., Furuta Y., Kurihara A. Novel comb-shaped PEG modification enhances the osteoclastic inhibitory effect and bone delivery of osteoprotegerin after intravenous administration in ovariectomized rats // Pharm. Res. 2012. V. 29. P. 3143-3155.

159. Ryan S.M., Wang X., Mantovani G., Sayers C.T. Conjugation of salmon calcitonin to a combed-shaped end functionalized poly(poly(ethylene glycol) methyl ether methacrylate) yields a bioactive stable conjugate // J. Control. Release. 2009. V. 135. P. 51-59.

160. Da Pieve C., Blackshaw E., Missailidis S., Perkins A.C. PEGylation and biodistribution of an anti-MUC1 aptamer in MCF-7 tumor-bearing mice // Bioconjug. Chem. 2012. V. 23. P. 1377-1381.

161. Boomer R.M., Lewis S.D., Healy J.M., Kurz M. Conjugation to polyethylene glycol polymer promotes aptamer biodistribution to healthy and inflamed tissues // Oligonucleotides. 2005. V. 15. P. 183-195.

162. Setijadi E., Tao L., Liu J., Jia Z. Biodegradable star polymers functionalized with beta-cyclo-dextrin inclusion complexes // Biomacromolecules. 2009. V. 10. P. 2699-2707.

163. Santi D.V., Schneider E.L., Reid R., Robinson L., Ashley G.W. Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates // Proc. Natl. Acad. Sci. USA. 2012. V. 109. P. 6211-6216.

164. Asayama S., Maruyama A., Cho C.S., Akaike T. Design of comb-type polyamine copolymers for a novel pH-sensitive DNA carrier // Bioconjug. Chem. 1997. V. 8. P. 833-838.

165. Srividhya M., Preethi S., Gnanamani A., Reddy B.S. Sustained release of protein from poly(ethylene glycol) incorporated amphiphilic comb like polymers // Int. J. Pharm. 2006. V. 326. P. 119-127.

166. Heredia K.L., Bontempo D., Ly T., Byers J.T. [et al.]. In situ preparation of protein-«smart» polymer conjugates with retention of bioactivity // J. Am. Chem. Soc. 2005. V. 127. P. 16955-16960.

167. Bontempo D., Maynard H.D. Streptavidin as a macroinitiator for polymerization: In situ protein-polymer conjugate formation // J. Am. Chem. Soc. 2005. V. 127. P. 6508-6509.

168. Le Droumaguet B., Mantovani G., Haddleton D.M., Velonia K. Formation of giant amphiphiles by post-functionalization of hydrophilic protein-polymer conjugates // J. Mater. Chem. 2007. V. 17. P. 1916-1922.

169. Booth C., Gaspar H.B. Pegademase bovine (PEG-ADA) for the treatment of infants and children with severe combined immunodeficiency (SCID) // Biologics. 2009. V. 3. P. 349-358.

170. Dinndorf P.A., Gootenberg J., Cohen M.H., Keegan P., Pazdur R. FDA drug approval summary: Pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL) // Oncologist. 2007. V. 12. P. 991-998.

171. Foster G.R. Pegylated interferons: Chemical and clinical differences (Review article) // Aliment. Pharmacol. Ther. 2004. V. 20. P. 825-830.

172. Foser S., Schacher A., Weyer K.A., Brugger D. Isolation, structural characterization, and anti-viral activity of positional isomers of monopegylated interferon alpha-2a (PEGASYS) // Protein Expr. Purif. 2003. V. 30. P. 78-87.

173. Thankamony G.N., Dunger D.B., Acerini C.L. Pegvisomant: Current and potential novel therapeutic applications // Expert Opin. Biol. Ther. 2009. V. 9. P. 1553-1563.

174. McGahan L. Continuous erythropoietin receptor activator (Mircera) for renal anemia // Issues Emerg. Health Technol. 2008. V. 113. P. 1-6.

175. Jevševar S., Kusterle M., Kenig M. PEGylation of antibody fragments for half-life extension // Methods Mol. Biol. 2012. V. 901. P. 233-246.

176. Khalili H., Godwin A., Choi J.W., Lever R., Brocchini S. Comparative binding of disulfide-bridged PEG-Fabs // Bioconjug. Chem. 2012. V. 23. P. 2262-2277.

177. Rader C. Overview on concepts and applications of Fab antibody fragments // Current Protocols in Protein Science. 2009. Chapter 6. Unit 6.9. (http://onlinelibrary.wiley.com/doi/10.1002/0471140864.ps0609s55/abstract).

178. Deeks E.D. Certolizumab pegol: A review of its use in the management of rheumatoid arthritis // Drugs. 2013. V. 73. P. 75-97.

179. Humphreys D.P., Heywood S.P., Henry A., Ait-Lhadj L. [et al.]. Alternative antibody Fab’ fragment PEGylation strategies: Combination of strong reducing agents, disruption of the interchain disulphide bond and disulphide engineering // Protein Eng. Des. Sel. 2007. V. 20. P. 227-234.

180. Top A., Roberts C.J., Kiick K.L. Conformational and aggregation properties of a PEGylated alanine-rich polypeptide // Biomacromolecules. 2011. V. 12. P. 2184-2192.

181. Terpe K. Overview of tag protein fusions: From molecular and biochemical fundamentals to commercial systems // Appl. Microbiol. Biotechnol. 2003. V. 60. P. 523-533.

182. Deiters A., Cropp T.A., Summerer D., Mukherji M., Schultz P.G. Site-specific PEGylation of proteins containing unnatural amino acids // Bioorg. Med. Chem. Lett. 2004. V. 14. P. 5743-5745.

183. Nestor J.J. Jr. The medicinal chemistry of peptides // Curr. Med. Chem. 2009. V. 16. P. 4399-4418.

184. Deiters A., Schultz P.G. In vivo incorporation of an alkyne into proteins in Escherichia coli // Bioorg. Med. Chem. Lett. 2005. V. 15. P. 1521-1524.

185. Cho H., Daniel T., Buechler Y.J., Litzinger D.C., Maio Z. Optimized clinical performance of growth hormone with an expanded genetic code // Proc. Natl. Acad. Sci. USA. 2011. V. 108. P. 9060-9065.

186. Fares F., Guy R., Bar-Ilan A., Felikman Y., Fima E. Designing a long-acting human growth hormone (hGH) by fusing the carboxyl-terminal peptide of human chorionic gonadotropin beta-subunit to the coding sequence of hGH // Endocrinology. 2010. V. 151. P. 4410-4417.

187. Sato H. Enzymatic procedure for site-specific pegylation of proteins // Adv. Drug Deliv. Rev. 2002. V. 54. P. 487-504.

188. Fontana A., Spolaore B., Mero A.,Veronese F.M. Site-specific modification and PEGylation of pharmaceutical proteins mediated by transglutaminase // Adv. Drug Deliv. Rev. 2008. V. 60. P. 13-28.

189. DeFrees S., Wang Z.G., Xing R., Scott A.E., Wang J. GlycoPEGylation of recombinant therapeutic proteins produced in Escherichia coli // Glycobiology. 2006. V. 16. P. 833-843.

190. Schjoldager K.T., Clausen H. Site-specific protein O-glycosylation modulates proprotein processing - deciphering specific functions of the large polypeptide GalNAc-transferase gene family // Biochim. Biophys. Acta. 2012. V. 1820. P. 2079-2094.

191. Yu C.C., Kuo Y.Y., Liang C.F., Chien W.T., Wu H.T. Site-specific immobilization of enzymes on magnetic nanoparticles and their use in organic synthesis // Bioconjug. Chem. 2012. V. 23. P. 714-724.

192. Пучков И.А., Кононова Н.В., Бобрускин А.И., Баирамашвили Д.И., Мартьянов В.А., Шустер А.М. Рекомбинантный гранулоцитарный колониестимулирующий фактор (Филграстим): Оптимизация условий конъюгирования с полиэтиленгликолем // Биоорган. химия. 2012. № 5. С. 545-554.

193. Yoshimoto N., Yamamoto S. PEGylated protein separations: Challenges and opportunities // Biotechnol. J. 2012. V. 7. P. 592-593.

194. Payne R.W., Murphy B.M., Manning M.C. Product development issues for PEGylated proteins // Pharm. Dev. Technol. 2011. V. 16. P. 423-440.

195. Busby T.F., Ingham K.C. Separation of macromolecules by ultrafiltration: Removal of poly(ethylene glycol) from human albumin // J. Biochem. Biophys. Methods. 1980. V. 2. P. 191-206.

196. Seely J.E., Richey C.W. Use of ion-exchange chromatography and hydrophobic interaction chromatography in the preparation and recovery of polyethylene glycol-linked proteins // J. Chromatogr. A. 2001. V. 908. P. 235-241.

197. Пучков И.А., Баирамашвили Д.И., Мягких И.В., Швец В.И. Пэгилированный рекомбинант-ный гранулоцитарный колониестимулирующий фактор пролонгированного действия: новая схема получения активной фармацевтической субстанции // Биотехнология. 2014. № 2. C. 31-62.

198. Morstyn G., Dexter T.M., Foote M. Filgrastim (r-metHuGCSF) In Clinical Practice. Second Edition. N.Y., Basel, Hong Kong: Marcel Dekker, 1998. 696 p.

199. Tanaka H., Satake-Ishikawa R., Ishikawa M., Matsuki S., Asano K. Pharmacokinetics of recombinant human granulocyte colony-stimulating factor conjugated to polyethylene glycol in rats // Cancer Res. 1991. V. 51. P. 3710-3714.

200. Allen R.C. Ex vivo half-life of neutrophils from healthy human subjects pre and post treatment with daily filgrastim or single-dose pegfilgrastim // Blood. 2002. V. 100. P. 243.

201. Molineux G., Kinstler O., Briddell B., Hartley C. [et al.]. A new form of Filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans // Exp. Hematol. 1999. V. 27. P. 1724-1734.

202. Johnston E., Crawford J., Blackwell S., Bjurstrom T., Lockbaum P., Roskos L. [et al.]. Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy // J. Clin. Oncol. 2000. V. 18. P. 2522-2528.

203. Holmes F.A., O'Shaughnessy J.A., Vukelja S., Jones S.E. [et al]. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer // J. Clin. Oncol. 2002. V. 20. P. 727-731.

204. Green M., Koelbl H., Baselga J., Galid A. [et al]. A randomized, double blind, phase 3 study evaluating fixeddose, once-per-cycle pegylated filgrastim (SD/01) vs. daily filgrastim to support chemotherapy for breast cancer // Ann. Oncol. 2003. V. 14. P. 29-35.

205. Lyman G.H., Kuderer N., Greene J., Balducci L. The economics of febrile neutropenia: Implications for the use of colony-stimulating factors // Eur. J. Cancer. 1998. V. 34. P. 1857-1864.

206. Vose J.M., Crump M., Lazarus H., Emmanouilides C., Schenkein D., Moore J. [et al]. Single dose pegfilgrastim (SD/01) is as effective as daily filgrastim following ESHAP chemotherapy for subjects with non-Hodgkin’s lymphoma of Hodgkin’s disease: Results of a randomized, open-label study // Blood. 2001. V. 98. P. 799.

207. Morstyn G., Foote M., Walker T., Molineux G. Filgrastim (rmetHuG-CSF) in the 21st century: SD/01 // Acta Haematol. 2001. V. 105. P. 151-155.