Advertisement

Novel Constructs—Half-Life Extensions

  • Jeonghoon Sun
  • Mark Michaels
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 38)

Abstract

A dearth of biologics have been developed and used as therapeutics for numerous disease indications, including IgG monoclonal antibodies, non-IgG recombinant proteins, bi- and multi-specific antibodies, and antibody drug conjugates. A remarkable portion of these biologic constructs exhibits a short plasma half-life that results in a significant reduction in therapeutic efficacy. Frequently, biologic drugs need to be designed to maintain the effective concentration range during the therapeutic window with an extended serum half-life. Provided here is a comprehensive overview of various half-life extension methods involving FcRn engagement, chemical and genetic fusion, post-translational modifications and formulation.

Keywords

Half-life extension FcRn PEGylation Human serum albumin Fc loop 

References

  1. 1.
    Walsh G. Biopharmaceutical benchmarks. Nat Biotechnol. 2010;28:917–24.CrossRefPubMedGoogle Scholar
  2. 2.
    Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12:278–87.CrossRefPubMedGoogle Scholar
  3. 3.
    Kontermann RE. Strategies for extended serum half-life of protein therapeutics. Curr Opin Biotech. 2011;22:868–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Ghetie V, Hubbard JG, Kim JK, Tsen MF, Lee Y, Ward ES. Abnormally short serum half-lives of IgG in β2-microglobulin-deficient mice. Eur J Immunol. 1996;26:690–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Tesar DB, Bjorkman PJ. An intracellular traffic jam: Fc receptor-mediated transport of Immunoglobulin G. Curr Opin Struct Biol. 2010;20:226–33.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Roopenian DC, Akilesh S. FcRn the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–25.CrossRefPubMedGoogle Scholar
  7. 7.
    Sun J, Han SJ, Harris SM, Ketchem RR, Lu J, Michaels ML, Retter MW, Tsai MM. Variant fc-polypeptides with enhanced binding to the neonatal fc receptor. WO2013096221 A1, PCT/US2012/070146;2012.Google Scholar
  8. 8.
    Sarkar CS, Lowenhaupt K, Horan T, Boone TC, Tidor B, Lauffenburger DA. Rational cytokine design for increased lifetime and enhanced potentcy using pH-activated histidine switching. Nat Biotechnol. 2002;20:908–13.CrossRefPubMedGoogle Scholar
  9. 9.
    Igawa T, Ishii S, Tachibana T, Maeda A, Higuchi, Shimaoka S, Moriyama C, Watanabe T, Takubo R, Doi Y et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol. 2010;28:1203–1208.CrossRefPubMedGoogle Scholar
  10. 10.
    Tang L, Persky AM, Hochhaus G, Meibohm B. Pharmacokinetic aspects of biotechnology products. J Pharmaceut Sci. 2004;93:2184–204.CrossRefGoogle Scholar
  11. 11.
    Tryggvason K, Wartiovaara K. How does the kidney filter plasma? Physiology. 2005;20:96–101.CrossRefPubMedGoogle Scholar
  12. 12.
    Gramppa G, Kozakb RW, Schreitmuellerc T. Policy considerations for originator and similar biotherapeutic products. Pharm Policy Law. 2016;18:121–39.Google Scholar
  13. 13.
    World Heath Organization. Regulatory expectations and risk assessment for biotherapeutic products. WHO/RRA BT_DRAFT/24; January 2014.Google Scholar
  14. 14.
    Kristoffersen EK. Human placental Fcγ-binding proteins in the maternofetal transfer of IgG. APMIS Suppl. 1996;64:5–36.CrossRefPubMedGoogle Scholar
  15. 15.
    Simister NE, Mostov KE. An Fc receptor structurally related to MHC class I antigens. Nature. 1989;337:184–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Ober RJ, Martinez C, Lai X, Zhou J, Ward ES. Exocytosis of IgG as mediated by the receptor, FcRn: an analysis at the single-molecule level. Proc Natl Acad Sci USA. 2004;11076–11081.CrossRefGoogle Scholar
  17. 17.
    Burmeister WP, Gastinel LN, Simister NE, Blum ML, Bjorkman PJ. Crystal structure at 2.2 Å resolution of the MHC-related neonatal Fc receptor. Nature. 1994;372:336–43.CrossRefPubMedGoogle Scholar
  18. 18.
    Ahouse JJ, et al. Mouse MHC class I-like Fc receptor encoded outside the MHC. J Immunol. 1993;151:6076–88.PubMedGoogle Scholar
  19. 19.
    West AP, Herr AB, Bjorkman PJ. The chicken yolk sac IgY receptor, a functional equivalent of the mammalian MHC-related Fc receptor, is a phospholipase A2 receptor homolog. Immunity. 2004;20:601–10.CrossRefPubMedGoogle Scholar
  20. 20.
    Vaughn DE, Bjorkman PJ. Structural basis of pH-dependent antibody binding by the neonatal Fc receptor. Structure. 1998;6:63–73.CrossRefPubMedGoogle Scholar
  21. 21.
    Strohl WR. Fusion proteins for half-life extension of biologics as a strategy to make biobetters. BioDrugs. 2015;29:215–39.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Qiu Y, Lv W, Xu M, Xu Y. Single chain antibody fragments with pH dependent binding to FcRn enabled prolonged circulation of therapeutic peptide in vivo. J Control Release. 2016;229:37–47.CrossRefPubMedGoogle Scholar
  23. 23.
    Huang C. Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology. Curr Opin Biotechnol. 2009;20:692–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Kontermann RE. Therapeutic proteins: strategies to extend plasma half-lives of recombinant antibodies. Wiley-VCH;2012. p. 158–62.Google Scholar
  25. 25.
    Suzuki T, Watabe AI, Tada M, Kobayashi T, Kanayasu-Toyoda T, Kawanishi T, Yamaguchi T. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J Immunol. 2010;184:1968–76.CrossRefPubMedGoogle Scholar
  26. 26.
    Shields RL, et al. High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR. J Biol Chem. 2001;276:6591–604.CrossRefPubMedGoogle Scholar
  27. 27.
    Petkova SB, et al. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol. 2006;18:1759–69.CrossRefPubMedGoogle Scholar
  28. 28.
    Hinton PR, et al. Engineered human IgG antibodies with longer serum half-lives in primates. J Biol Chem. 2004;279:6213–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Kamei DT, et al. Quantitative methods for developing Fc mutants with extended half-lives. Biotechnol Bioeng. 2005;92:748–60.CrossRefPubMedGoogle Scholar
  30. 30.
    Vaccaro C, Zhou J, Ober RJ, Ward ES. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol. 2005;23:1283–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Dall’Acqua WF, Kiener PA, Wu H. Properties of human IgG1 s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem. 2006;281:23514–24.CrossRefPubMedGoogle Scholar
  32. 32.
    Hinton PR, et al. An engineered human IgG1 antibody with longer serum half-life. J Immunol. 2006;176:346–56.CrossRefPubMedGoogle Scholar
  33. 33.
    Yeung YA, et al. Engineering Human IgG1 Affinity to Human Neonatal Fc Receptor: Impact of Affinity Improvement on Pharmacokinetics in Primates. J Immunol. 2009;182:7663–71.CrossRefPubMedGoogle Scholar
  34. 34.
    Raghavan M, et al. Analysis of the pH dependence of the neonatal Fc receptor/ immunoglobulin G interaction using antibody and receptor variants. Biochemistry. 1995;34:14649–57.CrossRefPubMedGoogle Scholar
  35. 35.
    Kim JK, et al. Mapping the site on human IgG for binding of the MHC class I-related receptor, FcRn. Eur J Immunol. 1999;29:2819–25.CrossRefPubMedGoogle Scholar
  36. 36.
    Firan M, et al. The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of -globulin in humans. Int Immunol. 2001;13:993–1002.CrossRefPubMedGoogle Scholar
  37. 37.
    Kamei DT, et al. Quantitative methods for developing Fc mutants with extended half-lives. Bioeng. 2005;92:748–60.CrossRefGoogle Scholar
  38. 38.
    Stern M, Herrmann R. Overview of monoclonal antibodies in cancer therapy: present and promise. Crit Rev Oncol Hematol. 2005;54:11–29.CrossRefPubMedGoogle Scholar
  39. 39.
    Kenanova V, et al. Tailoring the pharmacokineticsand positron emission tomography imaging properties of anti-carcinoembryonic antigen single-chain Fv-Fc antibody fragments. Cancer Res. 2005;65:622–31.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Datta-Mannan A, et al. Humanized IgG1 variants with differential binding properties to the neonatal Fc receptor: relationship to pharmacokinetics in mice and primates. Drug Metab Dispos. 2007;35:86–94.CrossRefPubMedGoogle Scholar
  41. 41.
    Gurubaxani BM, et al. Analysis of a family of antibodies with different half-lives in mice fails to find a correlation between affinity for FcRn and serum half-life. Mol Immunol. 2006;43:1462–73.CrossRefGoogle Scholar
  42. 42.
    Gurubaxani BM, et al. Development of new models for the analysis of Fc–FcRn interactions. Mol Immunol. 2006;43:1379–89.CrossRefGoogle Scholar
  43. 43.
    Borrok MJ, et al. pH-dependent binding engineering reveals an fcrn affinity threshold that governs IgG recycling. J Biol Chem. 2015;290:4282–90.CrossRefPubMedGoogle Scholar
  44. 44.
    Ward ES1, Ober RJ. Multitasking by exploitation of intracellular transport functions the many faces of FcRn. Adv Immunol. 2009;103:77–115.Google Scholar
  45. 45.
    Dall’Acqua WF, et al. Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences. J Immunol. 169:5171–80.CrossRefGoogle Scholar
  46. 46.
    Yeung YA, et al. A therapeutic anti-VEGF antibody with increased potency independent of pharmacokinetic half-life. Cancer Res. 2010;70:3269–77.CrossRefPubMedGoogle Scholar
  47. 47.
    Andersen JT, Sandlie I. The versatile MHC class I-related FcRn protects IgG and albumin from degradation: implications for development of new diagnostics and therapeutics. Drug Metab Pharmacokinet. 2009;24:318–32.CrossRefPubMedGoogle Scholar
  48. 48.
    Chaudhury C, et al. Albumin binding to FcRn: distinct from the FcRn-Igg interaction. 2006. Biochemistry. 2006;45:4983–90.CrossRefPubMedGoogle Scholar
  49. 49.
    Duttaroy A, et al. Development of a long-acting insulin analog using albumin fusion technology. Diabetes. 2005;54:251–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Weimer T, et al. Prolonged in-vivo half-life of factor VIIa by fusion to albumin. Thromb Haemost. 2008;99:659–67.CrossRefPubMedGoogle Scholar
  51. 51.
    Müller Dafne, et al. Improved pharmacokinetics of recombinant bispecific antibody molecules by fusion to human serum albumin. J Biol Chem. 2007;282:12650–60.CrossRefPubMedGoogle Scholar
  52. 52.
    Chuang VTG, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharm Res. 2002;19:569–77.CrossRefPubMedGoogle Scholar
  53. 53.
    Rustgi VK, et al. Albinterferon alf-2b, a novel fusion protein of human albumin and human interferon alf-2b, for chronic hepatitis C. Curr Med Res Opin. 2009;25:991–1002.CrossRefPubMedGoogle Scholar
  54. 54.
    Nelson DR, et al. Albinterferon alfa-2b was not inferior to PEGylated interferon-a in a randomized trial of patients with chronic hepatitis C virus genotype 2 or 3. Gastroenterology. 2010;139:1267–76.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Schulte S, et al. Half-life extension through albumin fusion technologies. Thromb Res. 2009;124:S6–8.CrossRefPubMedGoogle Scholar
  56. 56.
    Metzner HJ, et al. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost. 2009;102:634–44.PubMedGoogle Scholar
  57. 57.
    Müller D, et al. Improved pharmacokinetics of recombinant bispecific antibody molecules by fusion to human serum albumin. J Biol Chem. 2007;282:12650–60.CrossRefPubMedGoogle Scholar
  58. 58.
    Yazaki PJ, et al. Biodistribution and tumor imaging of an anti-CEA single-chain antibody- albumin fusion protein. Nucl Med Biol. 2008;35:151–8.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Evans L, et al. The production, characterisation and enhanced pharmacokinetics of scFv- albumin fusions expressed in Saccharomyces cerevisiae. Protein Expr. 2010;73:113–24.CrossRefGoogle Scholar
  60. 60.
    Kenanova VE, et al. Tuning the serum persistence of human serum albumin domain III: diabody fusion proteins. Protein Eng Des Sel. 2010;23:789–98.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Xie D, et al. An albumin-conjugated peptide exhibits potent anti-HIV activity and long in vivo half-life. Antimicrob Agents Chemother. 2010;54:191–6.CrossRefPubMedGoogle Scholar
  62. 62.
    Kontermann RE. Therapeutic proteins: Strategies to Extend Plasma Half-Lives of Recombinant Antibodies. Wiley-VCH;2012. p. 223–242.Google Scholar
  63. 63.
    Stork R, Müller D, Kontermann RE. A novel tri-functional antibody fusion protein with improved pharmacokinetic properties generated by fusing a bispecific single-chain diabody with an albumin-binding domain from streptococcal protein G. Protein Eng Des Sel. 2007;20:569–76.CrossRefPubMedGoogle Scholar
  64. 64.
    Hopp J, et al. The effects of affinity and valency of an albumin-binding domain (ABD) on the half-life of a single- chain diabody-ABD fusion protein. 2010. Protein Eng Des Sel. 2010;23:827–34.CrossRefPubMedGoogle Scholar
  65. 65.
    Stork R, et al. Biodistribution of a bispecific single-chain diabody and its half-life extended derivatives. J Biol Chem. 2009;284:25612–9.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Sand KMK, et al. Dissection of the neonatal Fc receptor (FcRn)-albumin interface using mutagenesis and anti-fcrn albumin-blocking antibodies. J Biol Chem. 2014;289:17228–39.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Löfbloma J, et al. Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications. FEBS Lett. 2010;584(12):2670–2680.CrossRefPubMedGoogle Scholar
  68. 68.
    Roovers RC, et al. Efficient inhibition of EGFR signalling and of tumour growth by antagonistic anti-EGFR nanobodies. Cancer Immunol Immunother. 2007;56:303–17.CrossRefPubMedGoogle Scholar
  69. 69.
    Tijink BM, et al. Improved tumor targeting of anti-epidermal growth factor receptor nanobodies through albumin binding: taking advantage of modular nanobody technology. Mol Cancer Ther. 2008;7:2288–97.CrossRefPubMedGoogle Scholar
  70. 70.
    Holt LJ, et al. Anti-serum albumin domain antibodies for extending the half-lives of short lived drugs. Protein Eng Des Sel. 2008;21:283–8.CrossRefPubMedGoogle Scholar
  71. 71.
    Walker A, et al. Anti-serum albumin domain antibodies in the development of highly potent, efficacious and long-acting interferon. Protein Eng Des Sel. 2010;23:271–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Dennis MS, et al. Albumin Binding as a General Strategy for Improving the Pharmacokinetics. J Biol Chem. 2002;277:35035–43.CrossRefPubMedGoogle Scholar
  73. 73.
    Petersen CE, et al. A Dynamic Model for Bilirubin Binding to Human Serum Albumin. J Biol Chem. 2000;275:20985–95.CrossRefPubMedGoogle Scholar
  74. 74.
    Kontermann RE. Therapeutic proteins: Strategies to Extend Plasma Half-Lives of Recombinant Antibodies. Wiley-VCH;2012. p. 269–294.Google Scholar
  75. 75.
    Havelund S, et al. The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm Res. 2004;21:1498–504.CrossRefPubMedGoogle Scholar
  76. 76.
    Owens DR et al. Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care. June 23 2000;813–819.CrossRefPubMedGoogle Scholar
  77. 77.
    Dumelin CE, et al. A portable albumin binder from a DNA-encoded chemical library. Angew Chem Int Ed. 2008;47:3196–201.CrossRefGoogle Scholar
  78. 78.
    Trussel S, et al. New strategy for the extension of the serum half-life of antibody fragments. Bioconjug Chem. 2009;20:2286–92.CrossRefPubMedGoogle Scholar
  79. 79.
    Brocchini S, et al. Disulfide bridge based PEGylation of proteins. Adv Drug Deliv Rev. 2008;60:3–12.CrossRefPubMedGoogle Scholar
  80. 80.
    Gaberc-Porekar V, et al. Obstacles and pitfalls in the PEGylation of therapeutic proteins. Curr Opin Drug Discov. 2008;11:242–50.Google Scholar
  81. 81.
    Jevsevar S1, Kunstelj M, Porekar VG. PEGylation of therapeutic proteins. Biotechnol. J. 2010;5:113–28.Google Scholar
  82. 82.
    Turecek PL, Bossard MJ, Schoetens F, Ivens IA. PEGylation of biopharmaceuticals: a review of chemistry and nonclinical safety information of approved drugs. J Pharm Sci. 2016;105:460–75.CrossRefPubMedGoogle Scholar
  83. 83.
    El-Komy MH1, Widness JA, Veng-Pedersen P. Pharmacokinetic analysis of continuous erythropoietin receptor activator disposition in adult sheep using a target-mediated, physiologic recirculation model and a tracer interaction methodology. Drug Metab Dispos. 2011;39:603–9.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
  85. 85.
  86. 86.
    Kinstler O, Molineux G, Treuheit M, Ladd D, Gegg C. Mono-N-terminal poly (ethylene glycol)-protein conjugates. Adv Drug Deliv Rev. 2002;54:477–85.CrossRefPubMedGoogle Scholar
  87. 87.
    Molineux G. The design and development of PEGfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des. 2004;10:1235–44.CrossRefPubMedGoogle Scholar
  88. 88.
    Means GE, Feeney RE. Reductive alkylation proteins. Anal Biochem. 1995;224:1–16.CrossRefPubMedGoogle Scholar
  89. 89.
    Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs. 2008;22:315–29.CrossRefPubMedGoogle Scholar
  90. 90.
    Veronese FM. Peptide and protein PEGylation: a review of problems and solutions. Biomaterials. 2001;22:405–17.CrossRefPubMedGoogle Scholar
  91. 91.
    Roberts MJ, Bentley MD, Harris JM. Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev. 2002;54:459–76.CrossRefPubMedGoogle Scholar
  92. 92.
    Schellenberger V, et al. A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner. Nat Biotechnol. 2009;27:1186–90.CrossRefPubMedGoogle Scholar
  93. 93.
    Geething NC, et al. Gcg-XTEN: an improved glucagon capable of preventing hypoglycemia without increasing baseline blood glucose. PLoS ONE 2010;5:e10175.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Baker JL, et al. Expanding the glycoengineering toolbox: the rise of bacterial N-linked protein glycosylation. Trends Biotechnol. 2013;31:313–23.CrossRefPubMedGoogle Scholar
  95. 95.
    Sola RJ, Griebenow K. Glycosylation of therapeutic proteins: an effective strategy to optimize efficacy. BioDrugs. 2010;24:9–21.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Elliott S, et al. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat Biotechnol. 2003;21:414–21.CrossRefPubMedGoogle Scholar
  97. 97.
    Stork R, et al. N-glycosylation as novel strategy to improve pharmacokinetic properties of bispecific single-chain diabodies. J Biol Chem. 2008;283:7804–12.CrossRefPubMedGoogle Scholar
  98. 98.
    Fares FA, et al. Design of a long-acting follitropin agonist by fusing the C-terminal sequence of the chorionic gonadotropin beta subunit to the follitropin beta subunit. Proc Natl Acad Sci U S A. 1992;89:4304–8.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    LaPolt PS, et al. Enhanced stimulation of follicle maturation and ovulatory potential by long acting follicle-stimulating hormone agonists with extended carboxyl-terminal peptides. Endocrinology. 1992;131:2514–20.CrossRefPubMedGoogle Scholar
  100. 100.
    Agreda-Vasquez GP, et al. Starch and albumin mixture as replacement fluid in therapeutic plasma exchange is safe and effective. J Clin Apher. 2008;23:163–7.CrossRefPubMedGoogle Scholar
  101. 101.
    Elliott S, et al. Control of rHuEPO biological activity: The role of carbohydrate. Exp Hematol. 2004;32:1146–55.CrossRefPubMedGoogle Scholar
  102. 102.
    Constantinou A, et al. Site-specific polysialylation of an antitumor single-chain Fv fragment. Bioconjug Chem. 2009;20:924–31.CrossRefPubMedGoogle Scholar
  103. 103.
    Akbarzadeh A, et al. Liposome: classification, preparation, and applications. Nanoscale Res Lett. 2013;8:102–10.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine. 2006;1:297–315.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Nag OK, Awasthi V. Surface engineering of liposomes for stealth behavior. Pharmaceutics. 2013;5:542–69.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Yatuv R, Robinson M, Dayan I, Baru M. The use of PEGylated liposomes in the development of drug delivery applications for the treatment of hemophilia. Int J Nanomedicine. 2010;5:581–91.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Yatuv R, Robinson M, Dayan I, Baru M. Enhancement of the efficacy of therapeutic proteins by formulation with PEGylated liposomes; a case of FVIII, FVIIa and G-CSF. Expert Opin Drug Deliv. 2010;7:187–201.CrossRefPubMedGoogle Scholar
  108. 108.
    Talelli M, et al. Core-crosslinked polymeric micelles: principles, preparation, biomedical applications and clinical translation. Nano Today. 2015;10:93–117.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Allouche J. Chapter 2: synthesis of organic and bioorganic nanoparticles: an overview of the preparation methods. In: Brayner R, et al., editors. Nanomaterials: a danger or a promise? London:Springer-Verlag;2013.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Department of BiotherapeuticsCelgene CorporationSan DiegoUSA
  2. 2.Amgen Inc.One Amgen Center DriveThousand OaksUSA

Personalised recommendations