Skip to main content
SpringerLink
Log in

Strategies to Extend Plasma Half-Lives of Recombinant Antibodies

  • Drug Development
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Recombinant antibodies, including whole antibodies, antibody fragments, antibody fusion proteins or conjugates, and more recently also small antibody mimetics, have found increasing applications as therapeutics, e.g. for the treatment of cancer or inflammatory diseases. While whole antibodies have an exceptionally long half-life, small antibody derivatives often suffer from rapid elimination from the circulation. In order to improve administration and therapeutic efficacy, modifications to extend the plasma half-life have been developed and implemented in these antibody formats. This review provides a comprehensive summary of the various strategies currently available to extend plasma half-lives of recombinant antibodies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Table I
Fig. 6

Similar content being viewed by others

References

  1. Dübel S. Recombinant therapeutic antibodies. Appl Microbiol Biotechnol 2007; 74: 723–9

    Article  PubMed  CAS  Google Scholar 

  2. Holliger P, Hudson PJ. Engineered antibody fragments and the rise of single domains. Nat Biotechn 2005; 23: 1126–36

    Article  CAS  Google Scholar 

  3. Tang L, Persky AM, Hochhaus G, et al. Pharmacokinetic aspects of biotechnology products. J Pharm Sci 2004; 93: 2184–96

    Article  PubMed  CAS  Google Scholar 

  4. Schaller J, Gerber S, Kämpfer U, et al. Human blood plasma proteins: structure and function. West Sussex: John Wiley & Sons, 2008

  5. Keer MA, Thorpe R. Immunochemistry Labfax. Oxford: Blackwell Scientific Publications, 1994; 29

    Google Scholar 

  6. Ternant D, Paintaud G. Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins. Expert Opin Biol Ther 2005; 5Suppl. 1: S37–47

    Article  PubMed  CAS  Google Scholar 

  7. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmcodynamics. J Pharm Sci 2004; 93: 2645–68

    Article  PubMed  CAS  Google Scholar 

  8. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol 2005; 23: 1137–46

    Article  PubMed  CAS  Google Scholar 

  9. Stork R, Zettlitz KA, Müller D, et al. N-glycosylation as novel strategy to improve pharmacokinetic properties of bispecific single-chain diabodies. J Biol Chem 2008; 283: 7804–12

    Article  PubMed  CAS  Google Scholar 

  10. Batra SK, Jain M, Wittel UA, et al. Pharmacokinetics and biodistribution of genetically engineered antibodies. Curr Opin Biotechnol 2002; 13: 603–8

    Article  PubMed  CAS  Google Scholar 

  11. Mahmood I, Green MD. Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins. Clin Pharmacokinet 2005; 44: 331–47

    Article  PubMed  CAS  Google Scholar 

  12. van de Weert M, Jorgensen L, Moeller EH, et al. Factors of importance for a successful delivery system for proteins. Expert Opin Drug Deliv 2005; 2: 1029–37

    Article  PubMed  Google Scholar 

  13. Jain M, Kamal N, Batra SK. Engineering antibodies for clinical applications. Trends Biotechnol 2007; 25: 307–16

    Article  PubMed  CAS  Google Scholar 

  14. Kortt AA, Dolezal O, Power BE, et al. Dimeric and trimeric antibodies: high avidity scFvs for cancer targeting. Biomol Eng 2001; 18: 95–108

    Article  PubMed  CAS  Google Scholar 

  15. Power BE, Shapira DR, Burns JE, et al. Noncovalent scFv multimers of tumor-targeting anti-Lewis Y hu3S193 humanized antibody. Protein Sci 2003; 12: 734–47

    Article  PubMed  CAS  Google Scholar 

  16. Wu AM, Williams LE, Zieran L, et al. Anti-carcinoembryonic antigen (CEA) diabody for rapid tumor targeting and imaging. Tumor Targeting 1999; 4: 47–58

    CAS  Google Scholar 

  17. Hu S, Shively L, Raubitschek A, et al. Minibody: a novel engineered anti-carcinoembryonic antigen antibody fragment (single-chain Fv-C(inH3) which exhibits rapid, high-level targeting of xenografts. Cancer Res 1996; 56: 3055–61

    PubMed  CAS  Google Scholar 

  18. Yazaki PJ, Wu AM, Tsai SW, et al. Tumor targeting of radiometal labeled anti-CEA recombinant T84.66 diabody and T84.66 minibody: comparison to radioiodinated fragments. Bioconjug Chem 2001; 12: 220–8

    Article  PubMed  CAS  Google Scholar 

  19. Adams GP, Schier R, McCall AM, et al. Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. Br J Cancer 1998; 77: 1405–12

    Article  PubMed  CAS  Google Scholar 

  20. Nielsen UB, Adams GP, Weiner LM, et al. Targeting of bivalent anti-erbB2 diabody antibody fragments to tumor cells is independent of the intrinsic affinity. Cancer Res 2000; 60: 6434–40

    PubMed  CAS  Google Scholar 

  21. Hamidi M, Azadi A, Rafiei P. Pharmacokinetic consequences of pegylation. Drug Deliv 2006; 13: 399–409

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Duncan R. Polymer conjugates as anticancer nanomedicines. Nat Rev Cancer 2006; 6: 688–701

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  26. Fishburn CS. The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. J Pharm Sci 2008; 97: 4168–83

    Article  CAS  Google Scholar 

  27. Leong SR, DeForge L, Presta L, et al. Adapting pharmacokinetic properties of a humanized anti-interleukin-8 antibody for therapeutic applications using site-specific PEGylation. Cytokine 2001; 16: 106–19

    Article  PubMed  CAS  Google Scholar 

  28. Lu Y, Harding SE, Turner A, et al. Effect of PEGylation on the solution conformation of antibody fragments. J Pharm Sci 2007; 97: 2062–79

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  30. Krinner EM, Hepp J, Hoffmann P, et al. A highly stable polyethylene glycol-conjugated human single-chain antibody neutralizing granulocyte-macrophage colony stimulating factor at low nanomolar concentrations. Prot Eng Design Sel 2006; 19: 461–70

    Article  CAS  Google Scholar 

  31. Yang K, Basu A, Wang M, et al. Tailoring structure-function and pharmacokinetic properties of single-chain Fv proteins by site-specific PEGylation. Protein Eng 2003; 16: 761–70

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  33. Rutgeerts P, Schreiber S, Feagan B, et al. Certolizumab pegol, a monthly subcutaneously administered Fc-free anti-TNFα, improves health-related quality of life in patients with moderate to severe Crohn’s disease. Int J Colorectal Dis 2008; 23: 289–96

    Article  PubMed  Google Scholar 

  34. Winter TA, Wright J, Ghosh S, et al. Intravenous CDP870, a PEGylated Fab′ fragment of a humanized antitumour necrosis factor antibody, in patients with moderate-to-severe Crohn’s disease: an exploratory study. Aliment Pharmacol Ther 2004; 20: 1337–46

    Article  PubMed  CAS  Google Scholar 

  35. Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs 2008; 22: 315–29

    Article  PubMed  CAS  Google Scholar 

  36. Gaberc-Porekar V, Zore I, Podobnik B, et al. Obstacles and pitfalls in the PEGylation of therapeutic proteins. Curr Opin Discov Develop 2008; 11: 242–50

    CAS  Google Scholar 

  37. 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: 9–16

    Article  CAS  Google Scholar 

  38. Bendele A, Seely J, Richey C. Short communication: renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins. Toxicol Sci 1998; 42: 152–7

    Article  PubMed  CAS  Google Scholar 

  39. Kim SH, Lee YS, Hwang SY, et al. Effects of PEGyated scFv antibodies against Plasmodium vivax duffy binding protein on the biological activity and stability in vitro. J Microbiol Biotechnol 2007; 17: 1670–7

    PubMed  CAS  Google Scholar 

  40. Kubetzko S, Sarkar CA, Plückthun A. Protein PEGylation decreases observed target association rates via a dual blocking mechanism. Mol Pharmacol 2005; 68: 1439–54

    Article  PubMed  CAS  Google Scholar 

  41. Cheng TL, Wu PY, Wu MF, et al. Accelerated clearance of polyethylene glycol-modified protiens by anti-polyethylene glycol IgM. Bioconjug Chem 1999; 10: 520–8

    Article  PubMed  CAS  Google Scholar 

  42. Skroda K, Rydlewski J, Langner M, et al. Repeated injections of PEG-PE liposomes generate anti-PEG antibodies. Cell Mol Biol Lett 2005; 10: 37–47

    Google Scholar 

  43. Schlapschy M, Theobald I, Mack H, et al. Fusion of a recombinant antibody fragment with a homo-amino-acid polymer: effects on biophysical properties and prolonged plasma half-life. Prot Eng Design Sel 2007; 20: 273–84

    Article  CAS  Google Scholar 

  44. Volker Schellenberger. Amunix low-immunogenic protein pharmaceuticals: technology [online]. Available from URL: http://www.amunix.com/Technology.html [Accessed 2009 Apr 24]

  45. Gregoriadis G, McCormack B, Wang Z, et al. Polysialic acid: potential in drug delivery. FEBS Lett 1993; 315: 271–6

    Article  PubMed  CAS  Google Scholar 

  46. Gregoriadis G, Jain S, Papaioannou I, et al. Improving the therapeutic efficacy of peptides and proteins: a role for polysialic acids. Int J Pharm 2005; 300: 125–30

    Article  PubMed  CAS  Google Scholar 

  47. Fernandes AI, Gregoriadis G. The effect of polysialylation on the immunogenicity and antigenicity of asparaginase: implication in its pharmacokinetics. Int J Pharm 2001; 217: 215–24

    Article  PubMed  CAS  Google Scholar 

  48. Gregoriadis G, Fernandes A, Mital M, et al. Polysialic acid: potential in improving the stability and pharmacokinetics of proteins and other therapeutics. Cell Mol Life Sci 2000; 57: 1964–9

    Article  PubMed  CAS  Google Scholar 

  49. Jain S, Hreczuk-Hirst DH, McCormack B, et al. Polysialylated insulin: synthesis, characterization and biological activity in vivo. Biochim Biophys Acta 2003; 1622: 42–9

    Article  PubMed  CAS  Google Scholar 

  50. Constantinou A, Epenetos AA, Hreczuk-Hirst D, et al. Modulation of antibody pharmacokinetics by chemical polysialylation. Bioconjug Chem 2008; 19: 643–50

    Article  PubMed  CAS  Google Scholar 

  51. Besheer A, Hause G, Kressler J, et al. Hydrophobically modified hydroxyethyl starch: synthesis, characterization, and aqueous self-assembly into nano-sized polymeric micelles and vesicles. Biomacromolecules 2007; 8: 359–67

    Article  PubMed  CAS  Google Scholar 

  52. Agreda-Vásquez GP, Espinosa-Poblano I, Sánchez-Guerrero SA, et al. Starch and albumin mixture as replacement fluid in therapeutic plasma exchange is safe and effective. J Clin Apher 2008; 23: 163–7

    Article  PubMed  Google Scholar 

  53. Brecher ME, Owen HG, Bandarenko N. Alternatives to albumin: starch replacement for plasma exchange. J Clin Apher 1997; 12: 146–53

    Article  PubMed  CAS  Google Scholar 

  54. Fresenius Kabi AG. HESylation® —introduction [online]. Available from URL: http://www2.fresenius-kabi.com/internet/kabi/corp/fkintpbn.nsf/Content/HESYLATION+INTRODUCTION [Accessed 2009 Apr 24]

  55. Wright A, Morrison SL. Antibody variable region glycosylation: biochemical and clinical effects. Springer Semin Immunopathol 1993; 15: 259–73

    Article  PubMed  CAS  Google Scholar 

  56. Jefferis R. Glycosylation of recombinant antibody therapeutics. Biotechnol Prog 2005; 21: 11–6

    Article  PubMed  CAS  Google Scholar 

  57. Wright A, Morrison SL. Effect of glycosylation on antibody function: implications for genetic engineering. Trends Biotechnol 1997; 15: 26–32

    Article  PubMed  CAS  Google Scholar 

  58. Tao MH, Morrison SL. Studies of aglycosylated chimeric mouse-human IgG: role of carbohydrate in the structure and effector functions mediated by the human IgG constant region. J Immunol 1989; 143: 2595–601

    PubMed  CAS  Google Scholar 

  59. Umaña P, Jean-Mairet J, Moudry R, et al. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol 1999; 17: 176–80

    Article  PubMed  Google Scholar 

  60. Ferrara C, Brünker P, Stuter T, et al. Modulation of therapeutic antibody effector functions by glycosylation engineering: influence of Golgi enzyme localization domain and co-expression of heterologous b1, 3-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II. Biotechnol Bioeng 2006; 93: 851–61

    Article  PubMed  CAS  Google Scholar 

  61. Shields RL, Lai J, Keck R, et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human FcgRIII an antibody-dependent cellular toxicity. J Biol Chem 2002; 277: 26733–40

    Article  PubMed  CAS  Google Scholar 

  62. Wright A, Morrison SL. Effect of altered C(inH2-associated carbohydrate structure on the functional properties and in vivo fate of chimeric mouse-human immunoglobulin G1. J Exp Med 1994; 180: 1087–96

    Article  PubMed  CAS  Google Scholar 

  63. Wright A, Sato Y, Okada T, et al. In vivo trafficking and catabolism of IgG1 antibodies with Fc associated carbohydrates of different structure. Glycobiology 2000; 10: 1347–55

    Article  PubMed  CAS  Google Scholar 

  64. Newkirk MM, Novick J, Stevenson MM, et al. Different clearance of glycoforms of IgG in normal and autoimmune-prone mice. Clin Exp Immunol 1996; 106: 259–64

    Article  PubMed  CAS  Google Scholar 

  65. Cohen O, Kronman C, Velan B, et al. Amino acid domains control the circulatory residence time of primate acetylcholineesterases in rhesus macaques (Macaca mulatta). Biochem J 2004; 378: 117–28

    Article  PubMed  CAS  Google Scholar 

  66. Meier W, Gill A, Rogge M, et al. Immunomodulation by LFA3TIP, an LFA-3/IgG1 fusion protein: cell line dependent glycosylation effects on pharmacokinetics and pharmacodynamic markers. Ther Immunol 1995; 2: 159–71

    PubMed  CAS  Google Scholar 

  67. Stockert RJ. The asialoyglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 1995; 75: 591–609

    PubMed  CAS  Google Scholar 

  68. Jones AJS, Papac DI, Chin EH, et al. Selective clearance of glycoforms of a complex glycoprotein pharmaceutical caused by terminal N-acetylglucosamine is similar in humans and cynomolgus monkeys. Glycobiology 2007; 17: 529–40

    Article  PubMed  CAS  Google Scholar 

  69. Millward TA, Heitzmann M, Bill K, et al. Effect of constant and variable domain glycosylation on pharmacokinetics of therapeutic antibodies in mice. Biologicals 2008; 36: 41–7

    Article  PubMed  CAS  Google Scholar 

  70. Weikert S, Papac D, Briggs J, et al. Engineering chinese hamster ovary cells to maximize sialic acid content of recombinant glycoproteins. Nat Biotechnol 1999; 17: 1116–21

    Article  PubMed  CAS  Google Scholar 

  71. Bragonzi A, Distefano G, Buckburry LD, et al. A new Chinese hamster ovary cell line expressing a2,6-sialyltransferase used as universal host for the production of human-like sialylated recombinant glycoproteins. Biochim Biophys Acta 2000; 1474: 273–82

    Article  PubMed  CAS  Google Scholar 

  72. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant 2001; 16Suppl. 3: 3–13

    Article  PubMed  Google Scholar 

  73. Wang M, Lee LS, Nepomich A, et al. Single-chain Fv with manifold N-glycans as bifunctional scaffolds for immunomolecules. Protein Eng 1998; 11: 1277–83

    Article  PubMed  CAS  Google Scholar 

  74. Weenen C, Peña JE, Pollak SV, et al. Long-acting follicle-stimulating hormone analogs containing N-linked glycosylation exhibited increased bioactivity compared with O-linked analogs in female rats. J Clin Endocrin Metabol 2004; 89: 5204–12

    Article  CAS  Google Scholar 

  75. Lencer WI, Blumberg RS. A passionate kiss, then run: exocytosis and recycling of IgG by FcRn. Trends Cell Biol 2005; 15: 5–9

    Article  PubMed  CAS  Google Scholar 

  76. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7: 715–25

    Article  PubMed  CAS  Google Scholar 

  77. West AP, Bjorkman PJ. Crystal structure and immunoglobulin G binding properties of the human major histocompatibility complex-related Fc receptor. Biochemistry 2000; 39: 9698–708

    Article  PubMed  CAS  Google Scholar 

  78. Firan M, Bawdon R, Radu C, et al. The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of g-globulin in humans. Int Immunol 2001; 13: 993–1002

    Article  PubMed  CAS  Google Scholar 

  79. Dall’Acqua WF, Kiener PA, Wu H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem 2006; 281: 23514–24

    Article  PubMed  CAS  Google Scholar 

  80. Andersen JT, Qian JD, Sandlie I. The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH-dependent binding to albumin. Eur J Immunol 2006; 36: 3044–51

    Article  PubMed  CAS  Google Scholar 

  81. Chaudhury C, Brooks CL, Carter DC, et al. Albumin binding to FcRn: distinct from the FcRn-IgG interaction. Biochemistry 2006; 45: 4983–90

    Article  PubMed  CAS  Google Scholar 

  82. Martin WL, West AP, Gan L, et al. Crystal structure at 2.8 Å of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding. Mol Cell 2001; 7: 867–77

    Article  PubMed  CAS  Google Scholar 

  83. Vaughn DE, Milburn CM, Penny DM, et al. Identification of critical IgG binding epitopes on the neonatal Fc receptor. J Mol Biol 1997; 274: 597–607

    Article  PubMed  CAS  Google Scholar 

  84. Raghavan M, Bonagura VR, Morrison SL, 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

    Article  PubMed  CAS  Google Scholar 

  85. Medesan C, Matesoi D, Radu C, et al. Delineation of the amino acid residues involved in transcytosis and catabolism of mouse IgG1. J Immunol 1997; 158: 2211–7

    PubMed  CAS  Google Scholar 

  86. Carter PJ. Potent antibody therapeutics by design. Nat Rev Immunol 2006; 6: 343–57

    Article  PubMed  CAS  Google Scholar 

  87. Presta LG. Molecular engineering and design of therapeutic antibodies. Curr Opin Immunol 2008; 20: 460–70

    Article  PubMed  CAS  Google Scholar 

  88. Lazar GA, Dang W, Karki S, et al. Engineering antibody Fc variants with enhanced effector function. Proc Natl Acad Sci U S A 2006; 103: 4005–10

    Article  PubMed  CAS  Google Scholar 

  89. Idusogie EE, Wong PY, Presta LG, et al. Engineered antibodies with increased activity to recruit complement. J Immunol 2001; 166: 2571–5

    PubMed  CAS  Google Scholar 

  90. Ghetie V, Popov S, Borvak J, et al. Increasing the serum persistence of an IgG fragment by random mutagenesis. Nat Biotechnol 1997; 15: 637–40

    Article  PubMed  CAS  Google Scholar 

  91. Hinton PR, Johlfs MG, Xiong JM, et al. Engineered human IgG antibodies with longer serum half-lives in primates. J Biol Chem 2004; 279: 6213–6

    Article  PubMed  CAS  Google Scholar 

  92. Hinton PR, Xiong JM, Johlfs MG, et al. An engineered human IgG1 antibody with longer serum half-life. J Immunol 2006; 176: 346–56

    PubMed  CAS  Google Scholar 

  93. Petkova SB, Akilesh S, Sproule TJ, 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

    Article  PubMed  CAS  Google Scholar 

  94. Gurbaxani B, Dela Cruz LL, Chitalacharuvu K, 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

    Article  PubMed  CAS  Google Scholar 

  95. Datta-Mannan A, Witcher DR, Tang Y, et al. Monoclonal antibody clearance: impact of modulating the interaction of IgG with the neonatal Fc receptor. J Biol Chem 2007; 282: 1709–17

    Article  PubMed  CAS  Google Scholar 

  96. Vaccaro C, Zhou J, Ober RJ, et al. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol 2005; 23: 1283–8

    Article  PubMed  CAS  Google Scholar 

  97. Kenanova V, Olafsen T, Crow DM, et al. Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti-carcinoem-bryonic antigen single-chain Fv-Fc antibody fragments. Cancer Res 2005; 65: 622–31

    PubMed  CAS  Google Scholar 

  98. Dall’Acqua WF, Woods RM, Ward ES, et al. Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences. J Immunol 2002; 169: 5171–80

    PubMed  Google Scholar 

  99. Jazayeri JA, Carroll GJ. Fc-based cytokines: prospects for engineering superior therapeutics. BioDrugs 2008; 22: 11–26

    Article  PubMed  CAS  Google Scholar 

  100. Colcher D, Pavlinkova G, Beresford G, et al. Pharmacokinetics and biodistribution of genetically-engineered antibodies. Q J Nucl Med 1998; 42: 225–41

    PubMed  CAS  Google Scholar 

  101. Holliger P, Wing M, Pound JD, et al. Retargeting serum immunoglobulin with bispecific diabodies. Nat Biotechnol 1997; 15: 632–6

    Article  PubMed  CAS  Google Scholar 

  102. Müller D, Kontermann RE. Recombinant bispecific antibodies for cellular cancer immunotherapy. Curr Opin Mol Ther 2007; 9: 319–26

    PubMed  Google Scholar 

  103. Chaudhury C, Mehnaz S, Robinson JM, et al. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med 2003; 197: 315–22

    Article  PubMed  CAS  Google Scholar 

  104. Chuang VTG, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharm Res 2002; 19: 569–77

    Article  PubMed  Google Scholar 

  105. Smith BJ, Popplewell A, Athwal D, et al. Prolonged in vivo residence times of antibody fragments associated with albumin. Bioconjug Chem 2001; 12: 750–6

    Article  PubMed  CAS  Google Scholar 

  106. Müller D, Karle A, Meissburger B, et al. Improved pharmacokinetics of recombinant bispecific antibody molecules by fusion to human serum albumin. J Biol Chem 2007; 282: 12650–60

    Article  PubMed  CAS  Google Scholar 

  107. Balan V, Nelson DR, Sulkowski MS, et al. A phase I/II study evaluating escalating doses of recombinant human albumin-interferon a fusion protein in chronic hepatitis C patients who have failed previous interferon-α-based therapy. Antivir Ther 2006; 11: 35–45

    PubMed  CAS  Google Scholar 

  108. Yazaki PJ, Kassa T, Cheung C, et al. Biodistribution and tumor imaging of an anti-CEA single-chain antibody-albumin fusion protein. Nucl Med Biol 2008; 35: 151–8

    Article  PubMed  CAS  Google Scholar 

  109. Sung C, Nardelli B, Lafleur DW, et al. An IFN-β-albumin fusion protein that displays improved pharmacokinetic and pharmacodynamic properties in nonhuman primates. J Interferon Cytokine Res 2003; 23: 25–36

    Article  PubMed  CAS  Google Scholar 

  110. Melder RJ, Osborn BL, Riccobene T, et al. Pharmacokinetics and in vitro and in vivo anti-tumor response of an interleukin-2-human serum albumin fusion protein. Cancer Immunol Immunother 2005; 54: 535–47

    Article  PubMed  CAS  Google Scholar 

  111. Kraulis PJ, Jonasson P, Nygren PA, et al. The serum albumin-binding domain of streptococcal protein G is a three-helix bundle: a heteronuclear NMR study. FEBS Lett 1996; 378: 190–4

    Article  PubMed  CAS  Google Scholar 

  112. Linhult M, Binz HK, Uhlén M, et al. Mutational analysis of the interaction between albumin-binding domain fromo streptococcal protein G and human serum albumin. Protein Sci 2002; 11: 206–13

    Article  PubMed  CAS  Google Scholar 

  113. Johannson MU, Frick IM, Nilsson H, et al. Structure, specificity, and mode of interaction for bacterial albumin-binding modules. J Biol Chem 2002; 277: 8114–29

    Article  CAS  Google Scholar 

  114. Stork R, Müller D, Kontermann R. 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 streptococcus protein G. Prot Eng Design Sel 2007; 20: 569–76

    Article  CAS  Google Scholar 

  115. Nilsson FY, Tolmachev V. Affibody molecules: new protein domains for molecular imaging and targeted tumor therapy. Curr Opin Drug Discov Develop 2007; 10: 167–75

    CAS  Google Scholar 

  116. Tolmachev V, Orlova A, Pehrson R, et al. Radionuclide therapy of HER2-positive microxenografts using a 177Lu-labeled HER2-specific Affibody molecule. Cancer Res 2007; 67: 2773–82

    Article  PubMed  CAS  Google Scholar 

  117. Jonsson A, Dogan J, Herne N, et al. Engineering of a femtomolar affinity binding protein to human serum albumin. Prot Eng Design Sel 2008; 21: 517–27

    Google Scholar 

  118. Libon C, Corvaia N, Haeuw JF, et al. The serum albumin-binding region of streptococcal protein G (BB) potentiates the immunogenicity of the G130-230 RSV-A protein. Vaccine 1999; 17: 406–14

    Article  PubMed  CAS  Google Scholar 

  119. Sato AK, Sexton DJ, Morganelli LA, et al. Development of mammalian serum albumin affinity purification media by peptide phage display. Biotechnol Prog 2002; 18: 182–92

    Article  PubMed  CAS  Google Scholar 

  120. Dennis MS, Zhang M, Meng G, et al. Albumin binding as a general strategy for improving pharmacokinetics of proteins. J Biol Chem 2002; 277: 35035–40

    Article  PubMed  CAS  Google Scholar 

  121. Bessette PH, Rice JL, Daugherty PS. Rapid isolation of high-affinity protein binding peptides using bacterial display. Prot Eng Design Sel 2004; 17: 731–9

    Article  CAS  Google Scholar 

  122. Nguyen A, Reyes II AE, Zhang M, et al. The pharmacokinetics of an albuminbinding Fab (AB.Fab) can be modulated as a function of affinity for albumin. Prot Eng Design Sel 2006; 19: 291–7

    Article  CAS  Google Scholar 

  123. sRoovers RC, Laeremans T, Huang L, et al. Efficient inhibition of EGFR signalling and of tumour growth by antagonistic anti-EGFR nanobodies. Cancer Immunol Immunother 2007; 56: 303–17

    Article  CAS  Google Scholar 

  124. Cortez-Retamozo V, Lauwereys M, Hassanzadeh Gh G, et al. Efficient tumor targeting by single-domain antibody fragments of camels. Int J Cancer 2002; 98: 456–62

    Article  PubMed  CAS  Google Scholar 

  125. Tijink BM, Laeremans T, Budde M, 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

    Article  PubMed  CAS  Google Scholar 

  126. Holt LJ, Herring C, Jespers LS, et al. Domain antibodies: proteins for therapy. Trends Biotechnol 2003; 21: 484–90

    Article  PubMed  CAS  Google Scholar 

  127. Holt LJ, Basran A, Jones K, et al. Anti-serum albumin domain antibodies for extending the half-lives of short lived drugs. Prot Eng Design Sel 2008; 21: 283–8

    Article  CAS  Google Scholar 

  128. Bhattacharya AA, Grüne T, Curry S. Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to human serum albumin. J Mol Biol 2000; 303: 721–32

    Article  PubMed  CAS  Google Scholar 

  129. Havelund S, Plum A, Ribel U, et al. The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm Res 2004; 21: 1498–504

    Article  PubMed  CAS  Google Scholar 

  130. Dumelin CE, Rüssel S, Buller F, et al. A portable albumin binder from a DNA-encoded chemical library. Angew Chem Int Ed Engl 2008; 47: 3196–201

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The author would like to thank Prof. Arne Skerra (Technische Universität, Munich, Germany) and Dr. Fredrik Frejd (Affibody, Bromma, Sweden) for providing unpublished data. This work was funded by grant no. KO1461/2-1 from the Deutsche Forschungsgemeinschaft.

Author information

Authors and Affiliations

  1. Institut für Zellbiologie und Immunologie, Universität Stuttgart, Allmandring 31, 70569, Stuttgart, Germany

    Roland E. Kontermann

Authors
  1. Roland E. Kontermann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roland E. Kontermann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kontermann, R.E. Strategies to Extend Plasma Half-Lives of Recombinant Antibodies. BioDrugs 23, 93–109 (2009). https://doi.org/10.2165/00063030-200923020-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00063030-200923020-00003

Keywords

Search

Navigation