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“Fc Fusion Proteins”

  • Carole Heath
  • Dean Pettit
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 38)

Abstract

IgG-based therapeutics has become an increasingly important category of the over two hundred biopharmaceutical products approved in the USA and the EU by late 2014. While a large percentage of this consists of monoclonal antibodies, Fc fusion proteins make up an important class of IgG-based biotechnology drugs. This chapter reviews the rationale for creating Fc fusion proteins, describes challenges, regulatory considerations, and improvements that have been made with this important class of therapeutics.

Keywords

Fc fusion Peptibody Mimetibody Expression Half-life Effector function 

References

  1. 1.
    Jiang X-R, et al. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat Rev Drug Disc. 2011;10:101–10.CrossRefGoogle Scholar
  2. 2.
    Capon D. Designing CD4 immunoadhesins for AIDS therapy. Nature. 1989;525–531.CrossRefPubMedGoogle Scholar
  3. 3.
    Aggarwal S. What’s fueling the biotech engine—2012–2013. Nat Biotechnol. 2014;32(1):32–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Mohler K, et al. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemial and function simultaneously as both TNF carriers and TNF agonists. J Immunol. 1993;151(3):1548–61.PubMedGoogle Scholar
  5. 5.
    Ducore JM, Miguelino MG, Powell JS. Alprolix (recombinant factor IX Fc fusion protein): extended half-life product for the prophylaxis and treatment of hemophilia B. Expert Re Hematology. 2014;7(5):559–71.CrossRefGoogle Scholar
  6. 6.
    Powell JS, et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood. 2012;119(13):3031–7.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Shapiro A. Development of long-acting recombinant FVIII and FIX Fc fusion proteins for the management of hemophilia. Expert Opin Biol Ther. 2013;13(9):1287–97.CrossRefPubMedGoogle Scholar
  8. 8.
    Rath T, et al. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit Rev Biotechnol. 2013.Google Scholar
  9. 9.
    Wu B, Sun Y-N. Pharmacokinetics of peptide-Fc fusion proteins. J Pharm Sci. 2014;103:53–64.CrossRefPubMedGoogle Scholar
  10. 10.
    Hermeling S, Crommelin D, Schellekens H, Jiskoot W. Structure-immunogenicity relationships of therapeutic proteins. Pharm Res. 2004;22(6):897–903.CrossRefGoogle Scholar
  11. 11.
    Dintzis H, Dintzis R, Vogelstein B. Moleculare determinants of immunogenicity: the immunon model of immune response. Proc Natl Acad Sci USA. 1976;73(10):3671–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Shimamoto G, Gegg C, Boone T, Queva C. Peptibodies: a flexible alternative format to antibodies. mAbs. 2012;4(5):586–591.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Cines D, Yasothan U, Kirkpatrick P. Romiplostim. Nat Rev Drug Discov. 2008;7:887–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Molineux G, Newland A. Development of romiplostim for the treatment of patients with chronic immune thrombocytopenia: From bench to bedside. Br J Haematol. 2010;150(1):9–20.PubMedGoogle Scholar
  15. 15.
    Huang C. Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology. Curr Opin Biotechnol. 2009;20:692–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Lindzen M, et al. A recombinant decoy comprising EGFR and ErbB-4 inhibits tumor growth and metastasis. Oncogene. 2012;31:3505–15.CrossRefPubMedGoogle Scholar
  17. 17.
    Holash J, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. PNAS. 2002;99:11393–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Kim ES, et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. PNAS. 2002;99:11399–404.CrossRefPubMedGoogle Scholar
  19. 19.
    Kimchi-Sarfaty C, et al. Building better drugs: developing and regulating engineered therapeutic proteins. Cell. 2013;34(10):534–48.Google Scholar
  20. 20.
    Dumont J, Low S, Bitonti A. Monomeric Fc fusions: Impact on pharmacokinetic and biological activity of protein therapeutics. Biodrugs. 2006;20(3):151–60.CrossRefPubMedGoogle Scholar
  21. 21.
    Economides A, Carpenter L. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med. 2003;9:47–52.CrossRefGoogle Scholar
  22. 22.
    Nimmerjahn F, Ravetch J. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8:34–47.CrossRefPubMedGoogle Scholar
  23. 23.
    Jacobs C, et al. Pharmacokinetic parameters and biodistribution of soluble cytokine receptors. Int Rev Exp Pathol. 1992;34B:123.Google Scholar
  24. 24.
    Yu H-K, et al. Immunoglobulin Fc domain fusion to apolipoprotein(a) kringle V significantly prolongs plasma half-life without affecting its anti-angiogenic activity. Protein Eng Des Sel. 2013;26(6):425–32.CrossRefPubMedGoogle Scholar
  25. 25.
    Shiga Y, et al. Recombinant human lactoferrin-Fc fusion with an improved plasma half-life. Eur J Pharm Sci. 2015;67:136–43.CrossRefPubMedGoogle Scholar
  26. 26.
    Jazayeri JA, Carroll GJ. Fc-based cytokines. Biodrugs. 2008;22(1):11–26.CrossRefPubMedGoogle Scholar
  27. 27.
    Valee S, et al. Pulmonary administration of interferon beta-1a-fc fusion protein in non-human primates using an immunoglobulin transport pathway. J Interferon Cytokine Res. 2012;32(4):178–84.CrossRefGoogle Scholar
  28. 28.
    Dixon W, et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated witn anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis. 2010;69(3):522–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Tubach F, et al. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum. 2009;60(7):1884–94.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hunt L, Emery P. Etanercept in the treatment of rheumatoid arthritis. Expert Opin Biol Ther. 2013;13(10):1441–50.CrossRefPubMedGoogle Scholar
  31. 31.
    Peppel K, Crawford D, Beutler B. A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. J Exp Med. 1991;174:1483–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Zhang J, et al. Fusion partners as a tool for the expression of difficult proteins in mammalian cells. Curr Pharm Biotechnol. 2010;11(3):241–5.CrossRefPubMedGoogle Scholar
  33. 33.
    Carter P. Introduction to current and future protein therapeutics: a protein engineering perspective. Exptl Cell Res. 2011;317:1261–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Kumagai Y, et al. Pharmacodynamics and pharmacokinetics of AMG 531, a thrombopoiesis-stimulating peptibody, in healthy Japanese subjects; a randomized, placebo-controlled study. J Clin Pharmacol. 2007;47(12):1489–97.CrossRefPubMedGoogle Scholar
  35. 35.
    Sathish J, et al. Challenges and approaches for the development of safer immunomodulatory biologics. Nat Rev Drug Disc. 2013;12:306–24.CrossRefGoogle Scholar
  36. 36.
    Grinyo J. An integrated safety profile analysis of belatacept in kidney transplant recipients. Transplantation. 2010;90:1521–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Chen X, Zaro J, Shen W-C. Pharmacokinetics of recombinant bifunctional fusion proteins. Expert Opin Drug Metab Toxicol. 2012;8(5):581–95.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Strohl W. Optimization of Fc-mediated effector functions of monoclonal antibodies. Curr Opin Biotechnol. 2009;20:685–91.CrossRefPubMedGoogle Scholar
  39. 39.
    Jefferis R. Glycosylation as a strategy to improve antibody-based therapeutics. Nat Rev Drug Discov. 2009;8:226–34.CrossRefPubMedGoogle Scholar
  40. 40.
    Kaneko Y, Nimmerjahn F, Ravetch J. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006;313:670–3.CrossRefPubMedGoogle Scholar
  41. 41.
    Stavenhagen J, et al. Enhancing the potency of therapeutic monoclonal antibodies via Fc optimization. Adv Enzyme Regul. 2008;48:152–64.CrossRefPubMedGoogle Scholar
  42. 42.
    Shoji-Hosaka E, et al. Enhanced Fc-dependent cellular cytotoxicity of Fc fusion proteins derived from TNF receptor II and LFC-3 by fucose removal from Asn-linked oligosaccharides. J Biochem. 2006;140:777–83.CrossRefPubMedGoogle Scholar
  43. 43.
    Matsuda K, et al. Enhanced binding affinity for FcgammaRIIIa of fucose-negative antibody is sufficient to induce maximal antibody-dependent cellular cytotoxicity. Mol Immunol. 2007;44(12):3122–31.CrossRefGoogle Scholar
  44. 44.
    Kellner C, Derer S, Valerius T, Peipp M. Boosting ADCC and CDC activity by Fc engineering and evaluation of antibody effector functions. Methods. 2014;65:105–13.CrossRefPubMedGoogle Scholar
  45. 45.
    Houde D, Peng Y, Berkowitz S, Engen J. Post-translational modifications differentially affect IgG1 conformation and receptor binding. Mol Cell Proteomics. 2010;9:1716–28.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Nagashima H, et al. TNF receptor II fusion protein with tandemly repeated Fc domains. J Biochem. 2011;149(3):337–46.CrossRefPubMedGoogle Scholar
  47. 47.
    Yeung Y, 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
  48. 48.
    Zalevsky J, et al. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol. 2010;28(2):157–9.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Czajkowsky D, Hu J, Shao Z, Pleass R. Fc-fusion proteins: new developments and future perspectives. EMBO Mol Med. 2012;4:1015–28.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Scallon B, et al. Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol Immunol. 2007;44(7):1524–34.CrossRefPubMedGoogle Scholar
  51. 51.
    Davis P, et al. Abatacept binds to the Fc receptor CD64 but does not mediate complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity. J Rheum. 2007;34(11):2204–10.PubMedGoogle Scholar
  52. 52.
    Bruhns P, et al. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood. 2009;113:3716–25.CrossRefPubMedGoogle Scholar
  53. 53.
    Wang Q, et al. Novel GLP-1 fusion chimera as potent long acting GLP-1 receptor agonist. PLoS ONE. 2010;5:e12734.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Vafa O, et al. An engineered Fc variant of an IgG eliminates all immune effector functions via structural perturbations. Methods. 2014;65:114–26.CrossRefPubMedGoogle Scholar
  55. 55.
    Lee J-H, et al. Biochemical characterization of a new recombinant TNF receptor-hyFc fusion protein expressed in CHO cells. Protein Expr Purif. 2013;87:17–26.CrossRefPubMedGoogle Scholar
  56. 56.
    Ishino T, et al. Engineering a monomeric Fc domain modality by N-glycosylation for the half-life extension of biotherapeutics. J Biol Chem. 2013;288(23):16529–37.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Ying T, et al. Engineered soluble monomeric IgG1 CH3 domain: generation, mechanisms of function, and implications for design of biological therapeutics. J Biol Chem. 2013;288(35):25154–64.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    FDAGov. Guidance for industry: Immunogenicity assessment for therapeutic protein products. [Online] Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338856.pdf. Accessed 24 Mar 2015.

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Process DevelopmentAmgenThousand OaksUSA
  2. 2.Just BiotherapeuticsSeattleUSA

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