Half-life extended biotherapeutics

Expert Opinion on Biological Therapy

Volumn 16, Issue 7, 2016, Pages 903-915

  Kontermann, Roland E ^a  

^a UNIVERSITY OF STUTTGART   (Germany)

Author keywords

Albumin; Fc region; FcRn; fusion protein; glycosylation; half life extension; PEGylation; polymer

Indexed keywords

ALBUMIN; BIOLOGICAL PRODUCT; FC RECEPTOR; HYBRID PROTEIN; IMMUNOGLOBULIN FC FRAGMENT; MACROGOL; PLASMA PROTEIN; ALBUMINOID; FC RECEPTOR, NEONATAL; HLA ANTIGEN CLASS 1;

BINDING AFFINITY; BIOLOGICAL THERAPY; DRUG ACCUMULATION; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG PENETRATION; GLYCOSYLATION; HUMAN; HYDRODYNAMICS; IMMUNOGENICITY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); POLYMERIZATION; PROTEIN PROCESSING; REVIEW; ANIMAL; DRUG EFFECTS; HALF LIFE TIME; METABOLISM; PROCEDURES; TRENDS;

ALBUMINS; ANIMALS; BIOLOGICAL THERAPY; GLYCOSYLATION; HALF-LIFE; HISTOCOMPATIBILITY ANTIGENS CLASS I; HUMANS; IMMUNOGLOBULIN FC FRAGMENTS; RECEPTORS, FC;

EID: 84963865285     PISSN: 14712598     EISSN: 17447682     Source Type: Journal    
DOI: 10.1517/14712598.2016.1165661     Document Type: Review

References (148)

1. G.Walsh Biopharmaceutical benchmarks 2014. Nat Biotechnol. 2014;32:992–1000. doi:10.1038/nbt.3040.•• Comprehensive summary of approved biotherapeutics.
2. L.Tang, A.M.Persky, G.Hochhaus, et al. Pharmacokinetic aspects of biotechnology products. J Pharmaceut Sci. 2004;93:2184–2204. doi:10.1002/jps.20125.
3. R.E.Kontermann. Strategies for extended serum half-life of protein therapeutics. Curr Opin Biotechnol. 2011;22:868–876. doi:10.1016/j.copbio.2011.06.012.• Comprehensive summary of half-life extension strategies.
4. R.E.Kontermann. Therapeutic proteins. Strategies to modulate their plasma half-lives. Weinheim: Wiley-Blackwell; 2012.
5. B.Meibohm. Pharmacokinetics and half-life of protein therapeutics. In: R.E.Kontermann, editor. Therapeutic proteins. Strategies to modulate their plasma half-lives. Weinheim: Wiley-Blackwell; 2012. p. 23–38.
6. R.P.Scott, S.E.Quaggin. The cell biology of renal filtration. J Cell Biol. 2015;209:199–210. doi:10.1083/jcb.201410017.
7. J.T.Sockolosky, F.C.Szoka. The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy. Adv Drug Deliv Reviews. 2015;30:109–124.
8. M.A.Tabrizi, C.M.Tseng, L.K.Roskos. Elimination mechanisms of therapeutic antibodies. Drug Discov Today. 2006;11:81–88. doi:10.1016/S1359-6446(05)03638-X.
9. G.Levy. Pharmacologic target-mediated drug disposition. Clin Pharmacol Ther. 1994;56:248–252.
10. D.E.Mager. Target-mediated drug disposition and dynamics. Biochem Pharmacol. 2006;72:1–10. doi:10.1016/j.bcp.2005.12.041.
11. H.Li, M.d’Anjou. Pharmacological significance of glycosylation in therapeutic proteins. Curr Opin Biotechnol. 2009;20:678–684. doi:10.1016/j.copbio.2009.10.009.
12. R.J.Solá, K.Griebenow. Glycosylation of therapeutic proteins: an effective strategy to optimize efficacy. BioDrugs. 2010;24:9–21. doi:10.2165/11530550-000000000-00000.
13. A.M.Sinclair. Erythropoiesis stimulating agents: approaches to modulate activity. Biologics. 2013;7:161–174. doi:10.2147/BTT.S45971.
14. R.De Boer, M.Clemens, G.Renczes, et al. Phase I/II randomised study of a novel erythropoiesis-stimulating agent (AMG 114) for the treatment of anaemia with concomitant chemotherapy in patients with non-myeloid malignancies. Med Oncol. 2011;28:1210–1217. doi:10.1007/s12032-010-9725-7.
15. K.Song, I.S.Yoon, N.A.Kim, et al. Glycoengineering of interferon-β 1a improves its biophysical and pharmacokinetic properties. PLoS One. 2014;9:e96967. doi:10.1371/journal.pone.0096967.
16. V.Garcia-Campayo, T.Sugahara, I.Boime. Unmasking a new recognition signal for O-linked glycosylation in the chorionic gonadotropin β subunit. Mol Cell Endocrinol. 2002;194:63–70.
17. M.M.Matzuk, A.J.Hsueh, P.Lapolt, et al. The biological role of the carboxy-terminal extension of human chorionic gonadotropin β subunit. Endocrinology. 1990;126:376–383. doi:10.1210/endo-126-1-376.
18. P.M.Bouloux, D.J.Handelsman, F.Jockenhövel, et al. FSH-CTP study group. First human exposure to FSH-CTP in hypgonadrotrophic hyogonadal males. Hum Repord. 2001;16:1592–1597. doi:10.1093/humrep/16.8.1592.
19. M.Patil. Gonadotrophins: the future. J Hum Reprod Sci. 2014;7:236–248. doi:10.4103/0974-1208.147490.
20. F.Fares, S.Ganem, T.Hajouj, et al. Development of a long-acting erythropoietin by fusing the carboxy-terminal peptide of human chorinic gonadotropin β-subunit to the coding sequence of human erythropoietin. Endocrinology. 2007;148:5081–5087. doi:10.1210/en.2007-0026.
21. F.Fares, R.Guy, A.Bar-Ilan, et al. Desinging a long-acting human growth hormone (hGH) byf using the carboxy-terminal peptide of human chorinic gonadotropin β-subunit to the coding sequence of hGH. Endocrinology. 2010;151:4410–4417. doi:10.1210/en.2009-1431.
22. M.Dicker, R.Strasser. Using glyco-engineering to produce therapeutic proteins. Expert Opin Bio Ther. 2015;15:1501–1516. doi:10.1517/14712598.2015.1069271.
23. S.Jevsevar, M.Kunstelj, V.G.Porekar. PEGylation of therapeutic proteins. Biotechnol J. 2010;5:113–128. doi:10.1002/biot.200900218.
24. E.M.Pelegri-O’Day, E.-W.Lin, et al. Therapeutic protein-polymer conjugates: advancing beyond PEGylation. J Am Chem Soc. 2014;136:14323–14332. doi:10.1021/ja504390x.
25. F.Zhang, M.R.Liu, H.T.Wan. Discussion about several potential drawbacks of PEGylated therapeutic proteins. Biol Pharm Bull. 2014;37:335–339.
26. P.Milla, F.Dosio, L.Cattel. PEGylation of proteins and liposomes: a powerful and flexible strategy to improve the drug delivery. Curr Drug Metabol. 2012;13:105–119. doi:10.2174/138920012798356934.
27. J.S.Powell. Longer-acting clotting factor concentrates for hemophilia. J Thromb Haemost. 2015;13 Suppl 1:S167–75. doi:10.1111/jth.12912.
28. R.Stidl, S.Fuchs, M.Bossard, et al. Safety of PEGylated recombinant human full-length coagulation factor VIII (BAX 855) in the overall context of PEG and PEG conjugates. Haemophilia. 2016;22:54–64. doi:10.1111/hae.12762.
29. R.P.Garay, R.El-Gewely, J.K.Armstrong, et al. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin Drug Deliv. 2012;9:1319–1323. doi:10.1517/17425247.2012.720969.
30. J.K.Dozier, M.D.Distefano. Site-specific PEGylation of therapeutic proteins. Int J Mol Sci. 2015;16:25831–25864. doi:10.3390/ijms161025831.
31. Y.Qi, A.Chilkoti. Protein-polymer conjugation – moving beyond PEGylation. Curr Opin Chem Biol. 2015;28:181–193. doi:10.1016/j.cbpa.2015.08.009.
32. Y.Kaneda, Y.Tsutsumi, Y.Yoshioka, et al. The use of PVP as a polymeric carrier to improve the plasma half-life of drugs. Biomaterials. 2004;25:3259–3266. doi:10.1016/j.biomaterials.2003.10.003.
33. A.Mero, Z.Fang, G.Pasut, et al. Selective conjugation of poly82-ethyl 2-oxazoline to granulocyte colony stimulating factor. J Control Release. 2012;159:353–361. doi:10.1016/j.jconrel.2012.02.025.
34. A.G.Lewis, Y.Tang, S.Brocchini, et al. Poly(2-methacryloyloxyethyl phosphorylcholine) for protein conjugation. Bioconjugate Chem. 2008;19:2144–2155. doi:10.1021/bc800242t.
35. C.Chen, A.Constantinou, M.Deonarain. Modulating antibody pharmacokinetics using hydrophilic polymers. Expert Opin Drug Deliv. 2011;8:1221–1236. doi:10.1517/17425247.2011.602399.
36. S.Terekhov, I.Smirnov, T.Bobik, et al. A novel expression cassette delivers efficient production of exclusively tetrameric human butyrylcholinesterase with improved pharmacokinetics for protection against organophosphate poisoning. Biochimie. 2015;118:51–59. doi:10.1016/j.biochi.2015.07.028.
37. J.-H.Kong, E.J.Oh, S.Y.Chae, et al. Long acting hyaluronate-exendin 4 conjugate for the treatment of type 2 diabetes. Biomaterials. 2010;31:4121–4128. doi:10.1016/j.biomaterials.2010.01.091.
38. E.J.Oh, J.-S.Choi, H.Kim, et al. Anti-Flt1 peptide-hyaluronate conjugate for the treatment of retinal neovascularization and diabetes retinopathy. Biomaterials. 2011;32:3115–3123. doi:10.1016/j.biomaterials.2011.01.003.
39. R.Liebner, R.MAthaes, M.Meyer, et al. Protein HESylation for half-life extension: synthesis, characterization and pharmacokinetics of HESylated anakinra. Eur J Pharm Biopharm. 2014;87:378–385. doi:10.1016/j.ejpb.2014.03.010.
40. R.Liebner, M.Meyer, T.Hey, et al. Head to head comparison of the formulation and stability of concentrated solutions of HESylated versus PEGylated anakinra. J Pharm Sci. 2015;104:515–526. doi:10.1002/jps.24253.
41. R.Liebner, S.Bergmann, T.Hey, et al. Freeze-drying of HESylated IFN-2b: effect of HESylation on storage stability in comparison to PEGylation. Int J Pharm. 2015;495:608–611. doi:10.1016/j.ijpharm.2015.09.031.
42. U.Binder, A.Skerra. Half-life extension of therapeutic proteins via genetic fusion to recombinant PEG mimetics. In: R.E.Kontermann, editor. Therapeutic proteins. Strategies to modulate their plasma half-lives. Weinheim: Wiley-Blackwell; 2012. p. 63–80.
43. V.Schellenberger, C.-W.Wang, N.C.Geething, et al. A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner. Nat Biotechnol. 2009;27:1186–1190. doi:10.1038/nbt.1588.
44. V.N.Podust, S.Balan, B.-C.Sim, et al. Extension of in vivo half-life of biologically active molecules by XTEN protein polymers. J Control Release. 2015. doi:10.1016.
45. M.Schlapschy, U.Binder, C.Börger, et al. PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins. Protein Eng Des Sel. 2013;26:489–501. doi:10.1093/protein/gzt023.
46. V.Morath, F.Bolze, M.Schlapschy, et al. PASylation of murine leptin leads to extended plasma half-life and enhanced in vivo efficacy. Mol Pharm. 2015;12:1431–1442. doi:10.1021/mp5007147.
47. F.Bolze, V.Morath, A.Bast, et al. Long-acting PASylated leptin ameliorates obesity by promoting satiety and preventing hypometabolism in leptin-deficient Lep(ob/ob) mice. Endocrinology. 2016;157:233–244. doi:10.1210/en.2015-1519.• Study showing the therapeutic efficacy of PASylated biotherapeutic.
48. D.Harari, N.Kuhn, R.Abramovich, et al. Enhanced in vivo efficacy of a type I interferon superagonist with extended plasma half-life in a mouse model of multiple sclerosis. J. Biol Chem. 2014;289:29014–29029. doi:10.1074/jbc.M114.602474.
49. S.Di Cesare, U.Binder, T.Maier, et al. High-yield production of PASylated human growth hormone using secretory E. coli technology. Bioprocess Int. 2014:30–38.
50. C.T.Mendler, L.Friedrich, I.Laitinen, et al. High contrast tumor imaging with radio-labeled antibody Fab fragments tailored for optimized pharmacokinetics via PASylation. MAbs. 2015;7:96–109. doi:10.4161/19420862.2014.985522.
51. S.R.MacEwan, A.Chilkoti. Applications of elastin-like polypeptides in drug delivery. J Control Release. 2014;190:314–330. doi:10.1016/j.jconrel.2014.06.028.
52. M.Amiram, K.M.Luginbuhl, X.Li, et al. A depot-forming glucagon-like peptide-1 fusion protein reduces blood glucose for five days with a single injection. J Control Release. 2013;172:144–151. doi:10.1016/j.jconrel.2013.07.021.• Study showing flexible polypeptide chains can also serve as a depot-forming formulation.
53. M.F.Shamji, H.Betre, V.B.Kraus, et al. Development and characterization of a fusion protein between thermally responsive elastin-like polypeptide and interleukin-1 receptor antagonist: sustained release of a local anti-inflammatory therapeutic. Arthritis Rheum. 2007;56:3650–3661. doi:10.1002/art.22952.
54. K.M.Sand, M.Bern, J.Nilsen, et al. Unraveling the interation between FcRn and albumin: opportunities for design of albumin-based therapeutics. Front Immunol. 2015;5:682.
55. K.M.Sand, M.Bern, J.Nilsen, et al. Interaction with both domain I and III of albumin is required for optimal pH-dependent binding to the neonatal Fc receptor (FcRn). J Biol Chem. 2014;289:34583–34594. doi:10.1074/jbc.M114.587675.• Study showing the molecular interactions of albumin and FcRn with implications for improved albumin.
56. D.Sleep. Albumin and its application in drug delivery. Expert Opin Drug Deliv. 2015;12:793–812. doi:10.1517/17425247.2015.993313.
57. P.A.Hollander. Albumin detemir for the treament of obese patients with type 2 diabetes. Diabetes Metabl Syndr Obes. 2012;5:11–19.
58. S.Arnolds, B.Kuglin, C.Kapitza, et al. How pharmacokinetic and pharmacodynamic principles pave the way for optimal basal insulin therapy in type 2 diabetes. Int J Clin Pract. 2010;64:1415–1424. doi:10.1111/j.1742-1241.2010.02470.x.
59. H.Agerso, L.B.Jensen, B.Elbrond, et al. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002;45:195–202. doi:10.1007/s00125-001-0719-z.
60. T.Idorn, F.K.Knop, M.B.Jorgensen, et al. Elimination and degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with end-stage renal disease. J Clin Endorcrinol Metab. 2014;99:2457–2466. doi:10.1210/jc.2013-3809.
61. R.K.Kontermann. Strategies to extend plasma half-lives of recombinant antibodies. BioDrugs. 2009;23:93–109.
62. D.Sleep, J.Cameron, L.R.Evans. Albumin as a versatile platform for drug half-life extension. Biochimica Et Biophysica Acta. 2013;1830:5526–5534. doi:10.1016/j.bbagen.2013.04.023.
63. TM technology. Methods Mol Biol. 2012;911:457–473. doi:10.1007/978-1-61779-968-6_28.
64. E.M.Schmidt, M.Davies, P.Mistry, et al. Selective blockade of tumor necrosis factor receptor I inhibits proinflammatory cytokine and chemokine production in human rheumatoid arthritis synovial membrane cell cultures. Arthritis Rheumat. 2013;65:2262–2273. doi:10.1002/art.38055.
65. L.H.Goodall, M.Ovecka, D.Rycroft, et al. Pharmacokinetic and pharmacodynamic characterisation of an anti-mouse TNF receptor 1 domain antibody formatted for in vivo half-life extension. PLoS One. 2015;10:e137065.
66. W.Bao, L.H.Holt, R.D.Prince, et al. Novel fusion of GLP-1 with a domain antibody to serum albumin prolongs protection against myocardial ischemia/reperfusion injury in the rat. Cardiovasc Diabetol. 2013;12:148. doi:10.1186/1475-2840-12-148.
67. R.L.O’Connor-Semmes, J.Lin, R.J.Hodge, et al. GSK2374697, a novel albumin-binding domain antibody (albudAb), extends systemic exposure of exendin-4: first in humans - PK/PD and safety. Clin Pharmacol. 2014;96:704–712.
68. J.Lin, R.K.Hodge, R.L.O’Connor-Semmes, et al. GSK2374697, a long duration glucagon-like peptide-1 (GLP-1) receptor agonist, reduces postprandial circulating endogenous total GLP-1 and peptide YY in healthy subjects. Diabetes Obes Metab. 2015;17:1007–1010. doi:10.1111/dom.12533.• Study showing the therapeutic efficacy of an albumin-binding GLP-1 based on albumin-binding domain antibodies.
69. B.M.Tijink, T.Laeremans, M.Budde, 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;7:2288–2297. doi:10.1158/1535-7163.MCT-07-2384.
70. M.Van Roy, C.Ververken, E.Beirnaert, et al. The preclinical pharmacology of the high affinity anti-IL-6R Nanobody ALX-0061 supports its clinical development in rheumatoid arthritis. Arthritis Res Ther. 2015;17:135. doi:10.1186/s13075-015-0651-0.
71. S.Terryn, A.Francart, S.Lamoral, et al. Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice. PLoS One. 2014;9:e109367. doi:10.1371/journal.pone.0109367.
72. R.Stork, D.Müller, R.E.Kontermann. 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;20:569–576. doi:10.1093/protein/gzm061.
73. A.Jonsson, J.Dogan, N.Herne, et al. Engineering of a femtomolar affinity binding protein to human serum albumin. Protein Eng Des Sel. 2008;21:515–527. doi:10.1093/protein/gzn028.
74. R.Stork, K.A.Zettlitz, D.Müller, et al. N-glycosylation as novel strategy to improve pharmacokinetic properties of bispecific single-chain diabodies. J Biol Chem. 2008;283:7804–7812. doi:10.1074/jbc.M709179200.
75. A.Orlova, A.Jonsson, D.Rosik, et al. Site-specific radiometal labeling and improved biodistribution using ABY-027, a novel HER2-targeting affibody molecule-albumin-binding domain fusion protein. J Nucl Med. 2013;54:961–968. doi:10.2967/jnumed.112.110700.
76. J.Hoop, N.Hornig, K.A.Zettlitz, 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. Protein Eng Des Sel. 2010;23:827–834. doi:10.1093/protein/gzq058.
77. S.A.Jacobs, A.C.Gibbs, M.Conk, et al. Fusion to a highly stable consensus albumin binding domain allows for tunable pharmacokinetics. Protein Eng Des Sel. 2015;28:385–393. doi:10.1093/protein/gzv040.
78. J.Löfblom, F.Y.Frejd, S.Stahl. Non-immunoglobulin based protein scaffolds. Curr Opin Biotechnol. 2011;22:843–848. doi:10.1016/j.copbio.2011.06.002.
79. J.T.Andersen, B.Dalhus, D.Viuff, et al. Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding. J Biol Chem. 2014;289:13492–13502. doi:10.1074/jbc.M114.549832.
80. D.Müller, A.Karle, B.Meissburger, et al. Improved pharmacokinetics of recombinant bispecific antibody molecules by fusion to human serum albumin. J Biol Chem. 2007;282:12650–12660. doi:10.1074/jbc.M700820200.
81. C.F.McDonagh, A.Huhalov, B.D.Harms, et al. Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3. Mol Cancer Ther. 2012;11:582–593. doi:10.1158/1535-7163.MCT-11-0820.• Study showing that bispecific antibodies can be generated with albumin as building block.
82. B.Rogers, D.Dong, Z.Li, et al. Recombinant human serum albumin fusion proteins and novel applications in drug delivery and therapy. Curr Pharm Des. 2015;21:1899–1907.
83. W.R.Strohl. Fusion proteins for half-life extension of biologics as a strategy to make biobetters. BioDrugs. 2015;29:215–239. doi:10.1007/s40259-015-0133-6.
84. J.M.Trujillo, W.Nuffer. Albiglutide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes. Ann Pharmacother. 2014;48:1494–1501. doi:10.1177/1060028014545807.
85. M.A.Bush, J.E.Matthews, E.H.De Boever, et al. Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects. Diabetes Obes Metab. 2009;11:498–505. doi:10.1111/j.1463-1326.2008.00992.x.
86. A.Tiede. Half-life extended factor VIII for the treatment of hemophilia A. J Thromb Haemost. 2015;13(Suppl 1):S176–9. doi:10.1111/jth.12929.
87. S.Schulte. Pioneering designs for recombinant coagulation factors. Thromb Res. 2011;128 Suppl 1:S9–12. doi:10.1016/S0049-3848(12)70003-8.
88. S.Schulte. Half-life extension through albumin fusion technologies. Throm Res. 2009;124(Suppl 2):S6–8. doi:10.1016/S0049-3848(09)70157-4.
89. H.J.Metzner, T.Weimer, U.Kronthaler, et al. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost. 2009;102:634–644. doi:10.1160/TH09-04-0255.
90. E.Santagostino, C.Negrier, R.Klamroth, et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rXI-FP) in hemophilia B patients. Blood. 2012;120:2405–2411. doi:10.1182/blood-2012-05-429688.
91. E.Santagostino, U.Martinowitz, T.Lissitchkov, et al. Long acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016. Epub ahead of print
92. S.Björkman, A.Folkesson, S.Jönsson. Pharmacokinetics and dose requirements of factor VIII over the age range 3-74 years: a population analysis based on 50 patients with long-term prophylactic treatment for haemophilia A. Eur J Clin Pharmacol. 2009;65:989–998. doi:10.1007/s00228-009-0676-x.
93. S.Zollner, E.Raquet, P.Claar, et al. Non-clinical pharmacokinetics and pharmacodynamics of rVIII-Single-Chain, a novel recombinant single-chain factor VIII. Thromb Res. 2014;134:125–131. doi:10.1016/j.thromres.2014.03.028.• Study providing in vivo data of a novel single-chain derivative of a truncated factor VIII.
94. T.Weimer, W.Wormsbächer, U.Kronthaler, et al. Prolonged in-vivo half-life of factor VIIa by fusion to albumin. Thromb Haemost. 2008;99:659–667. doi:10.1160/TH07-08-0525.
95. G.Golor, D.Bensen-Kennedy, S.Haffner, et al. Safety and pharmacokinetics of a recombinant fusion protein linking coagulation factor VIIa with albumin in healthy volunteers. J Thromb Haemost. 2013;11:1977–1985. doi:10.1111/jth.12409.
96. O.Cohen-Barak, A.Sakov, M.Rasamoelisolo, et al. Safety, pharmacokinetic and pharmacodynamic properties of TV-1106, a long-acting GH treatment for GH deficiency. Eur J Endocrinol. 2015;173:541–551. doi:10.1530/EJE-15-0554.
97. C.Huang. Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology. Curr Opin Biotechnol. 2009;20:692–699. doi:10.1016/j.copbio.2009.10.010.
98. R.J.Keizer, A.D.Huitema, J.H.Schellens, et al. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493–507. doi:10.2165/11531280-000000000-00000.
99. T.Rath, K.Baker, J.A.Dumont, et al. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit Rev Biotechnol. 2013;35:235–254. doi:10.3109/07388551.2013.834293.
100. T.Suzuki, A.Ishii-Watabe, M.Tada, et al. 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;184:1968–1976. doi:10.4049/jimmunol.0903296.
101. C.A.Souders, S.C.Nelson, Y.Wang, et al. A novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half-life. MAbs. 2015;7:912–921. doi:10.1080/19420862.2015.1054585.
102. A.Schoch, H.Kettenberger, O.Mundigl, et al. Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics. Proc Natl Acad Sci USA. 2015;112:5997–6002. doi:10.1073/pnas.1408766112.
103. F.Unverdorben, F.Richter, M.Hutt, et al. Pharmacokinetic properties of IgG and various Fc fusion proteins in mice. MAbs. 2016;8:120–128. doi:10.1080/19420862.2015.1113360.
104. J.A.Jazayeri, G.J.Carroll. Fc-based cytokines: prospects for engineering superior therapeutics. BioDrugs. 2008;22:11–26.
105. J.A.Dumont, S.Low, R.T.Peters, et al. Monomeric Fc fusions: impact on pharmacokinetic and biological activity of protein therapeutics. BioDrugs. 2006;20:151–160.
106. T.Ishino, M.Wang, L.Mosyak, et al. Engineering a monomeric Fc domain modality by N-glycosylation for the half-life extension of biotherapeutics. J Biol Chem. 2013;288:16529–16537. doi:10.1074/jbc.M113.457689.
107. E.Ducharme, J.M.Weinberg. Etanercept. Expert Opin Biol Ther. 2008;8:491–502. doi:10.1517/14712598.8.4.491.
108. J.Holash, S.Davis, N.Papadopoulos, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99:11393–11398. doi:10.1073/pnas.172398299.
109. G.Trichonas, P.K.Kaiser. Aflibercept for the treatment of age-related macular degeneration. Ophthalmol Ther. 2013;2:89–98. doi:10.1007/s40123-013-0015-2.
110. C.Balaratnasingam, E.Dhrami-Gavazi, J.T.McCann, et al. Aflibercept: a review of its use in the treatment of choroidal neovascularization due to age-related macular degeneration. Clin Ophthalmol. 2015;9:2355–2371. doi:10.2147/OPTH.S80040.
111. S.L.Perkins, S.W.Cole. Ziv-aflibercept (Zaltrap) for the treatment of metastatic colorectal cancer. Ann Pharmacother. 2013;48:93–98. doi:10.1177/1060028013506562.
112. K.K.Ciombor, J.Berlin, E.Chan. Aflibercept. Clin Cancer Res. 2013;19:1920–1925. doi:10.1158/1078-0432.CCR-12-2911.
113. B.Wu, Y.-N.Sun. Pharmacokinetics of peptide-Fc fusion proteins. J Pharmaceut Sci. 2014;103:53–64. doi:10.1002/jps.23783.
114. G.Molineux. The development of romiplostim for patients with immune thrombocytopenia. Ann N Y Acad Sci. 2011;1222:55–63. doi:10.1111/j.1749-6632.2011.05975.x.
115. S.Chalmers, M.D.Tarantino. Romiplostim as a treatment for immune thrombocytopenia: a review. J Blood Med. 2015;6:37–44. doi:10.2147/JBM.S47240.
116. S.O.Ciurea, R.Hoffman. Cytokines for the treatment of thrombocytopenia. Semin Hematol. 2007;44:166–182. doi:10.1053/j.seminhematol.2007.04.005.
117. R.T.Peters, S.C.Low, G.D.Kamphaus, et al. Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood. 2010;115:2057–2064. doi:10.1182/blood-2009-08-239665.
118. J.M.Ducore, M.G.Miguelino, J.S.Powell. Alprolix (recombinant factor IX Fc fusion protein): extended half-life product for the prophylaxis and treatment of hemophilia B. Expert Rev Hematol. 2014;7:559–571. doi:10.1586/17474086.2014.951322.
119. M.G.Miguelino, J.S.Powell. Clinical utility and patient perspectives on the use of extended half-life rFIXFc in the management of hemophilia B. Patient Prefer Adherence. 2014;8:1073–1083. doi:10.2147/PPA.S54951.
120. R.T.Peters, G.Toby, Q.Lu, et al. Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein. J Thromb Haemost. 2013;11:132–141. doi:10.1111/jth.12076.
121. J.Mahlangu, J.S.Powell, M.V.Ragni, et al. A-LONG Investigators. Phase 3 study of recombinant factor VIII Fc fusion protein in server hemophilia A. Blood. 2014;123:317–325. doi:10.1182/blood-2013-10-529974.
122. J.Salas, T.Liu, Q.Lu, et al. Enhanced pharmacokinetics of factor VIIa as a monomeric Fc fusion. Thromb Res. 2015;135:970–976. doi:10.1016/j.thromres.2014.12.018.
123. J.N.Mahlangu, M.J.Coetzee, M.Laffan, et al. Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia. J Thromb Haemost. 2012;10:773–780. doi:10.1111/j.1538-7836.2012.04667.x.
124. J.N.Mahlangu, K.N.Weldingh, S.R.Lentz, et al. Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. J Thromb Haemost. 2015;13:1989–1998. doi:10.1111/jth.13141.
125. W.Glaesner, A.M.Vick, R.Millican, et al. Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes Metab Res Rev. 2010;26:287–296. doi:10.1002/dmrr.1080.
126. E.F.Zhu, S.A.Gai, C.F.Opel, et al. Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2. Cancer Cell. 2015;27:489–501. doi:10.1016/j.ccell.2015.03.004.
127. K.N.Moore, M.W.Sill, M.E.Tenney, et al. A phase II trial of trebananib (AMG 386; IND#111071), a selective angiopoietin 1/2 neutralizing peptibody, in patients with persistent/recurrent carcinoma of the endometrium: an NRG/Gynecologic Oncology Group trial. Gynecol Oncol. 2015;138:513–518. doi:10.1016/j.ygyno.2015.07.006.
128. S.H.Yang, S.I.Yang, Y.-K.Chung. A long-acting erythropoietin fused with noncytolytic human Fc for the treatment of anemia. Arch Pharm Res. 2012;35:757–759. doi:10.1007/s12272-012-0500-5.
129. J.Tuettenberg, M.Seiz, K.-M.Debatin, et al. Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101: a CD95-Fc fusion protein, in healthy volunteers and two glioma patients. Int Immunopharmacol. 2012;13:93–100. doi:10.1016/j.intimp.2012.03.004.
130. W.Wick, H.Fricke, K.Junge, et al. A phase II, randomized, study of weekly APG101+reirradiation versus reirradiation in progressive glioblastoma. Clin Cancer Res. 2014;20:6304–6313. doi:10.1158/1078-0432.CCR-14-0951-T.
131. A.R.Mezo, K.A.McDonnell, S.C.Low, et al. Atrial natriuretic peptide-Fc, ANP-Fc, fusion proteins: semisynthesis, in vitro activity and pharmacokinetics in rats. Bioconjug Chem. 2012;23:518–526. doi:10.1021/bc200592c.
132. L.G.Presta. Molecular engineering and design of therapeutic antibodies. Curr Opin Immunol. 2008;20:460–470. doi:10.1016/j.coi.2008.06.012.
133. T.T.Kuo, V.G.Aveson. Neonatal Fc receptor and IgG-based therapeutics. MAbs. 2011;3:422–430. doi:10.4161/mabs.3.5.16983.
134. Y.Wang, Z.Tian, D.Thirumalai, et al. Neonatal Fc receptor (FcRn): a novel target for therapeutic antibodies and antibody engineering. J Drug Target. 2014;22:269–278. doi:10.3109/1061186X.2013.875030.
135. G.J.Robbie, R.Criste, W.F.Dall’acqua, et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother. 2013;57:6147–6153. doi:10.1128/AAC.01285-13.• Study showing in vivo results from a half-life extended antibody with increased FcRn binding.
136. F.Unverdorben, A.Färber-Schwarz, F.Richter, et al. Half-life extension of a single-chain diabody by fusion to domain B of staphylococcal protein A. Protein Eng Des Sel. 2012;25:81–88. doi:10.1093/protein/gzr061.
137. M.Hutt, A.Färber-Schwarz, F.Unverdorben, et al. Plasma half-life extension of small recombinant antibodies by fusion to immunoglobulin-binding domains. J Biol Chem. 2012;287:4462–4469. doi:10.1074/jbc.M111.311522.
138. F.Unverdorben, M.Hutt, O.Seifert, et al. A Fab-selective immunoglobulin-binding domain from streptococcal protein G with improved half-life extension properties. PLoS One. 2015;10:e139838. doi:10.1371/journal.pone.0139838.
139. D.C.Roopenian, S.Akilesh. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–725. doi:10.1038/nri2155.
140. J.Seijsing, M.Lindborg, I.Höidén-Guthenberg, et al. An engineered affibody molecule with pH-dependent binding to FcRn mediates extended circulatory half-life of a fusion protein. Proc Natl Acad Sci USA. 2014;111:17110–17115. doi:10.1073/pnas.1417717111.
141. J.T.Sockolosky, M.R.Tiffany, F.C.Szoka. Engineering neonatal Fc receptor-mediated recycling and transcytosis in recombinant proteins by short terminal peptide extensions. Proc Natl Acad Sci USA. 2012;109:16095–16100. doi:10.1073/pnas.1208857109.
142. H.Li, Z.M.Qian. Transferrin/transferrin receptor-mediated drug delivery. Med Res Rev. 2002;22:225–230.
143. B.-J.Kim, J.Zhou, B.Martin, et al. Transferrin fusion technology: a novel approach to prolonging biological half-life of insulinotropic peptides. J Pharmacol Exp Ther. 2010;334:682–692. doi:10.1124/jpet.110.166470.
144. Y.Wang, J.Shao, J.L.Zaro, et al. Proinsulin-transferrin fusion protein as a novel long-acting insulin analog for the inhibition of hepatic glucose production. Diabetes. 2014;63:1779–1788. doi:10.2337/db13-0973.
145. X.Chen, H.-F.Lee, J.L.Zaro, et al. Effects of receptor binding on plasma half-life of bifunctional transferrin fusion proteins. Mol Pharm. 2011;8:457–465. doi:10.1021/mp1003064.
146. M.De Kort, B.Gianotten, J.A.Wisse, et al. Conjugation of ATIII-binding pentasaccharides to extend the half-life of proteins. long-acting insulin. ChemMedChem. 2008;3:1189–1193. doi:10.1002/cmdc.200800053.
147. A.M.Miltenburg, M.Prohn, J.H.Van Kuijk, et al. Half-life prolongation of therapeutic proteins by conjugation to ATIII-binding pentasaccharides: a first-in-human study of CarboCarrier insulin. Br J Clin Pharmacol. 2015;75:1221–1230. doi:10.1111/j.1365-2125.2012.04460.x.
148. J.Harenberg, S.Marx, M.Krejczy, et al. New anticoagulants - promising and failed developments. Br J Pharmcol. 2012;165:363–372. doi:10.1111/j.1476-5381.2011.01578.x.