Erythropoietin: New approaches to improved molecular designs and therapeutic alternatives

Current Pharmaceutical Design

Volumn 14, Issue 13, 2008, Pages 1302-1310

  Debeljak, N ^a   Sytkowski, A J ^b  

^a UNIVERSITY OF LJUBLJANA   (Slovenia)

^b BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

Author keywords

Cancer; Erythropoietin; Erythropoietin receptor; Fusion proteins; Glycosylation; Heteroreceptor; Mimetics; Pegylation

Indexed keywords

ANTIANEMIC AGENT; CONTINUOUS ERYTHROPOIESIS RECEPTOR ACTIVATOR; ERYTHROPOIETIN; ERYTHROPOIETIN ANTIBODY; ERYTHROPOIETIN FC FUSION PROTEIN; ERYTHROPOIETIN GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR FUSION PROTEIN; ERYTHROPOIETIN INTERLEUKIN 3 FUSION PROTEIN; ERYTHROPOIETIN MIMETIC PEPTIDE; ERYTHROPOIETIN RECEPTOR; FG 2216; FG 4539; HYBRID PROTEIN; HYPOXIA INDUCIBLE FACTOR 1ALPHA; JANUS KINASE 2; MACROGOL; MIRCERA; NOVEL ERYTHROPOIESIS STIMULATING PROTEIN; OLIGOMER; PEPTIDE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN TYROSINE PHOSPHATASE SHP 1; PROTEIN TYROSINE PHOSPHATASE SHP 2; PT 401; RECOMBINANT ERYTHROPOIETIN; STAT5 PROTEIN; SYNTHETIC ERYTHROPOIESIS PROTEIN;

ANEMIA; APOPTOSIS; CANCER CELL CULTURE; CLINICAL TRIAL; DIMERIZATION; DRUG DESIGN; DRUG EFFICACY; DRUG FORMULATION; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; ERYTHROPOIESIS; HEMATOPOIESIS; HUMAN; IMMUNOGENICITY; IN VIVO STUDY; KIDNEY FAILURE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN GLYCOSYLATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; SITE DIRECTED MUTAGENESIS; SUSTAINED RELEASE FORMULATION; UNSPECIFIED SIDE EFFECT;

EID: 47349115466     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161208799316393     Document Type: Review

References (164)

1. Sytkowski AJ. Erythropoietin: Blood, brain and beyond. WILEY-VCH, Weinheim 2004.
2. Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, et al. Erythropoietin mediates tissue protection through an erythropoietin and common {beta}-subunit heteroreceptor. Proc Natl Acad Sci USA 2004; 101: 14907-12.
3. Bondurant MC, Koury MJ. Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Mol Cell Biol 1986; 6: 2731-3.
4. Jelkmann W. Renal erythropoietin: Properties and production. Rev Physiol Biochem Pharmacol 1986; 104: 139-215.
5. Bachmann S, Le Hir M, Eckardt KU. Co-localization of erythropoietin mRNA and ecto-5′-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin. J Histochem Cytochem 1993; 41: 335-41.
6. Maxwell PH, Ferguson DJ, Nicholls LG, Iredale JP, Pugh CW, Johnson MH, et al. Sites of erythropoietin production. Kidney Int 1997; 51: 393-401.
7. Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin. J Biol Chem 1977; 252: 5558-64.
8. Jacobs Y, Shoemaker C, Rudersdorf R, Neill SD, Kaufman RJ, Mufson A, et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 1985; 313: 806-10.
9. Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 1985; 82: 7580-4.
10. Powell JS, Berkner KL, Lebo RV, Adamson JW. Human erythropoietin gene: High level expression in stably transfected mammalian cells and chromosome localization. Proc Natl Acad Sci USA 1986; 83: 6465-9.
11. Wen D, Boissel J, Tracy T, Gruninger R, Mulcahy L, Czelusniak J, et al. Erythropoietin structure-function relationships: High degree of sequence homology among mammals. Blood 1993; 82: 1507-16.
12. Lai PH, Everett R, Wang FF, Arakawa T, Goldwasser E. Structural characterization of human erythropoietin. J Biol Chem 1986; 261: 3116-21.
13. Recny MA, Scoble HA, Kim Y. Structural characterization of natural human urinary and recombinant DNA-derived erythropoietin. Identification of des-arginine 166 erythropoietin. J Biol Chem 1987; 262: 17156-63.
14. Romanowski RR, Sytkowski AJ. The molecular structure of human erythropoietin. Hematol Oncol Clin North Am 1994; 8: 885-94.
15. Sytkowski AJ, Feldman L, Zurbuth DJ. Biological activity and structural stability of N-deglycosylated recombinant human erythropoietin. Biochem Biophys Res Commun 1991; 176: 698-704.
16. Delorme E, Lorenzini T, Giffin J, Martin F, Jacobsen F, Boone T, et al. Role of glycosylation on the secretion and biological activity of erythiopoietin. Biochemistry 1992; 31: 9871-6.
17. Dube S, Fisher JW, Powell JS. Glycosylation at specific sites of erythropoietin is essential for biosynthesis, secretion, and biological function. J Biol Chem 1988; 263: 17516-21.
18. Briggs DW, Fisher JW, George WJ. Hepatic clearance of intact and desialylated erythropoietin. Am J Physiol 1974; 227: 1385-8.
19. Fukuda MN, Sasaki H, Lopez L, Fukuda M. Survival of recombinant erythropoietin in the circulation: The role of carbohydrates. Blood 1989; 73: 84-9.
20. Tsuda E, Goto M, Murakami A, Akai K, Ueda M, Kawanishi G, et al. Comparative structural study of n-linked oligosaccharides of urinary and recombinant erythropoietins. Biochemistry 1988; 27: 5646-54.
21. Toyoda T, Arakawa T, Yamaguchi H. N-glycans stabilize human erythropoietin through hydrophobic interactions with the hydrophobic protein surface: Studies by surface plasmon resonance analysis. J Biochem (Tokyo) 2002; 131: 511-5.
22. Imai N, Kawamura A, Higuchi M, Oh-eda M, Orita T, Kawaguchi T. et al. Physicochemical and biological comparison of recombinant human erythropoietin with human urinary erythropoietin. J Biochem. (Tokyo) 1990; 107: 352-9.
23. Skibeli V, Nissen-Lie G, Torjesen P. Sugar profiling proves that human serum erythropoietin differs from recombinant human erythropoietin. Blood 2001; 98: 3626-34.
24. Lasne F, Martin L, Martin JA, de Ceaurriz J. Isoelectric profiles of human erythropoietin are different in serum and urine. Int J Biol Macromol 2007; 41: 354-7.
25. Boissel JP, Bunn HF. Erythropoietin structure-function relationships. Prog Clin Biol Res 1990; 352: 227-32.
26. Boissel J, Lee W. Presnell S, Cohen F, Bunn H. Erythropoietin structure-function relationships. Mutant proteins that test a model of tertiary structure. J Biol Chem 1993; 268: 15983-93.
27. Syed RS, Reid SW, Li C, Cheetham JC, Aoki KR, Liu B, et al. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature 1998; 395: 511-6.
28. Cheetham JC, Smith DM, Aoki KH, Stevenson JL, Hoeffel TJ, Syed RS, et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation. Nat Struct Biol 1998; 5: 861-6.
29. Grodberg J, Davis KL, Sytkowski AJ. Alanine scanning mutagenesis of human erythropoietin identifies four amino acids which are critical for biological activity. Eur J Biochem 1993; 218: 597-601.
30. Wen D, Boissel J, Showers M, Ruch B, Bunn H. Erythropoietin structure-function relationships. Identification of functionally important domains. J Biol Chem 1994; 269: 22839-46.
31. Philo JS, Aoki KH, Arakawa T, Narhi LO, Wen J. Dimerization of the extracellular domain of the erythropoietin (Epo) receptor by Epo: One high-affinity and one low-affinity interaction. Biochemistry 1996; 35: 1681-91.
32. Jones SS, D'Andrea AD, Haines LL, Wong GG. Human erythropoietin receptor: Cloning, expression, and biologic characterization. Blood 1990; 76: 31-5.
33. Winkelmann J, Penny L, Deaven L, Forget B, Jenkins R. The gene for the human erythropoietin receptor. Analysis of the coding sequence and assignment to chromosome 19p. Blood 1990; 76: 24-30.
34. Bailey SC, Feldman L, Romanowski RR, Davis KL, Sytkowski AJ. Antipeptide antibodies as probes of the recombinant and endogenous murine erythropoietin receptors. Exp Hematol 1993; 21: 1535-43.
35. Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA 1990; 87: 6934-8.
36. Watowich SS, Wu H, Socolovsky M, Klingmuller U, Constantinescu SN, Lodish HF. Cytokinc receptor signal transduction and the control of hematopoietic cell development. Annu Rev Cell Devel Biol 1996; 12: 91-128.
37. McCaffery PJ, Fraser JK, Lin FK, Berridge MV. Subunit structure of the erythropoietin receptor. J Biol Chem 1989; 264: 10507-12.
38. Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Silvennoinen O. Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol 1995; 13: 369-98.
39. Yoshimura A, Zimmers T, Neumann D, Longmore G, Yoshimura Y, Lodish HF. Mutations in the Trp-Ser-X-Trp-Ser motif of the erythropoietin receptor abolish processing, ligand binding, and activation of the receptor. J Biol Chem 1992; 267: 11619-25.
40. Quelle DE, Quelle FW, Wojchowski DM. Mutations in the WSAWSE and cytosolic domains of the erythropoietin receptor affect signal transduction and ligand binding and internalization. Mol Cell Biol 1992; 12: 4553-61.
41. O'Neal KD, Yu-Lec LY. The proline-rich motif (PRM): A novel feature of the cytokine/hematopoietin receptor superfamily. Lymphokine Cytokine Res 1993; 12: 309-12.
42. Miller CP, Liu ZY, Noguchi CT, Wojchowski DM. A minimal cytoplasmic subdomain of the erythropoietin receptor mediates erythroid and megakaryocytic cell development. Blood 1999; 94: 3381-7.
43. Watowich SS. Activation of erythropoietin signaling by receptor dimerization. Int J Biochem Cell Biol 1999; 31: 1075-88.
44. Frank SJ. Minireview: Receptor dimerization in GH and erythropoietin action-it takes two to tango, but how? Endocrinology 2002; 143: 2-10
45. Remy I, Wilson IA, Michnick SW. Erythropoietin receptor activation by a ligand-induced conformation change. Science 1999; 283: 990-3.
46. Livnah O, Stura EA, Middleton SA, Johnson DL, Jolliffe LK, Wilson IA. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science 1999; 283: 987-90.
47. Constantinescu SN, Keren T, Socolovsky M, Nam H-S, Henis YI, Lodish HF. Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain. Proc Natl Acad Sci USA 2001; 98: 4379-84.
48. Wilson IA, Jolliffe LK. The structure, organization, activation and plasticity of the erythropoietin receptor. Curr Opin Struct Biol 1999; 9: 696-704.
49. Richmond TD, Chohan M, Barber DL. Turning cells red: Signal transduction mediated by erythropoietin. Trends Cell Biol 2005; 15: 146-55.
50. Debeljak N, Sytkowski AJ. EpoR. UCSD-nature molecule pages 2007: A000863.
51. Jelkmann W, Wagner K. Beneficial and ominous aspects of the pleiotropic action of erythropoietin. Ann Hematol 2004; 83: 673-86.
52. Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA 2005; 293: 90-5.
53. Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci USA 1990; 87: 5978-82.
54. Carlini RG, Reyes AA, Rothstein M. Recombinant human erythropoietin stimulates angiogencsis in vitro. Kidney Int 1995; 47: 740-5
55. Chong ZZ, Kang JQ, Maiese K. Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation 2002; 106: 2973-9.
56. Fuste B, Serradell M, Escolar G, Cases A, Mazzara R, Castillo R, et al. Erythropoietin triggers a signaling pathway in endothelial cells and increases the thrombogenicity of their extracellular matrices in vitro. Thromb Haemost 2002; 88: 678-85.
57. Haroon ZA, Amin K, Jiang X, Arcasoy MO. A novel role for erythropoietin during fibrin-induced, wound-healing response. Am J Pathol 2003; 163: 993-1000.
58. Buemi M, Galeano M, Sturiale A, Ientile R, Crisafulli C, Parisi A, et al. Recombinant human crythropoietin stimulates angiogenesis and healing of ischemic skin wounds. Shock 2004; 22: 169-73.
59. Galeano M, Altavilla, D, Cucinotta D, Russo GT, Calo M, Bitto A, et al. Recombinant human erythropoietin stimulates angiogenesis and wouncd healing in the genetically diabetic mouse. Diabetes 2004; 53: 2509-17.
60. Anagnostou A, Liu Z, Steiner M, Chin K, Lee ES, Kessimian N, et al. Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci USA 1994; 91: 3974-8.
61. Akimoto T, Kusano, E, Inaba T, Iimura, O, Takahashi H, Ikeda H, et al. Erythropoietin regulates vascular smooth muscle cell apoptosis by a phosphatidylinasitol 3 kinase-dependent pathway. Kidney Int 2000; 58: 269-82.
62. Ammarguellat F, Gogusev J, Drueke TB. Direct effect of erythropoietin on rat vascular smooth-muscle cell via a putative erythropoietin receptor. Nephrol Dial Transplant 1996; 11: 687-92.
63. Tramontano AF, Muniyappa R, Black AD, Blendea MC, Cohen I, Deng L, et al. Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun 2003; 108: 990-4.
64. Lipsic E, Schoemaker RG, van der Meer P, Voors AA, van Veldhuisen DJ, van Gilst WH. Protective effects of erythropoietin in cardiac ischemia: From bench to bedside. J Am College Cardiol 2006; 48: 2161-7.
65. Wu H, Lee SH, Gao, J, Liu X, Iruela-Arispe ML. Inactivation of erythropoietin leads to defects in cardiac morphogentsis. Development 1999; 126: 3597-605.
66. Suzuki N, Ohneda O, Takahashi S, Higuchi M, Mukai HY, Nakahata T, et al. Erythroid-specific expression of the erythropoicetin receptor rescued its null mutant mice from lethality. Blood 2002; 100: 2279-88
67. Tan CC, Eckardt KU, Firth JD, Ratcliffe PJ. Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am J Physiol Renal Physiol 1992; 263: F474-81.
68. Digicaylioglu M, Bichet S, Marti H, Wenger R, Rivas L, Bauer C, et al. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci USA 1995; 92: 3717-20.
69. Marti HH, Wenger RH, Rivas LA, Straumann U, Digicaylioglu M, Henn V, et al. Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci 1996; 8: 666-76.
70. Juul SE, Yachnis AT, Rojiani AM, Christensen RD. Immunohistochemical localization of erythropoietin and its receptor in the developing human brain. Pediatr Dev Pathol 1999; 2: 148-58.
71. Koshimura K, Murakami Y, Sohmiya M, Tanaka J, Kato Y. Effects of erythropoietin on neuronal activity. J Neurochem 1999; 72: 2565-72.
72. Assandri R, Egger M, Gassmann M, Niggli E, Bauer C, Forster I, et al. Erythropoietin modulates intracellular calcium in a human neuroblastoma cell line. J Physiol 1999; 516(Pt 2): 343-52.
73. Sugawa M, Sakurai Y, Ishikawa-Ieda Y, Suzuki H, Asou H. Effects of erythropoietin on glial cell development; oligodendrocyte maturation and astrocyte proliferation. Neurosci Res 2002; 44: 391-403.
74. Brines ML, Ghezzi P, Keenan N, Agnello D, de Lanerolle NC, Cerami C, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000; 97: 10526-31.
75. Marti HH. Erythropoietin and the hypoxic brain. J Exp Biol 2004; 207: 3233-42.
76. Junk AK, Mammis A, Savitz SI, Singh M, Roth S, Malhotra S, et al. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci USA 2002; 99: 10659-64.
77. Siren A-L, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 2001; 98: 4044-9.
78. Agnello D, Bigini P, Villa P, Mennini T, Cerami A, Brines ML, et al. Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis. Brain Res 2002; 952: 128-34.
79. Chong ZZ, Kang J-Q, Maiese K. Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades. J Cereb Blood Flow Metab 2002; 22: 503-14.
80. Kling PJ, Sullivan TM, Roberts RA, Philipps AF, Koldovsky O. Human milk as a potential enteral source of erythropoietin. Pediatr Res 1998; 43: 216-21.
81. Semba RD, Juul SE. Erythropoietin in human milk: Physiology and role in infant health. J Hum Lact 2002; 18: 252-61.
82. Kling PJ. Roles of erythropoietin in human milk. Acta Paediatr Suppl 2002; 91: 31-5.
83. Juul SE, Zhao Y, Dame JB, Du Y, Hutson AD, Christensen RD. Origin and fate of erythropoietin in human milk. Pediatr Res 2000; 48: 660-7.
84. Itoh K, Sawasaki Y, Takeuchi K, Kato S, Imai N, Kato Y, et al. Erythropoietin-induced proliferation of gastric mucosal cells. World J Gastroenterol 2006; 12: 234-9.
85. Venkatesan N, Uchino K, Amagase K, Ito Y, Shibata N, Takada K. Gastro-intestinal patch system for the delivery of erythropoietin. J Controlled Release 2006; 111: 19-26.
86. Ito Y, Venkatesan N, Hirako N, Sugioka N, Takada K. Effect of fiber length of carbon nanotubes on the absorption of erythropoietin from rat small intestine. Int J Pharm 2007; 337: 357-60.
87. Maitani Y, Moriya H, Shimoda N, Takayama K, Nagai T. Distribution characteristics of entrapped recombinant human erythropoietin in liposomes and its intestinal absorption in rats. Int J Pharm 1999; 185: 13-22.
88. Juul SE, Ledbetter DJ, Joyce AE, Dame C, Christensen RD, Zhao Y, et al. Erythropoietin acts as a trophic factor in neonatal rat intestine. Gut 2001; 49: 182-9.
89. Kumral A, Baskin H, Duman N, Yilmaz O, Tatli M, Ozer E, et al. Erythropoietin protects against necrotizing enterocolitis of newborn rats by the inhibiting nitric oxide formation. Biol Neonate 2003; 84: 325-9.
90. Ozer EA, Kurmal A, Ozer E, Yilmaz O, Duman N, Ozkal S, et al. Effects of erythropoietin on hyperoxic lung injury in neonatal rats. Pediatr Res 2005; 58: 38-41.
91. Koroglu TF, Yilmaz O, Ozer E, Baskin H, Gokmen N, Kumral A, et al. Erythropoietin attenuates lipopolysaccharide-induced splenic and thymic apoptosis in rats. Physiol Res 2006; 55: 309-16.
92. Westenfelder C, Biddle DI, Baranowski RL. Human, rat, and mouse kidney cells express functional erythropoietin receptors. Kidney Int 1999; 55: 808-20.
93. Fenjves ES, Ochoa MS, Cabrera O, Mendez AJ, Kenyon NS, Inverardi L, et al. Human, nonhuman primate, and rat pancreatic islets express erythropoietin receptors. Transplantation 2003; 75: 1356-60.
94. Magnanti M, Gandini O, Giuliani L, Gazzaniga P, Marti HH, Gradilone A, et al. Erythropoietin expression in primary rat Sertoli and peritubular myoid cells. Blood 2001; 98: 2872-4.
95. Yamazaki T, Kanzaki M, Karnidono, S, Fujisawa M. Effect of erythropoietin on Leydig cell is associated with the activation of stat5 pathway. Mol Cell Endocrinol 2004; 213: 193-8.
96. Temma K, Shimoya K, Hashimoto K, Zhang Q, Koyama M, Murata Y. Detection of erythropoietin in human seminal plasma. Fertil Steril 2004; 81: 798-801.
97. Conrad KP, Benyo DF, Westerhausen-Larsen A, Miles TM. Expression of erythropoietin by the human placenta. FASEB J 1996; 10: 760-8.
98. Masuda S, Kobayashi T, Chikuma M, Nagao M, Sasaki R. The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner. Am J Physiol Endocrinol Metab 2000; 278: E1038-44.
99. Yasuda Y, Masuda S, Chikuma M, Inoue K, Nagao M, Sasaki R. Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J Biol Chem 1998; 273: 25381-7
100. Juul SE, Yachnis AT, Christensen RD. Tissue distribution of erythropoietin and erythropoietin receptor in the developing human fetus. Early Human Dev 1998; 52: 235-49.
101. Udupa KB. Functional significance of erythropoietin receptor on tumor cells. World J Gastroenterol 2006; 12: 7460-2.
102. Farrell F, Lee A. The erythropoietin receptor and its expression in tumor cells and other tissues. Oncologist 2004; 9: 18-30.
103. Hardee ME, Arcasoy MO, Blackwell KL, Kirkpatrick JP, Dewhirst MW. Erythropoietin biology in cancer. Clin Cancer Res 2006; 12: 332-9.
104. Sytkowski AJ. Does erythropoietin have a dark side? Epo signaling and cancer cells. Sci STKE 2007: Stke.3952007pe38.
105. Osterberg A, Aapro M, Cornes P, Haselbeck A, Hayward CR, Jelkmann W. Preclinical studies of erythropoietin receptor expression in tumour cells: Impact on clinical use of erythropoietic proteins to correct cancer-related anaemia. Eur J Cancer 2007; 43: 510-9.
106. Arcasoy MO, Jiang X, Haroon ZA. Expression of erythropoietin receptor splice variants in human cancer. Biochem Biophys Res Commun 2003; 307: 999-1007.
107. Masuda S, Nagao M, Takahata K, Konishi Y, Gallyas F Jr, Tabira T, et al. Functional erythropoietin receptor of die cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem 1993; 268: 11208-16.
108. Jubinsky PT, Krijanovski OI, Nathan DG, Tavernier J, Sieff CA. The beta chain of the interleukin-3 receptor functionally associates with die erythropoietin receptor. Blood 1997; 90: 1867-73.
109. Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ 2004; 11 (Suppl 1): S37-44.
110. Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 2004; 305: 239-42.
111. Morlock M, Kissel T, Li YX, Koll H, Winter G. Erythropoietin loaded microspheres preared from biodegradable LPLG-PEO-LPLG triblock copolymers: Protein stabilization and in-vitro release properties. J Control Release 1998; 56: 105-15.
112. Piatel KF, Bittner B, Koll H, Winter G, Kissel T. Biodegradable recombinant human erythropoietin loaded microspheres prepared from linear and star-branched block copolymers: Influence of encapsulation technique and polymer composition an particle characteristics. J Control Release 1999; 59: 309-25.
113. Qiu B, Stefanos S, Ma J, Lalloo A, Perry BA, Leibowitz MJ, et al. A hydrogel prepared by in situ cross-linking of a thiol-containing poly(ethylene glycol)-based copolymer A new biomaterial for protein drug delivery. Biomaterials 2003; 24: 11-8.
114. Egrie JC, Dwyer I, Browne JK, Hitz A, Lykes MA. Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Exp Hematol 2003; 31: 290-9.
115. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant 2001; 16: 3-13.
116. Gross AW, Lodish HF. Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem 2006; 281: 2024-32.
117. Delgado C, Francis GE, Fisher D. The uses and properties of PEG-linked proteins. Crit Rev Ther Drug Carrier Syst 1992; 9: 249-304.
118. Knusli C, Delgado C, Malik F, Domine M, Tejedor MC, Irvine AE, et al. Polyethylene glycol (PEG) modification of granulocytemacrophage colony stimulating factor (GM-CSF) enhances neutrophil priming activity but not colony stimulating activity. Br J Haematol 1992; 82: 654-63.
119. Pettit DK, Bonnert TP, Eisenman J, Srinivasan S, Paxton R, Beers C, et al. Structure-function studies of interleukin 15 using site-specific mutagenesis, polyethylene glycol conjugation, and homology modeling. J Biol Chem 1997; 272: 2312-8.
120. Tsutsumi Y, Tsunoda S, Kamada H, Kihira T, Kaneda Y, Ohsugi Y, et al. Pegylation of interleukin-6 effectively increases its thrombopoietic potency. Thromb Haemost 1997; 77: 168-73.
121. Haselbeck A, Bailon P, Pahlke W, Brandt M, Grol M. The discovery and characterization of CERA, an innovative agent for the treatment of anemia. Blood 2002; 100: 227a.
122. Haselbeck A, Tarc N, Pill J. Pre-clinical pharmacokinetics and pharmacodynamics of CERA (continuous erythropoiesis receptor activator) indicate a superior new therapy for anemia. Blood 2002; 100: 228a.
123. Kochendoerfer GG, Chen SY, Mao F, Cressman S, Traviglia S, Shao H, et al. Design and chemical synthesis of a homogeneous polymer-modified erythropoiesis protein. Science 2003, 299. 884-7.
124. Sytkowski AJ, Lunn ED, Davis KL, Feldman L, Siekman S. Human erythropoietin dimers with markedly enhanced in vivo activity. Proc Natl Acad Sci USA 1998; 95: 1184-8.
125. Sytkowski AJ, Lunn ED, Risinger MA, Davis KL. An erythropoietin fusion protein comprised of identical repeating domains exhibits enhanced biological properties. J Biol Chem 1999; 274: 24773-8.
126. Weich NS, Tullai J, Guido E, McMahon M, Jolliffe LK, Lopez AF, et al. Interleukin-3/erythropoietin fusion proteins: In vitro effects on hematopoietic cells. Exp Hematol 1993; 21: 647-55.
127. Coscarella, A, Carloni C, Liddi R, Mauro S, Novelli S, Mele A, et al. Production of recombinant human GM-CSF-Epo hybrid proteins: In vitro biological characterization. Eur J Haematol 1997; 59: 238-46
128. Coscarella A, Liddi R, Di Loreto M, Bach S, Faiella A, van der Meide PH, et al. The rhGM-CSF-Epo hybrid protein MEN 11300 induces anti-Epo antibodies and severe anaemia in rhesus monkeys. Cytokine 1998; 10: 964-9.
129. Zheng XX, Steele AW, Hancock WW, Stevens AC, Nickerson PW, Roy-Chaudhury P, et al. A noncytolytic IL-10/Fc fusion protein prevents diabetes, blocks autoimmunity, and promotes suppressor phenomena in nod mice. J Immunol 1997; 158: 4507-13.
130. Kim YS, Maslinski W, Zheng XX, Stevens AC, Li XC, Tesch GH, et al. Targeting the IL-15 receptor with an antagonist IL-15 mutant/Fc gamma2a protein blocks delayed-type hypersensitivity. J Immunol 1998; 160: 5742-8.
131. Feng X. Zheng XX, Yi S. Lehnert AM, Strom TB, O'Connell PJ. IL-10/Fc inhibits macrophage function and prolongs pancreatic islet xenograft survival. Transplantation 1999; 68: 1775-83.
132. Zheng XX, Steele AW, Hancock WW, Kawamoto K, Li XC, Nickerson PW, et al. IL-2 receptor-targeted cytolytic IL-2/Fc fusion protein treatment blocks diabotogenic autoimmunity in nonobese diabetic mice. J Immunol 1999; 163: 4041-8.
133. Ferrari-Lacraz S, Zheng XX, Kim YS, Li Y, Maslinski W, Li XC, et al. An antagonist IL-15/Fc protein prevents costimulation blockade-resistant rejection. J Immunol 2001; 167: 3478-85.
134. Ferrari-Lacraz S, Zheng XX, Kim YS, Maslinski W, Strom TB. Addition of an IL-15 mutant/Fcgamma2a antagonist protein protects islet allografts from rejection overriding costimulation blockade. Transplant Proc 2002; 34: 745-7.
135. Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS, et al. Receptor-mediated immunoglobulin g transport across mucosal barriers in adult life: Functional expression of FcRn in the mammalian lung. J Exp Med 2002; 196: 303-10.
136. Way JC, Lauder S, Brunkhorst B, Kong S-M, Qi A, Webster G, et al. Improvement of Fc-erythropoietin structure and pharmacokinetics by modification at a disulfide bond. Protein Eng Des Sel 2005; 18: 111-8.
137. Elliott S, Lorenzini T, Yanagihara D, Chang D, Elliott G. Activation of the erythropoietin (Epo) receptor by bivalent anti-Epo receptor antibodies. J Biol Chem 1996; 271: 24691-7.
138. Liu Z, Stoll VS, DeVries PJ, Jakob CG, Xie N, Simmer RL, et al. A potent erythropoietin mimic human antibody interacts through a novel binding site. Blood 2007; 110: 2408-13.
139. Wrighton NC, Farrell FX, Chang R, Kashyap AK, Barbone FP, Mulcahy LS, et al. Small peptides as potent mimetics of the protein hormone erythropoietin. Science 1996; 273: 458-63.
140. Wrighton NC, Balasubramanian P, Barbone FP, Kashyap AK, Farrell FX, Jolliffe LK, et al. Increased potency of an erythropoietin peptide mimetic through covalent dimerization. Nat Biotech 1997; 15: 1261-5
141. McConnell SJ, Dmh T, Le MH, Brown SJ, Becherer K, Blumeyer K, et al. Isolation of erythropoietin receptor agonist peptides using evolved phage libraries. Biol Chem 1998; 379: 1279-86.
142. Qureshi SA, Kim RN, Konteatis Z, Biazzo DE, Motamedi H, Rodrigues R, et al. Mimicry of erythropoietin by a nonpeptide molecule. Proc Natl Acad Sci USA 1999; 96: 12156-61.
143. Goldberg J, Jin Q, Ambroise Y, Satoh S, Desharnais J, Capps K, et al. Erythropoietin mimetics derived from solution phase combinatorial libraries. J Am Chem Soc 2002; 124: 544-55.
144. Fan Q, Leuther KK, Holmes CP, Fong KL, Zhang J, Velkovska S, et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol 2006; 34: 1303-11.
145. Macdougall IC. Recent advances in erythropoietic agents in renal anemia. Semin Nephrol 2006; 26: 313-8.
146. Stead RB, Lambert J, Wessels D, Iwashita JS, Leuther KK, Woodburn KW, et al. Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers. Blood 2006; 108: 1830-4.
147. Semenza GL. HIF-1, O2, and the 3 PhDs: How animal cells signal hypoxia to the nucleus. Cell 2001; 107: 1-3.
148. Semenza GL. Hydroxylation of HIF-1: Oxygen sensing at the molecular level. Physiology 2004; 19: 176-82.
149. Grodberg J, Davis KL, Sytkowski AJ. Functional and structural role of arginine 103 in human erythropoietin. Arch Biochem Biophys 1996; 333: 427-31.
150. Fiordaliso, F, Chimenti S, Staszewsky L, Bai A, Carlo E, Cuecovillo I, et al. A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury. Proc Natl Acad Sci USA 2005; 102: 2046-51.
151. Moon C, Krawczyk M, Paik D, Coleman T, Brines M, Juhaszova M, et al. Erythropoietin, modified to not stimulate red blood cell production, retains its cardioprotective properties. J Pharmacol Exp Ther 2006; 316: 999-1005.
152. Mennini T, De Paola M, Bigini P, Mastrotto C, Fumagalli E, Barbera S, et al. Nonhematopoietic erythropoietin derivatives prevent motoneuron degeneration in vitro and in vivo. Mol Med 2006; 12: 153-60.
153. King VR, Averill SA, Hewazy D, Priestley JV, Torup L, Michael-Titus AT. Erythropoietin and carbamylated erythropoietin are neuroprotective following spinal cord, hemisection in the rat. Eur J Neurosci 2007; 26: 90-100.
154. Elliott S, Busse L, Bass MB, Lu H, Sarosi I, Sinclair AM, et al. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 2006; 107: 1892-5.
155. Mohyeldin A, Lu H, Dalgard C, Lai SY, Cohen N, Acs G, et al. Erythropoietin signaling promotes iuvasiveness of human head and neck squamous cell carcinoma. Neoplasia 2005; 7: 537-43.
156. Lester RD, Jo M, Campana WM, Gonias SL. Erythropoietin promotes MCF-7 breast cancer cell migration by an Erk/mitogen-activated protein kinase-dependent pathway and is primarily responsible for the increase in migration observed in hypoxia. J Biol Chem 2005; 280: 39273-7.
157. Feldman L, Wang Y, Rhim JS, Bhattacharya N, Loda M, Sytkowski AJ. Erythropoietin stimulates growth and STAT5 phosphorylation in human prostate epithelial and prostate cancer cells. Prostate 2006; 66: 135-45.
158. Kumar SM, Yu H, Fong D, Acs G, Xu X. Erythropoietin activates the phosphoinositide 3-kinase/akt pathway in human melanoma cells. Melanoma Res 2006; 16: 275-83.
159. Dunlop EA, Percy MJ, Boland MP, Maxwell AP, Lappin TR. Induction of signalling in non-erythroid cells by pharmacological levels of erythropoietin. Neurodegener Dis 2006; 3: 94-100.
160. Jeong J-Y, Feldman L, Solar P, Szenajch J, Sytkowski AJ. Characterization of erythropoietin receptor and erythropoietin expression and function in human ovarian cancer cells. Int J Cancer 2008; 122: 274-80.
161. Solar P, Feldman L, Jeong J-Y, Busingye JR, Sytkowski AJ. Erythropoietin treatment of human ovarian cancer cells results in enhanced signaling and a paclitaxel-resistant phenotype. Int J Cancer 2008; 122: 281-8.
162. Henke M, Laszig R, Rube C, Schafer U, Haase KD, Schilcher B, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 2003; 362: 1255-60.
163. Leyland-Jones B, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol 2005; 23: 5960-72.
164. Overgaard J. Interim analysis of DAHANCA 10: Study of the importance of novel erythropoiesis stimulating protein (Aranesp®) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck. Danish Head and Neck Cancer Group: Aarhus 2006; pp. 1-3.