Experimental Hematology
Volume 36, Issue 12 , Pages 1573-1584 , December 2008

Erythropoietins: A common mechanism of action

  • Steve Elliott

      Affiliations

    • Amgen Inc, Thousand Oaks, Calif., USA
    • Corresponding Author InformationOffprint requests to: Steve Elliott, Ph.D., Amgen Inc., One Amgen Center, M/S 29-1-A, Thousand Oaks, CA 91320-1799
  • ,
  • Elizabeth Pham

      Affiliations

    • Amgen Inc, Thousand Oaks, Calif., USA
  • ,
  • Iain C. Macdougall

      Affiliations

    • Renal Unit, Kings College Hospital, London, UK

Received 20 June 2008 ,Revised 20 June 2008 ,Accepted 12 August 2008.

References 

  1. Erslev A. Humoral regulation of red cell production. Blood. 1953;8:349–357
  2. Lai PH, Everett R, Wang FF, Arakawa T, Goldwasser E. Structural characterization of human erythropoietin. J Biol Chem. 1986;261:3116–3121
  3. Kelley LL, Green WF, Hicks GG, Bondurant MC, Koury MJ, Ruley HE. Apoptosis in erythroid progenitors deprived of erythropoietin occurs during the G1 and S phases of the cell cycle without growth arrest or stabilization of wild-type p53. Mol Cell Biol. 1994;14:4183–4192
  4. Koury MJ, Bondurant MC. Maintenance by erythropoietin of viability and maturation of murine erythroid precursor cells. J Cell Physiol. 1988;137:65–74
  5. Lin FK, Suggs S, Lin CH, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A. 1985;82:7580–7584
  6. Skibeli V, Nissen-Lie G, Torjesen P. Sugar profiling proves that human serum erythropoietin differs from recombinant human erythropoietin. Blood. 2001;98:3626–3634
  7. Elliott S, Lorenzini T, Asher S, et al. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat Biotechnol. 2003;21:414–421
  8. Delorme E, Lorenzini T, Giffin J, et al. Role of glycosylation on the secretion and biological activity of erythropoietin. Biochemistry. 1992;31:9871–9876
  9. Egrie JC, Dwyer E, Browne JK, Hitz A, Lykos MA. Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Exp Hematol. 2003;31:290–299
  10. Macdougall IC, Robson R, Opatrna S, et al. Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous continuous erythropoietin receptor activator (C.E.R.A.) in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:1211–1215
  11. Locatelli F, Olivares J, Walker R, et al. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int. 2001;60:741–747
  12. Nissenson AR, Swan SK, Lindberg JS, et al. Randomized, controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients. Am J Kidney Dis. 2002;40:110–118
  13. Ling B, Walczyk M, Agarwal A, Carroll W, Liu W, Brenner R. Darbepoetin alfa administered once monthly maintains hemoglobin concentrations in patients with chronic kidney disease. Clin Nephrol. 2005;63:327–334
  14. Sulowicz W, Locatelli F, Ryckelynck JP, et al. Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. Clin J Am Soc Nephrol. 2007;2:637–646
  15. Canon JL, Vansteenkiste J, Bodoky G, et al. Randomized, double-blind, active-controlled trial of every-3-week darbepoetin alfa for the treatment of chemotherapy-induced anemia. J Natl Cancer Inst. 2006;98:273–284
  16. Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell. 1995;83:59–67
  17. Broudy VC, Lin N, Brice M, Nakamoto B, Papayannopoulou T. Erythropoietin receptor characteristics on primary human erythroid cells. Blood. 1991;77:2583–2590
  18. Sawada K, Krantz SB, Kans JS, et al. Purification of human erythroid colony-forming units and demonstration of specific binding of erythropoietin. J Clin Invest. 1987;80:357–366
  19. Koury ST, Bondurant MC, Koury MJ. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood. 1988;71:524–527
  20. Lacombe C, Da Silva JL, Bruneval P, et al. Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. J Clin Invest. 1988;81:620–623
  21. Maxwell PH, Osmond MK, Pugh CW, et al. Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int. 1993;44:1149–1162
  22. Koury ST, Bondurant MC, Koury MJ, Semenza GL. Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood. 1991;77:2497–2503
  23. Browne JK, Cohen AM, Egrie JC, et al. Erythropoietin: gene cloning, protein structure, and biological properties. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):693–702
  24. Erslev AJ. Erythropoietin titers in health and disease. Semin Hematol. 1991;28:2–7
  25. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst. 1999;91:1616–1634
  26. Eckardt KU, Boutellier U, Kurtz A, Schopen M, Koller EA, Bauer C. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia. J Appl Physiol. 1989;66:1785–1788
  27. Koury ST, Koury MJ, Bondurant MC, Caro J, Graber SE. Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration. Blood. 1989;74:645–651
  28. Elliott S, Egrie J, Browne J, et al. Control of rHuEPO biological activity: the role of carbohydrate. Exp Hematol. 2004;32:1146–1155
  29. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 1987;316:73–78
  30. Erslev AJ, Wilson J, Caro J. Erythropoietin titers in anemic, nonuremic patients. J Lab Clin Med. 1987;109:429–433
  31. Finch CA, Harker LA, Cook JD. Kinetics of the formed elements of human blood. Blood. 1977;50:699–707
  32. Hillman RS, Finch CA. Erythropoiesis: normal and abnormal. Semin Hematol. 1967;4:327–336
  33. Smith JA. Exercise, training and red blood cell turnover. Sports Med. 1995;19:9–31
  34. Sawyer ST, Krantz SB, Goldwasser E. Binding and receptor-mediated endocytosis of erythropoietin in Friend virus-infected erythroid cells. J Biol Chem. 1987;262:5554–5562
  35. Jones SS, D'Andrea AD, Haines LL, Wong GG. Human erythropoietin receptor: cloning, expression, and biologic characterization. Blood. 1990;76:31–35
  36. D'Andrea AD, Lodish HF, Wong GG. Expression cloning of the murine erythropoietin receptor. Cell. 1989;57:277–285
  37. Syed RS, Reid SW, Li C, et al. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature. 1998;395:511–516
  38. 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;35:1681–1691
  39. 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;271:24691–24697
  40. Elliott S, Lorenzini T, Chang D, Barzilay J, Delorme E. Mapping of the active site of recombinant human erythropoietin. Blood. 1997;89:493–502
  41. Constantinescu SN, Keren T, Socolovsky M, Nam H, Henis YI, Lodish HF. Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain. Proc Natl Acad Sci U S A. 2001;98:4379–4384
  42. Kubatzky KF, Liu W, Goldgraben K, Simmerling C, Smith SO, Constantinescu SN. Structural requirements of the extracellular to transmembrane domain junction for erythropoietin receptor function. J Biol Chem. 2005;280:14844–14854
  43. Seubert N, Royer Y, Staerk J, et al. Active and inactive orientations of the transmembrane and cytosolic domains of the erythropoietin receptor dimer. Mol Cell. 2003;12:1239–1250
  44. Krantz SB, Sawyer ST, Sawada KI. Purification of erythroid progenitor cells and characterization of erythropoietin receptors. Br J Cancer Suppl. 1988;9:31–35
  45. Sawada K, Krantz SB, Sawyer ST, Civin CI. Quantitation of specific binding of erythropoietin to human erythroid colony-forming cells. J Cell Physiol. 1988;137:337–345
  46. Fraser JK, Lin FK, Berridge MV. Expression of high affinity receptors for erythropoietin on human bone marrow cells and on the human erythroleukemic cell line, HEL. Exp Hematol. 1988;16:836–842
  47. Somervaille TC, Linch DC, Khwaja A. Growth factor withdrawal from primary human erythroid progenitors induces apoptosis through a pathway involving glycogen synthase kinase-3 and Bax. Blood. 2001;98:1374–1381
  48. Landschulz KT, Noyes AN, Rogers O, Boyer SH. Erythropoietin receptors on murine erythroid colony-forming units: natural history. Blood. 1989;73:1476–1486
  49. Mayeux P, Billat C, Jacquot R. The erythropoietin receptor of rat erythroid progenitor lens. Characterization and affinity cross-linkage. J Biol Chem. 1987;262:13985–13990
  50. Perrotta PL, Snyder EL. Non-infectious complications of transfusion therapy. Blood Rev. 2001;15:69–83
  51. Lasne F, de Ceaurriz J. Recombinant erythropoietin in urine. Nature. 2000;405:635
  52. Martin KJ. The first human cell line-derived erythropoietin, epoetin-delta (Dynepo), in the management of anemia in patients with chronic kidney disease. Clin Nephrol. 2007;68:26–31
  53. Heatherington AC. Clinical pharmacokinetic properties of rHuEpo: a review. In:  Molineux G,  Foot MA,  Elliott SG editor. Erythropoietins and Erythropoiesis Molecular, Cellular, Preclinical, and Clinical Biology. Boston: Birkhäuser Basel; 2003;p. 87–112
  54. Veng-Pedersen P, Chapel S, Al-Huniti NH, et al. Pharmacokinetic tracer kinetics analysis of changes in erythropoietin receptor population in phlebotomy-induced anemia and bone marrow ablation. Biopharm Drug Dispos. 2004;25:149–156
  55. Veng-Pedersen P, Widness JA, Pereira LM, Schmidt RL, Lowe LS. A comparison of nonlinear pharmacokinetics of erythropoietin in sheep and humans. Biopharm Drug Dispos. 1999;20:217–223
  56. Kinoshita H, Ohishi N, Kato M, Tokura S, Okazaki A. Pharmacokinetics and distribution of recombinant erythropoietin in rats. Arzneimittelforschung. 1992;42:174–178
  57. Kato M, Kamiyama H, Okazaki A, Kumaki K, Kato Y, Sugiyama Y. Mechanism for the nonlinear pharmacokinetics of erythropoietin in rats. J Pharmacol Exp Ther. 1997;283:520–527
  58. Agoram B, Molineux G, Jang G, et al. Effects of altered receptor binding activity on the clearance of erythropoiesis-stimulating proteins: a minor role of erythropoietin receptor-mediated pathways. [abstract] Nephrol Dial Transplant. 2006;21:iv303–iv304. Abstract MP013
  59. Dinkelaar RB, Engels EY, Hart AA, Schoemaker LP, Bosch E, Chamuleau RA. Metabolic studies on erythropoietin (EP): II. The role of liver and kidney in the metabolism of Ep. Exp Hematol. 1981;9:796–803
  60. Jensen JD, Jensen LW, Madsen JK, Poulsen L. The metabolism of erythropoietin in liver cirrhosis patients compared with healthy volunteers. Eur J Haematol. 1995;54:111–116
  61. Macdougall IC, Roberts DE, Coles GA, Williams JD. Clinical pharmacokinetics of epoetin (recombinant human erythropoietin). Clin Pharmacokinet. 1991;20:99–113
  62. Yoon WH, Park SJ, Kim IC, Lee MG. Pharmacokinetics of recombinant human erythropoietin in rabbits and 3/4 nephrectomized rats. Res Commun Mol Pathol Pharmacol. 1997;96:227–240
  63. Widness JA, Veng-Pedersen P, Schmidt RL, Lowe LS, Kisthard JA, Peters C. In vivo 125I-erythropoietin pharmacokinetics are unchanged after anesthesia, nephrectomy and hepatectomy in sheep. J Pharmacol Exp Ther. 1996;279:1205–1210
  64. Gross AW, Lodish HF. Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem. 2006;281:2024–2032
  65. Chapel S, Veng-Pedersen P, Hohl RJ, Schmidt RL, McGuire EM, Widness JA. Changes in erythropoietin pharmacokinetics following busulfan-induced bone marrow ablation in sheep: evidence for bone marrow as a major erythropoietin elimination pathway. J Pharmacol Exp Ther. 2001;298:820–824
  66. Chapel SH, Veng-Pedersen P, Schmidt RL, Widness JA. Receptor-based model accounts for phlebotomy-induced changes in erythropoietin pharmacokinetics. Exp Hematol. 2001;29:425–431
  67. Glaspy J, Henry D, Patel R, et al. Effects of chemotherapy on endogenous erythropoietin levels and the pharmacokinetics and erythropoietic response of darbepoetin alfa: a randomised clinical trial of synchronous versus asynchronous dosing of darbepoetin alfa. Eur J Cancer. 2005;41:1140–1149
  68. Flaharty KK. Clinical pharmacology of recombinant human erythropoietin (r-HuEPO). Pharmacotherapy. 1990;10:9S–14S
  69. Porter CJ, Charman SA. Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci. 2000;89:297–310
  70. Agoram B, Sutjandra L, Molineux G, Jang G, Elliott S. Tissue distribution and excretion of 125I-darbepoetin alfa in Sprague Dawley rats following a single subcutaneous or intravenous administration abstract]. Nephrol Dial Transpl. 2006;21:iv304. Abstract MP014
  71. Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov. 2002;1:457–462
  72. Sasu BJ, Hartley C, Schultz H, et al. Comparison of epoetin alfa and darbepoetin alfa biological activity under different administration schedules in normal mice. Acta Haematol. 2005;113:163–174
  73. Elliott SG. New molecules and formulations of recombinant human erythropoietin. In:  Molineux G,  Foot MA,  Elliott SG editor. Erythropoietins and Erythropoiesis Molecular, Cellular, Preclinical, and Clinical Biology. Boston: Birkhäuser Basel; 2003;p. 241–258
  74. Egrie J, Browne J. Darbepoetin alfa is more potent in vivo and can be administered less frequently than rHuEPO. Br J Cancer. 2002;87:476–477
  75. Macdougall IC, Eckardt KU. Novel strategies for stimulating erythropoiesis and potential new treatments for anaemia. Lancet. 2006;368:947–953
  76. Bunn HF. New agents that stimulate erythropoiesis. Blood. 2007;109:868–873
  77. Chen SA, Sawchuk RJ, Brundage RC, et al. Plasma and lymph pharmacokinetics of recombinant human interleukin-2 and polyethylene glycol-modified interleukin-2 in pigs. J Pharmacol Exp Ther. 2000;293:248–259
  78. Kochendoerfer G. Chemical and biological properties of polymer-modified proteins. Expert Opin Biol Ther. 2003;3:1253–1261
  79. Darling RJ, Kuchibhotla U, Glaesner W, Micanovic R, Witcher DR, Beals JM. Glycosylation of erythropoietin affects receptor binding kinetics: role of electrostatic interactions. Biochemistry. 2002;41:14524–14531
  80. Rush RS, Derby PL, Strickland TW, Rohde MF. Peptide mapping and evaluation of glycopeptide microheterogeneity derived from endoproteinase digestion of erythropoietin by affinity high-performance capillary electrophoresis. Anal Chem. 1993;65:1834–1842
  81. Sasaki H, Bothner B, Dell A, Fukuda M. Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. J Biol Chem. 1987;262:12059–12076
  82. Takeuchi M, Kobata A. Structures and functional roles of the sugar chains of human erythropoietins. Glycobiology. 1991;1:337–346
  83. Macdougall IC, Gray SJ, Elston O, et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999;10:2392–2395
  84. Tolman C, Richardson D, Bartlett C, Will E. Structured conversion from thrice weekly to weekly erythropoietic regimens using a computerized decision-support system: a randomized clinical study. J Am Soc Nephrol. 2005;16:1463–1470
  85. Locatelli F, Canaud B, Giacardy F, Martin-Malo A, Baker N, Wilson J. Treatment of anaemia in dialysis patients with unit dosing of darbepoetin alfa at a reduced dose frequency relative to recombinant human erythropoietin (rHuEpo). Nephrol Dial Transplant. 2003;18:362–369
  86. Yamaoka T, Tabata Y, Ikada Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci. 1994;83:601–606
  87. Basser RL, O'Flaherty E, Green M, et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood. 2002;99:2599–2602
  88. Francis GE, Fisher D, Delgado C, Malik F, Gardiner A, Neale D. PEGylation of cytokines and other therapeutic proteins and peptides: the importance of biological optimisation of coupling techniques. Int J Hematol. 1998;68:1–18
  89. Long DL, Doherty DH, Eisenberg SP, et al. Design of homogeneous, monopegylated erythropoietin analogs with preserved in vitro bioactivity. Exp Hematol. 2006;34:697–704
  90. Macdougall IC. CERA (Continuous Erythropoietin Receptor Activator): a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep. 2005;4:436–440
  91. Jarsch M, Brandt M, Lanzendorfer M, Haselbeck A. Comparative erythropoietin receptor binding kinetics of C.E.R.A. and epoetin-beta determined by surface plasmon resonance and competition binding assay. Pharmacology. 2007;81:63–69
  92. Goodson RJ, Katre NV. Site-directed pegylation of recombinant interleukin-2 at its glycosylation site. Biotechnology (N Y). 1990;8:343–346
  93. He XH, Shaw PC, Tam SC. Reducing the immunogenicity and improving the in vivo activity of trichosanthin by site-directed pegylation. Life Sci. 1999;65:355–368
  94. Chen SY, Cressman S, Mao F, et al. Synthetic erythropoietic proteins: tuning biological performance by site-specific polymer attachment. Chem Biol. 2005;12:371–383
  95. Jolling K, Ruixo JJ, Hemeryck A, Piotrovskij V, Greway T. Population pharmacokinetic analysis of pegylated human erythropoietin in rats. J Pharm Sci. 2004;93:3027–3038
  96. Stead RB, Lambert J, Wessels D, 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;108:1830–1834
  97. Fan Q, Leuther KK, Holmes CP, et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol. 2006;34:1303–1311
  98. Macdougall IC, Temple RM, Kwan JT. Is early treatment of anaemia with epoetin-alpha beneficial to pre-dialysis chronic kidney disease patients? Results of a multicentre, open-label, prospective, randomized, comparative group trial. Nephrol Dial Transplant. 2007;22:784–793
  99. Revicki DA, Brown RE, Feeny DH, et al. Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis. 1995;25:548–554
  100. Perlman RL, Finkelstein FO, Liu L, et al. Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the Renal Research Institute-CKD study. Am J Kidney Dis. 2005;45:658–666
  101. Roger SD, McMahon LP, Clarkson A, et al. Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4): results of a randomized clinical trial. J Am Soc Nephrol. 2004;15:148–156
  102. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–2098
  103. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–2084
  104. Ross SD, Allen IE, Henry DH, Seaman C, Sercus B, Goodnough LT. Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy-induced anemia: a systematic review of the literature. Clin Ther. 2006;28:801–831
  105. Provenzano R, Bhaduri S, Singh AK. Extended epoetin alfa dosing as maintenance treatment for the anemia of chronic kidney disease: the PROMPT study. Clin Nephrol. 2005;64:113–123
  106. Benz R, Schmidt R, Kelly K, Wolfson M. Epoetin alfa once every 2 weeks is effective for initiation of treatment of anemia of chronic kidney disease. Clin J Am Soc Nephrol. 2007;2:215–221
  107. Locatelli F, Pisoni RL, Combe C, et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2004;19:121–132
  108. Molineux G. Biology of erythropoietin In: Molineux G. In:  Foot MA,  Elliott SG editor. Erythropoietins and Erythropoiesis Molecular, Cellular, Preclinical, and Clinical Biology. Boston, MA: Birkhäuser Basel; 2003;p. 113–132

 S.E. and E.P. are employees of Amgen. I.C.M. has received support grants from Amgen Inc, Ortho Biotech, Roche, and Affymax, and is a consultant for Amgen Inc, Ortho Biotech, Roche, and Affymax.

PII: S0301-472X(08)00388-3

doi: 10.1016/j.exphem.2008.08.003

Experimental Hematology
Volume 36, Issue 12 , Pages 1573-1584 , December 2008