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• W1963516841 abstract "Clinical development of erythropoiesis-stimulating agents (ESAs) revolutionized the management of anemia. The major clinical benefits of ESAs are effective treatment of anemia and avoidance of blood transfusion risks. Erythropoietin (EPO) interacts directly with the EPO receptor on the red blood cell (RBC) surface, triggering activation of several signal transduction pathways, resulting in the proliferation and terminal differentiation of erythroid precursor cells and providing protection from RBC precursor apoptosis. The magnitude of increase in RBC concentration in response to administration of recombinant human EPO products (rhEPO) is primarily controlled by the length of time EPO concentrations are maintained, not by the EPO concentration level. Subcutaneous (SC) EPO administration results in slower absorption than intravenous (IV) administration, leading to lower peak plasma levels and an apparent extended terminal half-life. However, SC administration requires additional needle-sticks and is associated with an increased risk of immunogenicity compared with IV administration. Multiple pathways may play a role in EPO clearance from the body. Epoetin alfa was the first rhEPO produced and approved for pharmaceutical use, followed by several related products and by newer ESAs with the same mechanism but more prolonged action. Darbepoetin alfa is a hyperglycosylated EPO analog with an extended terminal half-life and a greater relative potency compared with rhEPO at extended dosing intervals. PEGylation of EPO (addition of polyethylene glycol) has been used to further extend the terminal half-life. Also, new strategies are under investigation for stimulating erythropoiesis through activation of the EPO receptor. Clinical development of erythropoiesis-stimulating agents (ESAs) revolutionized the management of anemia. The major clinical benefits of ESAs are effective treatment of anemia and avoidance of blood transfusion risks. Erythropoietin (EPO) interacts directly with the EPO receptor on the red blood cell (RBC) surface, triggering activation of several signal transduction pathways, resulting in the proliferation and terminal differentiation of erythroid precursor cells and providing protection from RBC precursor apoptosis. The magnitude of increase in RBC concentration in response to administration of recombinant human EPO products (rhEPO) is primarily controlled by the length of time EPO concentrations are maintained, not by the EPO concentration level. Subcutaneous (SC) EPO administration results in slower absorption than intravenous (IV) administration, leading to lower peak plasma levels and an apparent extended terminal half-life. However, SC administration requires additional needle-sticks and is associated with an increased risk of immunogenicity compared with IV administration. Multiple pathways may play a role in EPO clearance from the body. Epoetin alfa was the first rhEPO produced and approved for pharmaceutical use, followed by several related products and by newer ESAs with the same mechanism but more prolonged action. Darbepoetin alfa is a hyperglycosylated EPO analog with an extended terminal half-life and a greater relative potency compared with rhEPO at extended dosing intervals. PEGylation of EPO (addition of polyethylene glycol) has been used to further extend the terminal half-life. Also, new strategies are under investigation for stimulating erythropoiesis through activation of the EPO receptor. Erythropoiesis, a complex physiologic process maintaining homeostasis of oxygen (O2) levels in the body, is primarily regulated by erythropoietin (EPO), a 30-kDa, 165—amino acid hematopoietic growth factor produced by the kidneys [1Erslev A. Humoral regulation of red cell production.Blood. 1953; 8: 349-357Crossref PubMed Google Scholar, 2Lai P.H. Everett R. Wang F.F. Arakawa T. Goldwasser E. Structural characterization of human erythropoietin.J Biol Chem. 1986; 261: 3116-3121Abstract Full Text PDF PubMed Google Scholar]. Under normal conditions, endogenous EPO levels change with O2 tension. In the presence of EPO, bone marrow erythroid precursor cells proliferate and differentiate into red blood cells (RBCs). In its absence, these cells undergo apoptosis [3Kelley L.L. Green W.F. Hicks G.G. Bondurant M.C. Koury M.J. Ruley H.E. 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: 4183-4192Crossref PubMed Scopus (79) Google Scholar, 4Koury M.J. Bondurant M.C. Maintenance by erythropoietin of viability and maturation of murine erythroid precursor cells.J Cell Physiol. 1988; 137: 65-74Crossref PubMed Scopus (144) Google Scholar]. The human EPO gene was cloned in 1983 [5Lin F.K. Suggs S. Lin C.H. et al.Cloning and expression of the human erythropoietin gene.Proc Natl Acad Sci U S A. 1985; 82: 7580-7584Crossref PubMed Scopus (951) Google Scholar], allowing for clinical development of recombinant human EPO (rhEPO), a biotechnological advance that revolutionized anemia treatment. Endogenous EPO and rhEPO share the same amino acid sequence, with slight differences in the sugar profile [6Skibeli V. Nissen-Lie G. Torjesen P. Sugar profiling proves that human serum erythropoietin differs from recombinant human erythropoietin.Blood. 2001; 98: 3626-3634Crossref PubMed Scopus (193) Google Scholar]. In clinical practice, rhEPO is typically administered as a bolus injection, and the dose is titrated to give the desired effect. Administration of rhEPO initially corresponded to clinical practice patterns, with treatments being synchronized to dialysis frequencies or chemotherapy cycle schedules. Attempts to improve or “reengineer” rhEPO to meet the demands of patients and caregivers resulted in additional erythropoiesis-stimulating agents (ESAs) with increased serum half-lives (compared with rhEPO), as well as different receptor binding properties and in vivo biological potencies [7Elliott S. Lorenzini T. Asher S. et al.Enhancement of therapeutic protein in vivo activities through glycoengineering.Nat Biotechnol. 2003; 21: 414-421Crossref PubMed Scopus (425) Google Scholar, 8Delorme E. Lorenzini T. Giffin J. et al.Role of glycosylation on the secretion and biological activity of erythropoietin.Biochemistry. 1992; 31: 9871-9876Crossref PubMed Scopus (153) Google Scholar, 9Egrie J.C. Dwyer E. Browne J.K. Hitz A. Lykos M.A. Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin.Exp Hematol. 2003; 31: 290-299Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar, 10Macdougall I.C. 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: 1211-1215Crossref PubMed Scopus (171) Google Scholar]. The characteristics and properties of these new ESAs allowed extension of the dosing intervals beyond the original thrice weekly (TIW) administration to weekly (QW), once every 2 weeks (Q2 W), once every 3 weeks (Q3 W), and even monthly (QM) administration [11Locatelli F. Olivares J. Walker R. et al.Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency.Kidney Int. 2001; 60: 741-747Crossref PubMed Scopus (189) Google Scholar, 12Nissenson A.R. Swan S.K. Lindberg J.S. et al.Randomized, controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients.Am J Kidney Dis. 2002; 40: 110-118Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 13Ling 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: 327-334Crossref PubMed Scopus (86) Google Scholar, 14Sulowicz W. Locatelli F. Ryckelynck J.P. 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: 637-646Crossref PubMed Scopus (134) Google Scholar, 15Canon J.L. 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: 273-284Crossref PubMed Scopus (94) Google Scholar] All ESAs share the same mechanism of action, binding to and activating the EPO receptor (EPOR), but differences in pharmacokinetic, pharmacodynamic, and receptor-binding properties affect their clinical use. In this review, we examine the biology of erythropoiesis and EPO and evaluate the limitations and opportunities afforded by new approaches to stimulating erythropoiesis through activation of the EPOR. A primary function of RBCs is to transport O2 from the lungs to O2-dependent tissues. Changes in O2 levels necessitate both acute and long-term physiologic adaptations. Acute adaptations include increases in respiration and heart rate, vasoconstriction, and changes in blood volume; however, these changes cannot be sustained. Erythropoiesis is a longer—term adaptation to boost O2-carrying capacity by increasing the concentration of RBCs, and thus, hemoglobin (Hb) concentration. RBCs are the most abundant (∼99%) circulating cells in the bloodstream, representing 40% to 45% of total blood volume. In a healthy human with ∼5 L blood, this represents approximately 2.5×1013 cells, a quantity substantial enough to provide the large O2 transport capacity needed to support aerobic respiration. In humans, the RBC lifespan is ∼100 to 120 days, with a daily loss of ∼0.8% to 1.0% of circulating RBCs. To match this loss, the body assumes a normal, prodigious production capacity of ∼2.5×1011 cells/day. RBC production results from a tightly controlled proliferation and differentiation pathway (Fig. 1). Early hematopoietic progenitors differentiate into burst-forming unit–erythroid cells, in which EPORs appear for the first time; however, EPO is not required at this stage [16Wu H. Liu X. Jaenisch R. Lodish H.F. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor.Cell. 1995; 83: 59-67Abstract Full Text PDF PubMed Scopus (842) Google Scholar]. Burst-forming unit–erythroid cells differentiate into colony-forming unit–erythroid cells, which are dependent on EPO for survival, and there is a corresponding rise in expression of EPORs [17Broudy V.C. Lin N. Brice M. Nakamoto B. Papayannopoulou T. Erythropoietin receptor characteristics on primary human erythroid cells.Blood. 1991; 77: 2583-2590Crossref PubMed Google Scholar, 18Sawada K. Krantz S.B. Kans J.S. et al.Purification of human erythroid colony-forming units and demonstration of specific binding of erythropoietin.J Clin Invest. 1987; 80: 357-366Crossref PubMed Scopus (166) Google Scholar]. Continued stimulation with EPO triggers differentiation into erythroblasts, which enucleate to form reticulocytes and after a few days show loss of “reticulin,” resulting in RBCs. Reticulocytes and RBCs stop expressing EPOR and cease being responsive to EPO [18Sawada K. Krantz S.B. Kans J.S. et al.Purification of human erythroid colony-forming units and demonstration of specific binding of erythropoietin.J Clin Invest. 1987; 80: 357-366Crossref PubMed Scopus (166) Google Scholar]. Disease states and environmental conditions often alter the tightly controlled balance between RBC production and destruction. When RBC loss exceeds gain, anemia results. Increased RBC loss can occur because of bleeding, enhanced destruction (chemically induced hematotoxicity), or reduced lifespan (sickle cell anemia). Potential causes of insufficient RBC production include defects in O2 sensing, excess of erythropoiesis inhibitors, and inadequate concentrations of ESAs. Erythropoiesis primarily occurs in the kidney, but other organs (liver, brain) also produce EPO. Interstitial fibroblasts produce EPO in the kidney [19Koury S.T. Bondurant M.C. Koury M.J. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization.Blood. 1988; 71: 524-527Crossref PubMed Google Scholar, 20Lacombe C. Da Silva J.L. Bruneval P. et al.Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney.J Clin Invest. 1988; 81: 620-623Crossref PubMed Scopus (354) Google Scholar, 21Maxwell P.H. Osmond M.K. Pugh C.W. et al.Identification of the renal erythropoietin-producing cells using transgenic mice.Kidney Int. 1993; 44: 1149-1162Crossref PubMed Scopus (334) Google Scholar], while hepatocytes produce EPO in the liver [22Koury S.T. Bondurant M.C. Koury M.J. Semenza G.L. Localization of cells producing erythropoietin in murine liver by in situ hybridization.Blood. 1991; 77: 2497-2503Crossref PubMed Google Scholar]. Initially, EPO is synthesized as a 193-amino-acid precursor. A 27-amino-acid signal peptide and C-terminal arginine are removed, and carbohydrate is added to three N-linked glycosylation sites and one O-linked glycosylation site [23Browne J.K. Cohen A.M. Egrie J.C. et al.Erythropoietin: gene cloning, protein structure, and biological properties.Cold Spring Harb Symp Quant Biol. 1986; 51: 693-702Crossref PubMed Google Scholar]. The secreted protein contains 165 amino acids and is heavily glycosylated, with ∼40% of its mass composed of carbohydrate. The structure of rhEPO is a compact globular bundle that contains four α helices (Fig. 2). Generally, serum EPO concentrations of 10 to 25 mU/mL [24Erslev A.J. Erythropoietin titers in health and disease.Semin Hematol. 1991; 28: 2-7PubMed Google Scholar] maintain Hb levels within the normal range of 12 to 17 g/dL [25Groopman J.E. Itri L.M. Chemotherapy-induced anemia in adults: incidence and treatment.J Natl Cancer Inst. 1999; 91: 1616-1634Crossref PubMed Scopus (783) Google Scholar]. The terminal half-life (t1/2) of EPO is ∼5 hours [26Eckardt K.U. Boutellier U. Kurtz A. Schopen M. Koller E.A. Bauer C. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia.J Appl Physiol. 1989; 66: 1785-1788PubMed Google Scholar], which requires an average EPO production rate of ∼2 U/kg/day. The EPO production rate per cell appears constant [27Koury S.T. Koury M.J. Bondurant M.C. Caro J. Graber S.E. 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: 645-651Crossref PubMed Google Scholar], with fluctuations in EPO synthesis resulting from changes in the number of cells producing the molecule. In cases of severe anemia, circulating EPO levels can increase up to 1000—fold because of a logarithmic increase in the number of cells producing EPO [24Erslev A.J. Erythropoietin titers in health and disease.Semin Hematol. 1991; 28: 2-7PubMed Google Scholar, 27Koury S.T. Koury M.J. Bondurant M.C. Caro J. Graber S.E. 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: 645-651Crossref PubMed Google Scholar]. Other factors affecting EPO levels include iron availability, nutritional status, disease or comorbidities, environmental conditions, and genetic factors (congenital polycythemias). A direct correlation exists between RBC production and serum EPO concentrations [28Elliott S. Egrie J. Browne J. et al.Control of rHuEPO biological activity: the role of carbohydrate.Exp Hematol. 2004; 32: 1146-1155Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 29Eschbach J.W. Egrie J.C. Downing M.R. Browne J.K. Adamson J.W. 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: 73-78Crossref PubMed Scopus (1768) Google Scholar]. However, the rate of erythropoiesis change (∼4—fold) [29Eschbach J.W. Egrie J.C. Downing M.R. Browne J.K. Adamson J.W. 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: 73-78Crossref PubMed Scopus (1768) Google Scholar]) is small compared to the larger change in EPO concentrations (∼1000—fold) [30Erslev A.J. Wilson J. Caro J. Erythropoietin titers in anemic, nonuremic patients.J Lab Clin Med. 1987; 109: 429-433PubMed Google Scholar]. Thus, the magnitude of increase in RBC concentration is primarily controlled by the length of time EPO concentrations are maintained, and not by the EPO concentration level per se (Fig. 3). Increased EPO synthesis has a prolonged effect due to the disproportionate relationship between EPO t1/2 and RBC lifespan. Thirty minutes of hypoxia can result in production of EPO (t1/2 ∼5 hours) [26Eckardt K.U. Boutellier U. Kurtz A. Schopen M. Koller E.A. Bauer C. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia.J Appl Physiol. 1989; 66: 1785-1788PubMed Google Scholar]. In turn, EPO stimulates formation of enucleated reticulocytes (t1/2=1–5 days) [31Finch C.A. Harker L.A. Cook J.D. Kinetics of the formed elements of human blood.Blood. 1977; 50: 699-707PubMed Google Scholar, 32Hillman R.S. Finch C.A. Erythropoiesis: normal and abnormal.Semin Hematol. 1967; 4: 327-336PubMed Google Scholar], which rapidly mature into RBCs that have a long lifespan (100–120 days) [33Smith J.A. Exercise, training and red blood cell turnover.Sports Med. 1995; 19: 9-31Crossref PubMed Scopus (152) Google Scholar]. Thus, a short duration of EPO exposure results in a prolonged increase in RBC concentration. The mechanism of action by which EPO stimulates erythropoiesis has been under extensive investigation. Early evidence indicated that EPO interacted with a protein on the cell surface, triggering activation of the JAK-signal transducers and activators of transcription, phosphatidylinositol 3 kinase, and mitogen-activated protein kinase pathways (Fig. 4), resulting in the proliferation and terminal differentiation of erythroid precursor cells and providing protection from apoptosis [4Koury M.J. Bondurant M.C. Maintenance by erythropoietin of viability and maturation of murine erythroid precursor cells.J Cell Physiol. 1988; 137: 65-74Crossref PubMed Scopus (144) Google Scholar]. The EPO-binding component on cells was first detected by measuring physical attachment of radiolabeled EPO to erythroid precursor cells [18Sawada K. Krantz S.B. Kans J.S. et al.Purification of human erythroid colony-forming units and demonstration of specific binding of erythropoietin.J Clin Invest. 1987; 80: 357-366Crossref PubMed Scopus (166) Google Scholar, 34Sawyer S.T. Krantz S.B. Goldwasser E. Binding and receptor-mediated endocytosis of erythropoietin in Friend virus-infected erythroid cells.J Biol Chem. 1987; 262: 5554-5562Abstract Full Text PDF PubMed Google Scholar]. The EPOR gene was subsequently identified by expression cloning and found to be a single gene with no apparent homologs [35Jones S.S. D'Andrea A.D. Haines L.L. Wong G.G. Human erythropoietin receptor: cloning, expression, and biologic characterization.Blood. 1990; 76: 31-35Crossref PubMed Google Scholar, 36D'Andrea A.D. Lodish H.F. Wong G.G. Expression cloning of the murine erythropoietin receptor.Cell. 1989; 57: 277-285Abstract Full Text PDF PubMed Scopus (547) Google Scholar]. While other components may mediate affinity or aid in signal transduction, the activation of signal transduction is initiated by an early, direct interaction of EPO with EPOR. Activation of EPOR occurs following cross-linking of two EPORs via one EPO ligand [37Syed R.S. Reid S.W. Li C. et al.Efficiency of signalling through cytokine receptors depends critically on receptor orientation.Nature. 1998; 395: 511-516Crossref PubMed Scopus (475) Google Scholar, 38Philo J.S. Aoki K.H. Arakawa T. Narhi L.O. 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: 1681-1691Crossref PubMed Scopus (181) Google Scholar, 39Elliott 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: 24691-24697Crossref PubMed Scopus (70) Google Scholar, 40Elliott S. Lorenzini T. Chang D. Barzilay J. Delorme E. Mapping of the active site of recombinant human erythropoietin.Blood. 1997; 89: 493-502Crossref PubMed Google Scholar], which induces a conformational change in the receptor, triggering downstream signal transduction [41Constantinescu S.N. Keren T. Socolovsky M. Nam H. Henis Y.I. Lodish H.F. Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain.Proc Natl Acad Sci U S A. 2001; 98: 4379-4384Crossref PubMed Scopus (212) Google Scholar, 42Kubatzky K.F. Liu W. Goldgraben K. Simmerling C. Smith S.O. Constantinescu S.N. Structural requirements of the extracellular to transmembrane domain junction for erythropoietin receptor function.J Biol Chem. 2005; 280: 14844-14854Crossref PubMed Scopus (38) Google Scholar, 43Seubert 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: 1239-1250Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]. The affinity (Kd) of EPO for its receptor on human cells is ∼100 to 200 pM [17Broudy V.C. Lin N. Brice M. Nakamoto B. Papayannopoulou T. Erythropoietin receptor characteristics on primary human erythroid cells.Blood. 1991; 77: 2583-2590Crossref PubMed Google Scholar, 44Krantz S.B. Sawyer S.T. Sawada K.I. Purification of erythroid progenitor cells and characterization of erythropoietin receptors.Br J Cancer Suppl. 1988; 9: 31-35PubMed Google Scholar, 45Sawada K. Krantz S.B. Sawyer S.T. Civin C.I. Quantitation of specific binding of erythropoietin to human erythroid colony-forming cells.J Cell Physiol. 1988; 137: 337-345Crossref PubMed Scopus (86) Google Scholar], which is sufficient for low concentrations of EPO to maintain a Hb of ∼14 g/dL in healthy subjects. Normal circulating concentrations of EPO are ∼2 to 5 pM [24Erslev A.J. Erythropoietin titers in health and disease.Semin Hematol. 1991; 28: 2-7PubMed Google Scholar], significantly below the EPO:EPOR Kd. At the half-maximal effective dose (ED50; ∼70 mU [28Elliott S. Egrie J. Browne J. et al.Control of rHuEPO biological activity: the role of carbohydrate.Exp Hematol. 2004; 32: 1146-1155Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 46Fraser J.K. Lin F.K. Berridge M.V. Expression of high affinity receptors for erythropoietin on human bone marrow cells and on the human erythroleukemic cell line, HEL.Exp Hematol. 1988; 16: 836-842PubMed Google Scholar]) 6.8% of the receptors are occupied [46Fraser J.K. Lin F.K. Berridge M.V. Expression of high affinity receptors for erythropoietin on human bone marrow cells and on the human erythroleukemic cell line, HEL.Exp Hematol. 1988; 16: 836-842PubMed Google Scholar], suggesting that only a fraction of the receptors need be occupied by EPO to achieve an adequate erythropoiesis maintenance rate. Increased EPOR occupancy does not increase the rate of cell division, but instead increases the rate of RBC formation by recruitment and differentiation of more erythroid precursor cells. However, the erythropoiesis rate is maximized when all available erythroid progenitors are actively dividing. This was evident from phase I clinical trials with epoetin α in which the rate of hematocrit rise showed dose-dependent increases to a plateau at a 200- to 500-U/kg dose [29Eschbach J.W. Egrie J.C. Downing M.R. Browne J.K. Adamson J.W. 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: 73-78Crossref PubMed Scopus (1768) Google Scholar]. Higher doses did not further increase the rate of rise, but did increase the overall response by extending the exposure time and the duration of enhanced erythropoiesis. If EPOR occupancy is inadequate, apoptosis of precursor cells occurs [4Koury M.J. Bondurant M.C. Maintenance by erythropoietin of viability and maturation of murine erythroid precursor cells.J Cell Physiol. 1988; 137: 65-74Crossref PubMed Scopus (144) Google Scholar], with apoptosis beginning in as little as 2 to 8 hours following removal of EPO from the culture [3Kelley L.L. Green W.F. Hicks G.G. Bondurant M.C. Koury M.J. Ruley H.E. 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: 4183-4192Crossref PubMed Scopus (79) Google Scholar, 4Koury M.J. Bondurant M.C. Maintenance by erythropoietin of viability and maturation of murine erythroid precursor cells.J Cell Physiol. 1988; 137: 65-74Crossref PubMed Scopus (144) Google Scholar, 47Somervaille T.C. Linch D.C. 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: 1374-1381Crossref PubMed Scopus (106) Google Scholar]. Formation of erythroblasts from colony-forming unit–erythroid cells can take up to a week. Thus, a single EPO–EPOR binding event is insufficient for stimulation of complete differentiation of early erythroid precursors. Instead, adequate EPO concentrations must be present during the entire process to ensure survival, proliferation, and differentiation to mature RBCs. Only during the final stages of erythropoiesis is EPO no longer required for RBC survival [46Fraser J.K. Lin F.K. Berridge M.V. Expression of high affinity receptors for erythropoietin on human bone marrow cells and on the human erythroleukemic cell line, HEL.Exp Hematol. 1988; 16: 836-842PubMed Google Scholar, 48Landschulz K.T. Noyes A.N. Rogers O. Boyer S.H. Erythropoietin receptors on murine erythroid colony-forming units: natural history.Blood. 1989; 73: 1476-1486Crossref PubMed Google Scholar, 49Mayeux P. Billat C. Jacquot R. The erythropoietin receptor of rat erythroid progenitor lens. Characterization and affinity cross-linkage.J Biol Chem. 1987; 262: 13985-13990Abstract Full Text PDF PubMed Google Scholar]. EPO derivatives or analogs with reduced receptor affinity may require higher concentrations to maintain an effective number of occupied EPORs. Although low binding affinity can be overcome with higher dosing and the rate of erythropoiesis corresponds to the duration of EPO exposure [28Elliott S. Egrie J. Browne J. et al.Control of rHuEPO biological activity: the role of carbohydrate.Exp Hematol. 2004; 32: 1146-1155Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar], low receptor binding activity may be undesirable in some disease states, such as EPO resistance. In the case of longer-acting agents with very low receptor affinity, there may be low receptor occupancy for an extended period and consequently, a reduced rate of erythropoiesis, resulting in a slower rate of Hb rise. Before development of rhEPO, blood transfusion was the most common treatment for patients with anemia. However, blood transfusions carry inherent risks, including risk of transmission of infectious agents and iron overload. Additionally, the blood supply is limited, and immune reactions developed after transfusion can make organ transplantation more problematic [50Perrotta P.L. Snyder E.L. Non-infectious complications of transfusion therapy.Blood Rev. 2001; 15: 69-83Abstract Full Text PDF PubMed Scopus (149) Google Scholar]. Iron supplementation was largely ineffective as a stand-alone treatment for anemia. The need for an effective anemia treatment option was obvious, and attempts to make and test rhEPO via cloning of the human EPO gene began. Successfully cloning the EPO gene was difficult, as low circulating EPO levels made protein purification difficult, a primary source of EPO mRNA was not obvious, and mRNA was difficult to obtain. Once small quantities of purified human EPO became available (10 mg from 1000 L urine from human patients with aplastic anemia), oligonucleotide probes for EPO were designed. Two different probes were used to screen a λ phage library containing sheared human genomic DNA, and the human EPO gene was cloned [5Lin F.K. Suggs S. Lin C.H. et al.Cloning and expression of the human erythropoietin gene.Proc Natl Acad Sci U S A. 1985; 82: 7580-7584Crossref PubMed Scopus (951) Google Scholar]. Successful cloning of the EPO gene in 1983 [5Lin F.K. Suggs S. Lin C.H. et al.Cloning and expression of the human erythropoietin gene.Proc Natl Acad Sci U S A. 1985; 82: 7580-7584Crossref PubMed Scopus (951) Google Scholar] allowed for the large-scale production of rhEPO and its subsequent clinical use [29Eschbach J.W. Egrie J.C. Downing M.R. Browne J.K. Adamson J.W. 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: 73-78Crossref PubMed Scopus (1768) Google Scholar]. Epoetin alfa (Epogen; Amgen Inc., Thousand Oaks, CA, USA; Procrit; Ortho Biotech Products, L.P., Bridgewater, NJ, USA) was the first rhEPO commercialized in the United States, followed by a second epoetin α (Eprex; Ortho Biotech Products) and epoetin beta (NeoRecormon; F. Hoffmann-La Roche Ltd., Basel, Switzerland) in Europe. Epoetins alfa and beta, both produced by Chinese hamster ovary cells, have minor structural" @default.
• W1963516841 created "2016-06-24" @default.
• W1963516841 creator A5021273139 @default.
• W1963516841 creator A5048893439 @default.
• W1963516841 creator A5076664205 @default.
• W1963516841 date "2008-12-01" @default.
• W1963516841 modified "2023-10-14" @default.
• W1963516841 title "Erythropoietins: A common mechanism of action" @default.
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• W1963516841 doi "https://doi.org/10.1016/j.exphem.2008.08.003" @default.
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