Erythropoiesis stimulating agents: Approaches to modulate activity

Biologics: Targets and Therapy

Volumn 7, Issue 1, 2013, Pages 161-174

  Sinclair, Angus M ^a  

^a AMGEN INC   (United States)

Author keywords

Darbepoetin alfa; Erythropoiesis; Erythropoietin; Glycosylation; Pharmacokinetics; Pharmacology; Polyethylene glycols

Indexed keywords

ABT 007; ABT007; AMG 114; AMG 205; ANTIANEMIC AGENT; CNTO 528; CNTO 530; EMP1; ERYTHROPOIETIN; ERYTHROPOIETIN RECEPTOR ANTIBODY; HYPERGLYCOSYLATED ANALOG OF RECOMBINANT ERYTHROPOIETIN; MK 2578; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY 71; NOVEL ERYTHROPOIESIS STIMULATING PROTEIN; PEGINESATIDE; PEGZYREPOETIN ALFA; PEPTIDOMIMETIC AGENT; RECEPTOR ANTIBODY; RECOMBINANT ERYTHROPOIETIN; RECOMBINANT GRANULOCYTE COLONY STIMULATING FACTOR; RECOMBINANT HORMONE; UNCLASSIFIED DRUG;

ANEMIA; CHEMOTHERAPY INDUCED ANEMIA; DRUG HALF LIFE; HEMOGLOBIN BLOOD LEVEL; HUMAN; NONHUMAN; REVIEW; SEQUENCE HOMOLOGY; SINGLE DRUG DOSE;

EID: 84879923507     PISSN: 11775475     EISSN: 11775491     Source Type: Journal    
DOI: 10.2147/BTT.S45971     Document Type: Review

References (114)

1. Aapro M. Emerging topics in anaemia and cancer. Ann Oncol. 2012; 23 SUPPL. 10:x289-x293.
2. Elliott S, Sinclair AM. The effect of erythropoietin on normal and neoplastic cells. Biologics. 2012;6:163-189.
3. Molineux G, Sinclair A. Biology of erythropoietin. In: Parnham MJ, Bruinvels J, editors. Erythropoietins, Erythropoietic Factors, and Erythropoiesis, 2nd ed. Basel: Birkhauser; 2009:41-60.
4. Muchnik E, Kaplan J. HIF prolyl hydroxylase inhibitors for anemia. Expert Opin Investig Drugs. 2011;20(5):645-656.
5. Constantinescu SN, Keren T, Socolovsky M, Nam H, Henis YI, Lodish HF. Ligand-independent oligomerization of cell-surface eryth-ropoietin receptor is mediated by the transmembrane domain. Proc Natl Acad Sci U S A. 2001;98(8):4379-4384.
6. 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;6(35): 1681-1691.
7. Supino-Rosin L, Yoshimura A, Altaratz H, Neumann D. A cytosolic domain of the erythropoietin receptor contributes to endoplasmic reticulum-associated degradation. Eur J Biochem. 1999;263(2):410-419.
8. Hilton DJ, Watowich SS, Murray PJ, Lodish HF. Increased cell surface expression and enhanced folding in the endoplasmic reticulum of a mutant erythropoietin receptor. Proc Natl Acad Sci U S A. 1995;92(1): 190-194.
9. Neumann D, Wikstrom L, Watowich SS, Lodish H F. Intermediates in degradation of the erythropoietin receptor accumulate and are degraded in lysosomes. J Biol Chem. 1993;268(18):13639-13649.
10. Meyer L, Deau B, Forejtnikova H, et al. beta-Trcp mediates ubiquitination and degradation of the erythropoietin receptor and controls cell proliferation. Blood. 2007;109(12):5215-5222.
11. Walrafen P, Verdier F, Kadri Z, Chretien S, Lacombe C, Mayeux P. Both proteasomes and lysosomes degrade the activated erythropoietin receptor. Blood. 2005;105(2):600-608.
12. Huang LJ, Constantinescu SN, Lodish HF. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol Cell. 2001;8(6):1327-1338.
13. 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(5):1239-1250.
14. Wojchowski DM, Gregory RC, Miller C P, Pandit AK, Pircher TJ. Signal transduction in the erythropoietin receptor system. Exp Cell Res. 1999;253(1):143-156.
15. Wojchowski DM, Sathyanarayana P, Dev A. Erythropoietin receptor response circuits. Curr Opin Hematol. 2010;17(3):169-176.
16. Minoo P, Zadeh MM, Rottapel R, Lebrun JJ, Ali S. A novel SHP-1/ Grb2-dependent mechanism of negative regulation of cytokine-receptor signaling: contribution of SHP-1 C-terminal tyrosines in cytokine signaling. Blood. 2004;103(4):1398-1407.
17. Jegalian AG, Wu H. Differential roles of SOCS family members in EpoR signal transduction. J Interferon Cytokine Res. 2002;22(8):853-860.
18. de la Chapelle A, Traskelin AL, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci U S A. 1993;90(10):4495-4499.
19. Arcasoy MO, Karayal A F, Segal HM, Sinning JG, Forget BG. A novel mutation in the erythropoietin receptor gene is associated with familial erythrocytosis. Blood. 2002a;99(8):3066-3069.
20. Jacobs K, Shoemaker C, Rudersdorf R, et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature. 1985;313(6005):806-810.
21. 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(22): 7580-7584.
22. Davis JM, Arakawa T, Strickland T W, Yphantis DA. Characterization of recombinant human erythropoietin produced in Chinese hamster ovary cells. Biochemistry. 1987;26(9):2633-2638.
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. Egrie JC, Browne J, Lai P, Lin FK. Characterization of recombinant monkey and human erythropoietin. Prog Clin Biol Res. 1985;191: 339-350.
25. Rudd PM, Dwek RA. Glycosylation: heterogeneity and the 3D structure of proteins. Crit Rev Biochem Mol Biol. 1997;32(1):1-100.
26. 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(25):12059-12076.
27. Rush RS, Derby PL, Smith DM, et al. Microheterogeneity of erythro-poietin carbohydrate structure. Anal Chem. 1995;67(8):1442-1452.
28. Kiss Z, Elliott S, Jedynasty K, Tesar V, Szegedi J. Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact. Eur J Clin Pharmacol. 2010;66(4): 331-340.
29. Tsuda E, Kawanishi G, Ueda M, Masuda S, Sasaki R. The role of carbohydrate in recombinant human erythropoietin. Eur J Biochem. 1990;188(2):405-411.
30. Narhi LO, Arakawa T, Aoki KH, et al. The effect of carbohydrate on the structure and stability of erythropoietin. J Biol Chem. 1991;266(34): 23022-23026.
31. Endo Y, Nagai H, Watanabe Y, Ochi K, Takagi T. Heat-induced aggregation of recombinant erythropoietin in the intact and degly-cosylated states as monitored by gel permeation chromatography combined with a low-angle laser light scattering technique. J Biochem. 1992;112(5):700-706.
32. Uchida E, Morimoto K, Kawasaki N, Izaki Y, Abdu Said A, Hayakawa T. Effect of active oxygen radicals on protein and carbohydrate moieties of recombinant human erythropoietin. Free Radic Res. 1997;27(3): 311-323.
33. Goochee CF, Gramer M, Andersen D, Bahr J, Rasmussen JR. The oligosaccharides of glycoproteins: factors affecting their synthesis and their infuence on glycoprotein properties. In: Sikdar SK, Brier M, Todd P, editors. Frontiers in Bioprocessing II. Washington: American Chemical Society; 1991:199-240.
34. Stowers AW, Chen Lh LH, Zhang Y, et al. A recombinant vaccine expressed in the milk of transgenic mice protects Aotus monkeys from a lethal challenge with Plasmodium falciparum. Proc Natl Acad Sci U S A. 2002;99(1):339-344.
35. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antieryth-ropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346(7):469-475.
36. Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351(14):1403-1408.
37. Schellekens H, Jiskoot W. Eprex-associated pure red cell aplasia and leachates. Nat Biotechnol. 2006;24(6):613-614.
38. Imperiali B, O'Connor SE. Effect of N-linked glycosylation on glyco-peptide and glycoprotein structure. Curr Opin Chem Biol. 1999;3(6): 643-649.
39. Elliott S, Chang D, Delorme E, et al. Isolation and characterization of conformation sensitive antierythropoietin monoclonal antibodies: effect of disulfide bonds and carbohydrate on recombinant human erythropoietin structure. Blood. 1996;87(7):2714-2722.
40. Fernandes AI, Gregoriadis G. The effect of polysialylation on the immunogenicity and antigenicity of asparaginase: implication in its pharmacokinetics. Int J Pharm. 2001;217(1-2):215-224.
41. Ho CL, Lin YL, Chen WC, Rocchi R, Piek T. Comparison of the immunogenicity of wasp venom peptides with or without carbohydrate moieties. Toxicon. 1998;36(1):217-221.
42. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer. 2001; 84 SUPPL. 1:3-10.
43. Higuchi M, Oh-eda M, Kuboniwa H, Tomonoh K, Shimonaka Y, Ochi N. Role of sugar chains in the expression of the biological activity of human erythropoietin. J Biol Chem. 1992;267(11):7703-7709.
44. Fukuda MN, Sasaki H, Lopez L, Fukuda M. Survival of recombinant erythropoietin in the circulation: the role of carbohydrates. Blood. 1989;73(1):84-89.
45. Spivak JL, Hogans BB. The in vivo metabolism of recombinant human erythropoietin in the rat. Blood. 1989;73(1):90-99.
46. 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(3):1205-1210.
47. Kindler J, Eckardt KU, Ehmer B, et al. Single-dose pharmacokinetics of recombinant human erythropoietin in patients with various degrees of renal failure. Nephrol Dial Transplant. 1989;4(5):345-349.
48. Macdougall IC, Roberts DE, Coles GA, Williams JD. Clinical pharmacokinetics of epoetin (recombinant human erythropoietin). Clin Pharmacokinet. 1991;20(2):99-113.
49. 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(2):111-116.
50. Dinkelaar RB, Engels E Y, Hart AA, Schoemaker L P, 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(7):796-803.
51. Clarenburg R. Asialoglycoprotein receptor is uninvolved in clearing intact glycoproteins from rat blood. Am J Physiol. 1983;244(3):G247-G253.
52. Ishibashi S, Hammer RE, Herz J. Asialoglycoprotein receptor deficiency in mice lacking the minor receptor subunit. J Biol Chem. 1994;269(45):27803-27806.
53. Tozawa R, Ishibashi S, Osuga J, et al. Asialoglycoprotein receptor deficiency in mice lacking the major receptor subunit. Its obligate requirement for the stable expression of oligomeric receptor. J Biol Chem. 2001;276(16):12624-12628.
54. Sawyer ST, Krantz SB, Goldwasser E. Binding and receptor-mediated endocytosis of erythropoietin in Friend virus-infected erythroid cells. J Biol Chem. 1987;262(12):5554-5562.
55. Gross AW, Lodish HF. Cellular traffcking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem. 2006;281(4):2024-2032.
56. 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(2):820-824.
57. 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(4):149-156.
58. Hartley C, Elliott S, Begley CG, et al. Kinetics of haematopoietic recovery after dose-intensive chemo/radiotherapy in mice: optimized erythroid support with darbepoetin alpha. Br J Haematol. 2003;122(4): 623-636.
59. 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(8):1140-1149.
60. Agoram B, Aoki K, Doshi S, et al. Investigation of the effects of altered receptor binding activity on the clearance of erythropoiesis-stimulating proteins: nonerythropoietin receptor-mediated pathways may play a major role. J Pharm Sci. 2009;98(6):2198-2211.
61. Flaharty KK. Clinical pharmacology of recombinant human erythropoietin (r-HuEPO). Pharmacotherapy. 1990;10 (PT. 2):9S-14S.
62. Elliott S, Lorenzini T, Asher S, et al. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat Biotechnol. 2003;21(4):414-421.
63. Sinclair AM, Elliott S. Glycoengineering: the effect of glycosylation on the properties of therapeutic proteins. J Pharm Sci. 2005;94(8): 1626-1635.
64. Bause E. Structural requirements of N-glycosylation of proteins. Studies with proline peptides as conformational probes. Biochem J. 1983;209(2):331-336.
65. Kornfeld R, Kornfeld S. Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem. 1985;54:631-664.
66. Gavel Y, von Heijne G. Sequence differences between glycosylated and non-glycosylated Asn-X-Thr/Ser acceptor sites: implications for protein engineering. Protein Eng. 1990;3(5):433-442.
67. Apweiler R, Hermjakob H, Sharon N. On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta. 1999;1473(1):4-8.
68. Elliott S, Chang D, Delorme E, Eris T, Lorenzini T. Structural requirements for additional N-linked carbohydrate on recombinant human erythropoietin. J Biol Chem. 2004;279(16):16854-16862.
69. Imperiali B, Hendrickson TL. Asparagine-linked glycosylation: specificity and function of oligosaccharyl transferase. Bioorg Med Chem. 1995;3(12):1565-1578.
70. Van den Steen P, Rudd PM, Dwek RA, Van Damme J, Opdenakker G. Cytokine and protease glycosylation as a regulatory mechanism in inflammation and autoimmunity. Adv Exp Med Biol. 1998;435:133-143.
71. Hurtado-Guerrero R, Dorfmueller HC, van Aalten DM. Molecular mechanisms of O-GlcNAcylation. Curr Opin Struct Biol. 2008;18(5): 551-557.
72. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant. 2001;16 Suppl 3:3-13.
73. Elliott S, Egrie J, Browne J, et al. Control of rHuEPO biological activity: the role of carbohydrate. Exp Hematol. 2004;32(12):1146-1155.
74. 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(4):290-299.
75. 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(3):163-174.
76. Coccia MA, Cooke K, Stoney G, et al. Novel erythropoiesis stimulating protein (darbepoetin alfa) alleviates anemia associated with chronic inflammatory disease in a rodent model. Exp Hematol. 2001; 29(10):1201-1209.
77. 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(11):2392-2395.
78. Smalling R, Foote M, Molineux G, Swanson SJ, Elliott S. Drug-induced and antibody-mediated pure red cell aplasia: a review of literature and current knowledge. Biotechnol Annu Rev. 2004;10:237-250.
79. Wide L, Wikstrom B, Eriksson K. A new principle suggested for detection of darbepoetin-alpha (NESP) doping. Ups J Med Sci. 2003;108(3):229-238.
80. Elliott S. Glycoengineering of Erythropoietin. Post-Translational Modifcation of Protein Biopharmaceuticals. Weinheim, Germany. Wiley-Blackwell; 2009:295-317.
81. de Boer R, Clemens M, Renczes G, 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(4):1210-1217.
82. Macdougall IC. CERA (Continuous Erythropoietin Receptor Activator): a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep. 2005;4(6):436-440.
83. Haselbeck A, Bailon P, Pahlke W. The discovery and characterization of CERA, an innovative agent for the treatment of anemia. Blood. 2002;100(Abstract 857):227A.
84. Fishbane S, Tare N, Pill J, Haselbeck A. Preclinical pharmacodynamics and pharmacokinetics of CERA (Continuous Erythropoietin Receptor Activator), an innovative erythropoietic agent for anemia management in patients with kidney disease. J Am Soc Nephrol. 2003; 14(Abstract SA-FC 123):27A.
85. Macdougall IC, Robson R, Opatrna S, et al. Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous continuous erythropoietin receptor activator (CERA) in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2006;1(6):1211-1215.
86. Curran M P, McCormack PL. Methoxy polyethylene glycol-epoetin beta: a review of its use in the management of anaemia associated with chronic kidney disease. Drugs. 2008;68(8):1139-1156.
87. Molineux G. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des. 2004;10(11): 1235-1244.
88. Macdougall IC, Bailon P, Tare N. CERA (Continuous Erythropoiesis Receptor Activator) for the treatment of renal anemia: an innovative agent with unique receptor binding characteristics and prolonged serum half-life. J Am Soc Nephrol. 2003;14(Abstract SU-PO1063):479A.
89. El-Komy MH, Schmidt RL, Widness JA, Veng-Pedersen P. Differential pharmacokinetic analysis of in vivo erythropoietin receptor interaction with erythropoietin and continuous erythropoietin receptor activator in sheep. Biopharm Drug Dispos. 2011;32(5):276-288.
90. Bethencourt V. Merck joins the biotech game. Nat Biotech. 2009;27(2): 104.
91. Hamilton SR, Davidson RC, Sethuraman N, et al. Humanization of yeast to produce complex terminally sialylated glycoproteins. Science. 2006;313(5792):1441-1443.
92. Dorey E. Merck ditches biogeneric. Nat Biotech. 2010;28(7):636.
93. Wrighton NC, Farrell FX, Chang R, et al. Small peptides as potent mimetics of the protein hormone erythropoietin. Science. 1996;273(5274):458-464.
94. Barbone F P, Johnson DL, Farrell FX, et al. New epoetin molecules and novel therapeutic approaches. Nephrol Dial Transplant. 1999; 14 SUPPL. 2:80-84.
95. Wrighton NC, Balasubramanian P, Barbone F P, et al. Increased potency of an erythropoietin peptide mimetic through covalent dimerization. Nat Biotechnol. 1997;15(12):1261-1265.
96. Bouman-Thio E, Franson K, Miller B, et al. A phase I, single and fractionated, ascending-dose study evaluating the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of an erythropoietin mimetic antibody fusion protein (CNTO 528) in healthy male subjects. J Clin Pharmacol. 2008;48(10):1197-1207.
97. Bugelski PJ, Capocasale RJ, Makropoulos D, et al. CNTO 530: molecular pharmacology in human UT-7EPO cells and pharmacokinetics and pharmacodynamics in mice. J Biotechnol. 2008;134(1-2):171-180.
98. Sathyanarayana P, Houde E, Marshall D, et al. CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools. Blood. 2009;113(20):4955-4962.
99. Fan Q, Leuther KK, Holmes C P, et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol. 2006;34(10):1303-1311.
100. Doss S, Schiller B. Peginesatide: a potential erythropoiesis stimulating agent for the treatment of anemia of chronic renal failure. Nephrol Nurs J. 2010;37(6):617-626.
101. Besarab A, Zeig SN, Martin ER, et al. An open-label, sequential, dose-finding study of peginesatide for the maintenance treatment of anemia in chronic hemodialysis patients. BMC Nephrol. 2012;13:95.
102. Fishbane S, Schiller B, Locatelli F, et al. Peginesatide in patients with anemia undergoing hemodialysis. N Engl J Med. 2013;368(4): 307-319.
103. Macdougall IC, Provenzano R, Sharma A, et al. Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis. N Engl J Med. 2013;368(4):320-332.
104. Woodburn K W, Fan Q, Winslow S, et al. Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antieryth-ropoietin antibodies in a rat pure red cell aplasia model. Exp Hematol. 2007;35(8):1201-1208.
105. Macdougall IC, Rossert J, Casadevall N, et al. A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med. 2009;361(19):1848-1855.
106. 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(40):24691-24697.
107. Schneider H, Chaovapong W, Matthews DJ, et al. Homodimerization of erythropoietin receptor by a bivalent monoclonal antibody triggers cell proliferation and differentiation of erythroid precursors. Blood. 1997;89(2):473-482.
108. Liu Z, Stoll VS, Devries PJ, et al. A potent erythropoietin-mimicking human antibody interacts through a novel binding site. Blood. 2007;110(7):2408-2413.
109. Lacy SE, DeVries PJ, Xie N, Fung E, Lesniewski RR, Reilly EB. The potency of erythropoietin-mimic antibodies correlates inversely with affinity. J Immunol. 2008;181(2):1282-1287.
110. Zhang H, Wilson IA, Lerner RA. Selection of antibodies that regulate phenotype from intracellular combinatorial antibody libraries. Proc Natl Acad Sci U S A. 2012;109(39):15728-15733.
111. Sytkowski AJ, Lunn ED, Davis KL, Feldman L, Siekman S. Human erythropoietin dimers with markedly enhanced in vivo activity. Proc Natl Acad Sci U S A. 1998;95(3):1184-1188.
112. 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(35): 24773-24778.
113. Bitonti AJ, Dumont JA, Low SC, et al. Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc Natl Acad Sci U S A. 2004;101(26):9763-9768.
114. Dumont JA, Bitonti AJ, Clark D, Evans S, Pickford M, Newman S P. Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway. J Aerosol Med. 2005;18(3):294-303.