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Cited by 421Erythropoietin and Anemia TreatmentBiosimilars and Bioanalytical MethodsHemoglobin structure and function

Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin

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Egrie, Joan C, Dwyer, Erik, Browne, Jeffrey K, Hitz, Anna, Lykos, Michele A·2003·Experimental Hematology
DOI 10.1016/s0301-472x(03)00006-7
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Abstract

Objective Experiments on human erythropoietin (EPO) demonstrated that there is a direct relationship between the sialic acid-containing carbohydrate content of EPO, its circulating half-life, and in vivo bioactivity. This led to the hypothesis that an EPO analogue engineered to contain additional oligosaccharide chains would have enhanced biological activity. Darbepoetin alfa, a hyperglycosylated recombinant human EPO (rHuEPO) analogue with two extra carbohydrate chains, was designed and developed to test this hypothesis. Materials and methods Comparative pharmacokinetic and pharmacodynamic studies and biochemical analyses of darbepoetin alfa and rHuEPO were performed to define the consequences of the increased carbohydrate content. Results Due to its increased sialic acid-containing carbohydrate content, darbepoetin alfa has a higher molecular weight, a greater negative charge, and a approximately fourfold lower EPO receptor binding activity than rHuEPO. It also has a threefold longer circulating half-life than rHuEPO in rats and dogs. In spite of its lower receptor binding, and perhaps counterintuitively, darbepoetin alfa is significantly more potent in vivo than rHuEPO. Due to the pharmacokinetic differences, the relative potency of the two molecules varies as a function of the dosing frequency. Darbepoetin alfa is 3.6-fold more potent than rHuEPO in increasing the hematocrit of normal mice when each is administered thrice weekly, but when the administration frequency is reduced to once weekly, darbepoetin alfa is approximately 13-fold to 14-fold more potent than rHuEPO. Conclusions Increasing the sialic acid-containing carbohydrate content beyond the maximum found in EPO leads to a molecule with a longer circulating half-life and thereby an increased in vivo potency that can be administered less frequently.

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  • Darbepoetin alfa, an EPO molecule approved in 2001 with two additional N-oligosaccharides, increased in vivo potency and half-life.

    “An early example worth mentioning is the development of darbepoetin alfa, an EPO molecule approved in 2001 with two additional N-oligosaccharides that increased in vivo potency and half-life [117].”

    From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [117]

    The Results section says darbepoetin alfa has two additional N-linked carbohydrate chains, and the Abstract reports a longer circulating half-life and greater in vivo potency than rHuEPO. Our copy does not establish the claimed 2001 approval date (searched for approval and 2001). (LLM, conf=0.88)

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Research works printed but not linked: 4

  1. Lai PH, Everett R, Wang FF, Arakawa T, Goldwasser E. Structural char- acterization of human erythropoietin. J Biol Chem. 1986;261: 3116-3121.
  2. Hokke CH, Bergwerff AA, Van Dedem GWK, Kamerling JP, Vliegenthart FG. Structural analysis of the sialylated N-and O-linked car- bohydrate chains of recombinant human erythropoietin expressed in Chi- nese hamster ovary cells. Eur J Biochem. 1995;228:981-1008.
  3. Greenwood FC, Hunter WM, Glover JS. The preparation of 131 I-labeled human growth hormone of high specific activity. Biochem J. 1963; 89:493-502.
  4. Tallarida RJ, Murray RB. Manual of pharmacological calculations. 2 nd ed. New York: Springer-Verlag; 1987.

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Authors
Egrie, J. C., Dwyer, E., Browne, J. K., Hitz, A., & Lykos, M. A.
Affiliations
Amgen (United States) (US)
Corresponding author
Egrie, Joan C
Venue
Experimental Hematology
Publisher
Elsevier BV
Published
2003-04
Volume
31
Issue
4
Pages
290-299
ISSN
0301-472X (ISSN-L)
DOI
10.1016/s0301-472x(03)00006-7
OpenAlex
W2169177790
Cited by
421
References
47
Citations by year
2026: 10 · 2025: 14 · 2024: 6 · 2023: 7 · 2022: 11 · 2021: 12 · 2020: 3 · 2019: 12 · 2018: 14 · 2017: 12 · 2016: 13 · 2015: 19 · 2014: 16 · 2013: 16 · 2012: 19
FWCI
16.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental Hematology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
darbepoetin alfa, recombinant human erythropoietin, erythropoietin analogues, hyperglycosylation, serum half-life, in vivo potency, hematocrit, dosing frequency, pharmacokinetics, pharmacodynamics
MeSH terms
Darbepoetin alfa, Animals, Carbohydrates, Dogs, Dose-Response Relationship, Drug, Electrochemistry, Electrophoresis, Polyacrylamide Gel, Erythropoietin, Half-Life, Hematocrit, Humans, Kinetics, Male, Molecular Weight, Recombinant Proteins, Rats, Sprague-Dawley, Receptors, Erythropoietin, N-Acetylneuraminic Acid, Mice, Rats

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