The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin
Open accessAbstract
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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“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]
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Metadata
- 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)
- 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
- bronze
- doi.org
- 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 › Biochemistry › 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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