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Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

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Abstract

Cloning of the human erythropoietin (EPO) gene and development of the first recombinant human erythropoietin (rHuEPO) drug were truly breakthroughs. This allowed a deeper understanding of the structure and pharmacology of rHuEpo, which in turn inspired the discovery and development of additional erythropoiesis-stimulating agents (ESAs). In vivo specific activity and serum half-life of rHuEPO are influenced by the amount and structure of the attached carbohydrate. Increased numbers of sialic acids on carbohydrate attached to rHuEPO correlated with a relative increase in in-vivo-specific activity and increased serum half-life. The effect of increasing the number of sialic-acid-containing carbohydrates on in-vivo-specific activity was explored. Initial research focused on solving the problem of how the protein backbone could be engineered so a cell would add more carbohydrate to it. Additional work resulted in darbepoetin alfa, a longer-acting molecule with two additional carbohydrate chains.

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Acknowledgements

The manuscript was sponsored by Amgen (Hungary). Vladimir Tesar participated in the advisory board for Amgen and Novartis; received a research grant from Amgen and lecture fees from Amgen, Astra Zeneca, Fresenius Kabi, Novartis, Roche and Teva. János Szegedi received consulting fees from Amgen and Janssen Cilag and participated in the advisory board for Amgen. Zoltán Kiss, Steven Elliott, Kinga Jedynasty are employees of Amgen.

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Authors and Affiliations

  1. Amgen Kft., Budapest, Hungary

    Zoltán Kiss

  2. Amgen Inc., Thousand Oaks, CA, USA

    Steven Elliott

  3. Amgen Gmbh., Wien, Austria

    Kinga Jedynasty

  4. Department of Nephrology, 1st School of Medicine and University Hospital, Charles University, Prague, Czech Republic

    Vladimír Tesar

  5. Local Government of Szabolcs-Szatmár-Bereg County, Jósa András Instructional Hospital, Internal Medicine I., Nyíregyháza, Hungary

    János Szegedi

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  1. Zoltán Kiss
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Correspondence to Zoltán Kiss.

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Kiss, Z., Elliott, S., Jedynasty, K. et al. 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 66, 331–340 (2010). https://doi.org/10.1007/s00228-009-0780-y

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  • DOI: https://doi.org/10.1007/s00228-009-0780-y

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