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

作者：Kiss Zoltan^*; Elliott Steven; Jedynasty Kinga; Tesar Vladimir; Szegedi Janos

来源：European Journal of Clinical Pharmacology, 2010, 66(4): 331-340.

DOI：10.1007/s00228-009-0780-y

• Red blood cell (RBC)
• Biological activity
• Erythropoietin (EPO)
• Erythropoiesis-stimulating agent (ESA)
• Recombinant human erythropoietin (rHuEpo)
• Carbohydrate
• Sialic acid
• Darbepoetin alfa
• Glycoengineering
• Biosimilar
• FOB

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.

• 出版日期2010-4