Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact.
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.
Kiss
Zoltán
Z
Amgen Kft., Budapest, Hungary. zkiss@amgen.com
Elliott
Steven
S
Jedynasty
Kinga
K
Tesar
Vladimír
V
Szegedi
János
J
D002241:Carbohydrates / Q000494:pharmacology; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006207:Half-Life; D006397:Hematinics / Q000494:pharmacology*; D006801:Humans; D019158:N-Acetylneuraminic Acid / Q000494:pharmacology; D011485:Protein Binding / Q000235:genetics; D011994:Recombinant Proteins
D002241:Carbohydrates; D006397:Hematinics; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D019158:N-Acetylneuraminic Acid