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

Zoltán Kiss (1) , Steven Elliott (1) , Kinga Jedynasty (1) , Vladimír Tesar (2) , János Szegedi (3)

1 AMGen - Applied Molecular Genetics
2 Department of Nephrology
3 Local Government of Szabolcs-Szatmár-Bereg County

Cloning of the human erythropoietin () 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.

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

Zoltán Kiss, Steven Elliott, Kinga Jedynasty, Vladimír Tesar, János Szegedi. Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact. European Journal of Clinical Pharmacology, 2010, 66 (4), pp.331-340. ⟨10.1007/s00228-009-0780-y⟩. ⟨hal-00561811⟩