Development and characterization of novel erythropoiesis stimulating protein (NESP)

Studies on human erythropoietin (EPO) demonstrated that there is a direct r elationship between the sialic acid-containing carbohydrate content of the molecule and its serum half-life and in vivo biological activity, but an in verse relationship with its receptor binding affinity. These observations l ed to the hypothesis that increasing the carbohydrate content, beyond that found naturally, would lead to a molecule with enhanced biological activity . Hyperglycosylated recombinant human EPO (rHuEPO) analogues were developed to test this hypothesis. Darbepoetin alfa (novel erythropoiesis stimulatin g protein, NESP), which was engineered to contain five N-linked carbohydrat e chains (two more than rHuEPO), has been evaluated in preclinical animal s tudies. Due to its increased sialic acid-containing carbohydrate content, N ESP is biochemically distinct from rHuEPO, having an increased molecular we ight and greater negative charge. Compared with rHuEPO, it has an approxima tely 3-fold longer serum half-life, greater in vivo potency, and can be adm inistered less frequently to obtain the same biological response. NESP is c urrently being evaluated in human clinical trials for treatment of anaemia and reduction in its incidence.