Erythropoiesis-stimulating agents (ESAs) that exert long-acting antianemia 
effects have been developed recently, but their mechanisms are poorly 
understood. Analyses reveal unique erythropoietin receptor (EPOR)-binding 
properties for one such ESA, the synthetic EPOR agonist peginesatide. Compared 
with recombinant human EPO and darbepoietin, peginesatide exhibited a slow on 
rate, but sustained EPOR residency and resistant displacement. In EPO-dependent 
human erythroid progenitor UT7epo cells, culture in peginesatide unexpectedly 
upmodulated endogenous cell surface EPOR levels with parallel increases in 
full-length EPOR-68K levels. These unique properties are suggested to contribute 
to the durable activity of this (and perhaps additional) dimeric peptide 
hematopoietic growth factor receptor agonist.