EPO mimetic peptides (EMPs) have a completely different structure than erythropoietin (EPO) or new generation recombinant erythropoiesis stimulating agents (ESAs) like Darbepoietin alfa (Aranesp) and continuous erythropoiesis stimulating agent (CERA). This study intended to compare the effects of a novel compound called AGEM400(HES), consisting of a dimeric EMP conjugated to hydroxyethyl starch (HES), to those of recombinant EPO. AGEM400(HES) efficiently stimulated erythropoiesis in vitro and efficiently stimulated survival of EPO-dependent cell line UT7/EPO. It also efficiently induced phosphorylation of signaling proteins in these models. However, AGEM400(HES) was shown to have weak or absent effects on survival of, and signaling in, three different EPO-responsive hematopoietic cell lines. In the latter models, when added in excess to moderate concentrations of EPO, AGEM400(HES) inhibited the activity of EPO in a fashion indicating receptor binding competition between EPO and AGEM400(HES). It was furthermore shown, using stably transfected BA/F3 cells, that the degree of responsiveness of a cell to AGEM400(HES) relative to its responsiveness to EPO, correlated with the level of EPO receptor surface expression. The findings presented raise intriguing possibilities because they imply that not all side-effects said to be associated with EPO must necessarily be elicited by AGEM400(HES) too.
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