title: Erythropoietin mimetic compound AGEM400(HES) binds to the same receptor as erythropoietin but displays a different spectrum of activities.
abstract: 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.
authors.affiliation: AplaGen GmbH, Arnold-Sommerfeld-Ring 2, D-52499 Baesweiler, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kessler
authors.forename: Alexandra
authors.initials: A
authors.lastname: Greindl
authors.forename: Bettina
authors.initials: B
authors.lastname: Breuer
authors.forename: Udo
authors.initials: U
authors.lastname: Haberl
authors.forename: Andreas
authors.initials: A
authors.lastname: Rybka
authors.forename: Marco
authors.initials: M
authors.lastname: Emgenbroich
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Frank
authors.forename: Andy J G
authors.initials: AJ
authors.lastname: Pötgens
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006895:Hydroxyethyl Starch Derivatives / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D008954:Models, Biological; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017467:Receptors, Erythropoietin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: C571717:AGEM400(HES); D006895:Hydroxyethyl Starch Derivatives; D010455:Peptides; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D004921:Erythropoietin; D000068256:Darbepoetin alfa