title: CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools.
abstract: Anemia as associated with numerous clinical conditions can be debilitating, but frequently can be treated via administration of epoetin-alfa, darbepoietin-alfa, or methoxy-PEG epoetin-beta. Despite the complexity of EPO-EPO receptor interactions, the development of interesting EPO mimetic peptides (EMPs) also has been possible. CNTO 530 is one such novel MIMETIBODY Fc-domain dimeric EMP fusion protein. In a mouse model, single-dose CNTO 530 (unlike epoetin-alfa or darbepoietin-alfa) bolstered red cell production for up to 1 month. In 5-fluorouracil and carboplatin-paclitaxel models, CNTO 530 also protected against anemia with unique efficiency. These actions were not fully accounted for by half-life estimates, and CNTO 530 signaling events therefore were studied. Within primary bone marrow erythroblasts, kinetics of STAT5, ERK, and AKT activation were similar for CNTO 530 and epoetin-alfa. p70S6K activation by CNTO 530, however, was selectively sustained. In vivo, CNTO 530 uniquely stimulated the enhanced formation of PODXL(high)CD71(high) (pro)erythroblasts at frequencies multifold above epoetin-alfa or darbepoietin-alfa. CNTO 530 moreover supported the sustained expansion of a bone marrow-resident Kit(neg)CD71(high)Ter119(neg) progenitor pool. Based on these distinct erythropoietic and EPOR signaling properties, CNTO 530 holds excellent promise as a new EPO mimetic.
authors.affiliation: Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Sathyanarayana
authors.forename: Estelle
authors.initials: E
authors.lastname: Houde
authors.forename: Deborah
authors.initials: D
authors.lastname: Marshall
authors.forename: Amy
authors.initials: A
authors.lastname: Volk
authors.forename: Dorie
authors.initials: D
authors.lastname: Makropoulos
authors.forename: Christine
authors.initials: C
authors.lastname: Emerson
authors.forename: Anamika
authors.initials: A
authors.lastname: Pradeep
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bugelski
authors.forename: Don M
authors.initials: DM
authors.lastname: Wojchowski
mesh_terms: D000740:Anemia / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000502:physiology; D002452:Cell Count; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004900:Erythroblasts / Q000187:drug effects* / Q000502:physiology; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000737:chemistry; D005260:Female; D006397:Hematinics / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: C541126:CNTO 530; D006397:Hematinics; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin