CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools.
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.
Sathyanarayana
Pradeep
P
Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Houde
Estelle
E
Marshall
Deborah
D
Volk
Amy
A
Makropoulos
Dorie
D
Emerson
Christine
C
Pradeep
Anamika
A
Bugelski
Peter J
PJ
Wojchowski
Don M
DM
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
C541126:CNTO 530; D006397:Hematinics; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin