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.
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Authors | Pradeep Sathyanarayana, Estelle Houde, Deborah Marshall, Amy Volk, Dorie Makropoulos, Christine Emerson, Anamika Pradeep, Peter J Bugelski, Don M Wojchowski |
Journal | Blood
(Blood)
Vol. 113
Issue 20
Pg. 4955-62
(May 14 2009)
ISSN: 1528-0020 [Electronic] United States |
PMID | 19264917
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- CNTO 530
- Hematinics
- Recombinant Fusion Proteins
- Erythropoietin
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Topics |
- Anemia
(pathology)
- Animals
- Bone Marrow Cells
(drug effects, physiology)
- Cell Count
- Cells, Cultured
- Drug Evaluation, Preclinical
- Erythroblasts
(drug effects, physiology)
- Erythropoiesis
(drug effects)
- Erythropoietin
(analogs & derivatives, chemistry)
- Female
- Hematinics
(chemistry, pharmacology)
- Mice
- Mice, Inbred C57BL
- Molecular Mimicry
- Rats
- Rats, Sprague-Dawley
- Recombinant Fusion Proteins
(chemistry, pharmacology)
- Signal Transduction
(drug effects)
- Time Factors
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