Submitted August 5, 2008
Accepted February 26, 2009
CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools
Pradeep Sathyanarayana, Estelle Houde, Deborah Marshall, Amy Volk, Dorie Makropoulos, Christine Emerson, Anamika Pradeep, Peter J. Bugelski, and Don M. Wojchowski*
Stem & Progenitor Cell Biology Program, Molecular Medicine Division, Maine Medical Center Research Institute, Scarborough, ME, United States
Centocor Research and Development, Radnor, PA, United States
* Corresponding author; email: wojchd{at}mmc.org.
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 MIMETIBODYTM 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 one 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 epoietin-alfa. p70S6K activation by CNTO 530, however, was selectively sustained. In vivo, CNTO 530 uniquely stimulated the enhanced formation of PODXLhighCD71high (pro)erythroblasts at frequencies multi-fold above epoetin-alfa or darbepoietin-alfa. CNTO 530 moreover supported the sustained expansion of a bone marrow- resident KitnegCD71highTer119neg progenitor pool. Based on these distinct erythropoietic and EPOR signaling properties, CNTO 530 holds excellent promise as a new EPO mimetic.
