CNTO 530: Molecular pharmacology in human UT-7 sub(E) sub(P) sub(O) cells and pharmacokinetics and pharmacodynamics in mice

• Published in: Journal of biotechnology 2008-03, Vol.134 (1-2), p.171-180
• Main Authors: Bugelski, P J, Capocasale, R J, Makropoulos, D, Marshall, D, Fisher, P W, Lu, J, Achuthanandam, R, Spinka-Doms, T, Kwok, D, Graden, D, Volk, A, Nesspor, T, James, I E, Huang, C
• Format: Article
• Language: English
• ISSN: 0168-1656
• DOI: 10.1016/j.jbiotec.2007.12.005

CNTO 530 is a 58kD antibody Fc domain fusion protein, created using Centocor's MIMETIBODY(TM) platform, that contains two EMP1 sequences as a pharmacophore. CNTO 530 has no sequence homology with EPO but acts as a novel erythropoietin receptor agonist. In UT-7 sub(E) sub(P) sub(O) cells, CNTO 530 caused protein phosporylation of the erythropoietin receptor associated signaling pathway (Jak2, STAT5, AKT and ERK1/2). CNTO 530 also rescued these cells from apoptosis and mediated proliferation. In mice, pharmacokinetic analysis showed that CNTO 530 was slowly cleared from circulation with a t1 /2~40h. Pharmacodynamic analysis in mice showed that a single sc dose of CNTO 530 caused a long-lived stimulation of erythropoiesis that translated into increases in red blood cell counts and hemoglobin values that were maintained for at least 28 d. In conclusion, CNTO 530 is a long-lived EPO-R agonist that stimulates erythropoiesis in a manner similar to epoetin- alpha . These data suggest that CNTO 530 may be an effective treatment of anemia in humans.