title: CNTO 530: molecular pharmacology in human UT-7EPO cells and pharmacokinetics and pharmacodynamics in mice.
abstract: CNTO 530 is a 58 kD antibody Fc domain fusion protein, created using Centocor's MIMETIBODY 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(EPO) 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 t(1/2) approximately 40 h. 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.
authors.affiliation: Centocor Research and Development, Radnor, PA 19087, United States. pbugelsk@cntus.jnj.com
authors.forename: P J
authors.initials: PJ
authors.lastname: Bugelski
authors.forename: R J
authors.initials: RJ
authors.lastname: Capocasale
authors.forename: D
authors.initials: D
authors.lastname: Makropoulos
authors.forename: D
authors.initials: D
authors.lastname: Marshall
authors.forename: P W
authors.initials: PW
authors.lastname: Fisher
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.forename: R
authors.initials: R
authors.lastname: Achuthanandam
authors.forename: T
authors.initials: T
authors.lastname: Spinka-Doms
authors.forename: D
authors.initials: D
authors.lastname: Kwok
authors.forename: D
authors.initials: D
authors.lastname: Graden
authors.forename: A
authors.initials: A
authors.lastname: Volk
authors.forename: T
authors.initials: T
authors.lastname: Nesspor
authors.forename: I E
authors.initials: IE
authors.lastname: James
authors.forename: C
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D001853:Bone Marrow / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D017467:Receptors, Erythropoietin / Q000819:agonists; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3