RESUMEN
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.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/farmacocinética , Animales , Apoptosis/efectos de los fármacos , Disponibilidad Biológica , Médula Ósea/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Janus Quinasa 2/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Modelos Biológicos , Fosforilación/efectos de los fármacos , Receptores de Eritropoyetina/agonistas , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The electrocardiogram is shown to be of limited diagnostic value for determining pulmonary embolism in a prospective cohort study of unselected patients with suspected pulmonary embolism.