RESUMEN
The effects of treatment with a soluble IL-4 receptor (sIL-4R) on reproduction and neonatal development were assessed in pregnant cynomolgus monkeys and mice. When pregnant cynomolgus monkeys were administered a human sIL-4R intravenously twice a week during organogenesis (GD 20-51) at 0, 0.2 or 2.0mg/kg, there was an increase in abortion/embryo-fetal death in the 0.2 (42.9%) and 2.0 (26.3%) mg/kg groups compared to controls (17.6%). All fetuses removed at cesarean sectioning on GD 100-102 were alive and no abnormalities were noted. There were three stillborn neonates (2.0mg/kg group), which were determined to have died before birth. No neonates died after birth and no abnormalities were noted. Due to the unanticipated results in the monkey study, a mouse developmental study with a murine surrogate molecule was conducted. When pregnant Crl:CD-1((R))(ICR)BR mice were administered murine sIL-4R intravenously once daily during the organogenesis period (GD 6-15) at 0, 25, 75, 250, or 625microg/mouse ( approximately 20mg/kg), there were no test-article-related abnormalities in any parameters. Antibody development to the drug did not influence toxicity in the monkey or mouse. In conclusion, evaluation of reproductive effects in mice administered murine soluble IL-4R was not predictive of reproductive effects noted in cynomolgus monkeys administered human soluble IL-4R.
Asunto(s)
Exposición Materna/efectos adversos , Receptores de Interleucina-4 , Proteínas Recombinantes , Reproducción/efectos de los fármacos , Anomalías Inducidas por Medicamentos/etiología , Anomalías Inducidas por Medicamentos/patología , Animales , Animales Recién Nacidos , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Desarrollo Embrionario/efectos de los fármacos , Femenino , Desarrollo Fetal/efectos de los fármacos , Humanos , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Organogénesis/efectos de los fármacos , Embarazo , Receptores de Interleucina-4/administración & dosificación , Receptores de Interleucina-4/química , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/química , Proteínas Recombinantes/toxicidad , Solubilidad , Especificidad de la EspecieRESUMEN
Regulation of the activity of the proinflammatory cytokine IL-1 is complex, involving transcriptional and translational control, precursor processing, a receptor antagonist (IL-1ra), and a decoy receptor. Here we report that the soluble form of the IL-1 receptor accessory protein (AcP) increases the affinity of binding of human IL-1alpha and IL-1beta to the soluble human type II IL-1 receptor by approximately 100-fold, while leaving unaltered the low binding affinity of IL-1ra. Soluble AcP is present in normal human serum at an average concentration greater than 300 ng/ml. These findings suggest that the soluble form of IL-1R AcP contributes to the antagonism of IL-1 action by the type II decoy receptor, adding another layer of complexity to the regulation of IL-1 action.