RESUMEN
Interleukin-17A (IL-17A) is a soluble pro-inflammatory cytokine, which is mainly secreted by Th17â¯cells. In humans, IL-17A mRNA and protein levels are increased in several autoimmune diseases, including psoriasis and rheumatoid arthritis. This study describes the preclinical in vitro and in vivo characterization of GR1501, a human IL-17A-neutralizing IgG4 monoclonal antibody. GR1501 binds human, rhesus and cynomolgus IL-17A with high affinity but does not bind to mouse IL-17A or other IL-17 family members. GR1501 effectively blocks the interaction between IL-17A and its receptor IL-17RA, thereby inhibiting IL-17A-induced CXCL1 and IL-6 release in cells and mice. In mouse air pouch model, GR1501 effectively inhibits IL-17A induced leukocytes infiltration into the air pouch. GR1501 also reduces joint swelling and inflammation in mouse arthritis model. These data suggest that GR1501 is a potent and selective IL-17A-neutralizing monoclonal antibody and will support the clinical investigation of this monoclonal antibody in psoriasis and rheumatoid arthritis.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Interleucina-17/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/uso terapéutico , Artritis Experimental/inmunología , Artritis Experimental/terapia , Línea Celular , Femenino , Humanos , Macaca fascicularis , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Especificidad de la EspecieRESUMEN
Frequent local recurrence and metastasis are generally involved in human liposarcoma, but the management is a challenge. There is an urgent need for improved effective therapy. In the present study, we reported that SBF-1, a steroidal glycoside, inhibited the growth of cultured highly malignant human liposarcoma SW872-S cells in vitro and in vivo. SBF-1 down-regulated the phosphorylation of protein kinase B (AKT) and thus reduced cell adhesion to fibronectin and laminin. Then we found that SBF-1 inhibited the expression of oxysterol binding protein (OSBP) in SW872-S cells, indicating that OSBP may be involved in malignant liposarcoma cell survival. Cancer cell growth and AKT phosphorylation were inhibited significantly upon knockdown of OSBP in SW872-S cells in vitro. Taken together, these results suggest that SBF-1 causes an apparent loss of OSBP function in SW872-S cells, resulting in growth inhibition. Based on our findings, OSBP serves as a potential therapeutic target for human liposarcoma.