RESUMEN
CVX-22 is a CovX-Body, produced by covalently attaching a thrombospondin-1 (TSP-1) type 1 repeat peptide mimetic to a humanized IgG1 molecule. To dissect the antiangiogenic mechanism of CVX-22, the numbers and proliferative status of defined tumor endothelial cell (TEC) subsets from the B16 and C32 melanoma models were examined. CVX-22 treatment reduced the numbers of activated, vascular endothelial growth factor receptor 2 (VEGFR2)-positive TECs. Because the vast majority of mitotically active TECs reside in the VEGFR2 subset, a reduction in numbers of this compartment resulted in an 82% overall decrease in BrdU labeling of TEC. However, the rate of proliferation and VEGFR2 receptor density of this VEGFR2-positive subpopulation were unaffected. Instead, CVX-22 induced endothelial cell apoptosis both in vitro and in vivo, indicating that CVX-22 acts by selective deletion of activated, VEGFR2-positive TEC. The overrepresentation of activated cells in sites of tumor angiogenesis may confer a unique specificity of CVX-22 for tumor vasculature.
Asunto(s)
Proliferación Celular , Endotelio Vascular/efectos de los fármacos , Inmunoglobulina G/metabolismo , Melanoma Experimental/irrigación sanguínea , Neovascularización Patológica , Fragmentos de Péptidos/uso terapéutico , Trombospondina 1/uso terapéutico , Animales , Apoptosis , Relación Dosis-Respuesta a Droga , Endotelio Vascular/patología , Femenino , Citometría de Flujo , Inmunoglobulina G/inmunología , Melanoma Experimental/metabolismo , Melanoma Experimental/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Imitación Molecular , Fragmentos de Péptidos/farmacocinética , Trombospondina 1/farmacocinética , Distribución Tisular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/inmunología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Aryl sulfonamide-based endothelin antagonists were synthesized and covalently linked to the reactive lysine of the m38C2 antibody to create a series of CovX-Bodies. These chemically programmed antibodies behaved as potent endothelin receptor antagonists in vitro and had antitumor efficacy in a prostate cancer xenograft model which, on a molar basis, far exceeded the activity of the parent small molecule.