Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros













Base de datos
Intervalo de año de publicación
2.
Nat Biotechnol ; 26(8): 925-32, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18641636

RESUMEN

Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding. When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 is as efficacious as a conventional conjugate in mouse xenograft models. Moreover, it is tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches. The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that our strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity.


Asunto(s)
Anticuerpos Antineoplásicos/farmacología , Antineoplásicos/farmacología , Citotoxinas/farmacología , Inmunotoxinas/farmacocinética , Neoplasias Ováricas/inmunología , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/farmacología , Anticuerpos Antineoplásicos/genética , Especificidad de Anticuerpos , Sitios de Unión , Antígeno Ca-125/inmunología , Línea Celular Tumoral , Química Farmacéutica/métodos , Cisteína/genética , Femenino , Humanos , Macaca fascicularis , Proteínas de la Membrana/inmunología , Ratones , Mutagénesis Sitio-Dirigida , Oligopéptidos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Compuestos de Sulfhidrilo/farmacología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA