RESUMEN
To develop effective taxane-antibody immunoconjugates, we have prepared a series of modified taxanes that have both improved toxicity and solubility in aqueous systems as compared to paclitaxel (1a). These taxanes have been modified at either the C-10 or C-7 position and were found to be very cytotoxic against both normal and multi-drug-resistant (MDR) cells, as well as up to 30 times more soluble than paclitaxel in various buffer systems.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Paclitaxel/análogos & derivados , Taxoides/química , Taxoides/farmacología , Antineoplásicos/administración & dosificación , Bioquímica/métodos , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Disulfuros/química , Portadores de Fármacos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/química , Paclitaxel/farmacología , Polietilenglicoles/química , Solubilidad , Relación Estructura-Actividad , Taxoides/administración & dosificación , Células Tumorales CultivadasRESUMEN
The synthesis and biological evaluation of hydrophilic heterobifunctional cross-linkers for conjugation of antibodies with highly cytotoxic agents are described. These linkers contain either a negatively charged sulfonate group or a hydrophilic, noncharged PEG group in addition to an amine-reactive N-hydroxysuccinimide (NHS) ester and sulfhydryl reactive termini. These hydrophilic linkers enable conjugation of hydrophobic organic molecule drugs, such as a maytansinoid, at a higher drug/antibody ratio (DAR) than hydrophobic SPDB and SMCC linkers used earlier without triggering aggregation or loss of affinity of the resulting conjugate. Antibody-maytansinoid conjugates (AMCs) bearing these sulfonate- or PEG-containing hydrophilic linkers were, depending on the nature of the targeted cells, equally to more cytotoxic to antigen-positive cells and equally to less cytotoxic to antigen-negative cells than conjugates made with SPDB or SMCC linkers and thus typically displayed a wider selectivity window, particularly against multidrug resistant (MDR) cancer cell lines in vitro and tumor xenograft models in vivo.