RESUMO
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.
Assuntos
Anticorpos/química , Imunoconjugados/química , Maitansina/química , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Modelos Químicos , Transplante de Neoplasias , Polietilenoglicóis/química , Succinimidas/química , Sulfonas/químicaRESUMO
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.
