Antibody-maytansinoid conjugates designed to bypass multidrug resistance.
Cancer Res
; 70(6): 2528-37, 2010 Mar 15.
Article
en En
| MEDLINE
| ID: mdl-20197459
ABSTRACT
Conjugation of cytotoxic compounds to antibodies that bind to cancer-specific antigens makes these drugs selective in killing cancer cells. However, many of the compounds used in such antibody-drug conjugates (ADC) are substrates for the multidrug transporter MDR1. To evade the MDR1-mediated resistance, we conjugated the highly cytotoxic maytansinoid DM1 to antibodies via the maleimidyl-based hydrophilic linker PEG(4)Mal. Following uptake into target cells, conjugates made with the PEG(4)Mal linker were processed to a cytotoxic metabolite that was retained by MDR1-expressing cells better than a metabolite of similar conjugates prepared with the nonpolar linker N-succinimidyl-4-(maleimidomethyl)cyclohexane-1-carboxylate (SMCC). In accord, PEG(4)Mal-linked conjugates were more potent in killing MDR1-expressing cells in culture. In addition, PEG(4)Mal-linked conjugates were markedly more effective in eradicating MDR1-expressing human xenograft tumors than SMCC-linked conjugates while being tolerated similarly, thus showing an improved therapeutic index. This study points the way to the development of ADCs that bypass multidrug resistance.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Inmunotoxinas
/
Maitansina
Idioma:
En
Revista:
Cancer Res
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos