Mild method for succinimide hydrolysis on ADCs: impact on ADC potency, stability, exposure, and efficacy.
Bioconjug Chem
; 25(10): 1871-80, 2014 Oct 15.
Article
en En
| MEDLINE
| ID: mdl-25216346
ABSTRACT
The stability of the connection between the antibody and the toxin can have a profound impact on ADC safety and efficacy. There has been increasing evidence in recent years that maleimide-based ADCs are prone to payload loss via a retro-Michael type reaction. Herein, we report a mild method for the hydrolysis of the succinimide-thioether ring which results in a "ring-opened" linker. ADCs containing this hydrolyzed succinimide linker show equivalent cytotoxicity, improved in vitro stability, improved PK exposure, and improved efficacy as compared to their nonhydrolyzed counterparts. This method offers a simple way to improve the stability, exposure, and efficacy of maleimide-based ADCs.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Succinimidas
/
Sulfuros
/
Inmunotoxinas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioconjug Chem
Asunto de la revista:
BIOQUIMICA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos