Divinylsulfonamides enable the construction of homogeneous antibody-drug conjugates.
Bioorg Med Chem
; 28(23): 115793, 2020 12 01.
Article
em En
| MEDLINE
| ID: mdl-33039798
ABSTRACT
Methods that site-specifically attach payloads to an antibody with controlled DAR (Drug-Antibody Ratio) are highly desirable for the generation of homogeneous antibody-drug conjugates (ADCs). We describe the use of N-phenyl-divinylsulfonamide scaffold as a linker platform to site-specifically construct homogeneous DAR four ADCs through a disulfide re-bridging approach. Several monomethyl auristatin E (MMAE)-linkers were synthesized and the drug-linkers that contain electron-donating groups on the phenyl of the linker showed high stability. Her2-targeted MMAE-linker-herceptin and EGFR targeted MMAE-linker-cetuximab conjugates were prepared. The conjugates demonstrated high efficacy and selectivity for killing target-positive cancer cells in vitro. The EGFR-targeted conjugates also showed significant antitumor activities in vivo.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Imunoconjugados
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2020
Tipo de documento:
Article