A CXCR4-targeted site-specific antibody-drug conjugate.
Angew Chem Int Ed Engl
; 53(44): 11863-7, 2014 Oct 27.
Article
em En
| MEDLINE
| ID: mdl-25213874
ABSTRACT
A chemically defined anti-CXCR4-auristatin antibody-drug conjugate (ADC) was synthesized that selectively eliminates tumor cells overexpressing the CXCR4 receptor. The unnatural amino acid p-acetylphenylalanine (pAcF) was site-specifically incorporated into an anti-CXCR4 immunoglobulinâ
G (IgG) and conjugated to an auristatin through a stable, non-cleavable oxime linkage to afford a chemically homogeneous ADC. The full-length anti-CXCR4 ADC was selectively cytotoxic to CXCR4(+) cancer cells inâ
vitro (half maximal effective concentration (EC50 )≈80-100â
pM). Moreover, the anti-CXCR4 ADC eliminated pulmonary lesions from human osteosarcoma cells in a lung-seeding tumor model in mice. No significant overt toxicity was observed but there was a modest decrease in the bone-marrow-derived CXCR4(+) cell population. Because CXCR4 is highly expressed in a majority of metastatic cancers, a CXCR4-auristatin ADC may be useful for the treatment of a variety of metastatic malignancies.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Imunoconjugados
/
Receptores CXCR4
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Imunoterapia
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Anticorpos Monoclonais
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article