Use of 5-Thio-L-Fucose to modulate binding affinity of therapeutic proteins.
Biotechnol Bioeng
; 118(5): 1818-1831, 2021 05.
Article
em En
| MEDLINE
| ID: mdl-33501689
ABSTRACT
The reduction of antibody core-fucosylation is known to enhance antibody-dependent cellular cytotoxicity (ADCC). In this study, 5-Thio-l-Fucose (ThioFuc) was investigated as a media and feed supplement for modulating the fucosylation profile of therapeutic proteins and, thereby, improving the resulting effector functions. Glycan analysis of five different therapeutic proteins produced by a diverse set of Chinese hamster ovary cell lines demonstrated a clone dependent impact of ThioFuc treatment. Using rituximab as a model, an efficient dose- and time-dependent reduction of core-fucosylation up to a minimum of 5% were obtained by ThioFuc. Besides a concomitant increase in the afucosylation level up to 48%, data also revealed up to 47% incorporation of ThioFuc in place of core-fucosylation. In accordance with the glycan data, antibodies produced in the presence of ThioFuc revealed an enhanced FcγRIIIa binding up to 7.7-fold. Furthermore, modified antibodies subjected to a cell-based ADCC reporter bioassay proved to exert both a 1.5-fold enhanced ADCC efficacy and 2.6-fold enhancement in potency in comparison to their native counterparts-both of which contribute to an improvement in the ADCC activity. In conclusion, ThioFuc is a potent fucose derivative with potential applications in drug development processes.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Recombinantes
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Receptores de IgG
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Técnicas de Cultura de Células
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Reatores Biológicos
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Fucose
Limite:
Animals
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Humans
Idioma:
En
Revista:
Biotechnol Bioeng
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Alemanha