Tumor necrosis factor (TNF)-soluble high-affinity receptor complex as a TNF antagonist.
J Pharmacol Exp Ther
; 322(2): 822-8, 2007 Aug.
Article
em En
| MEDLINE
| ID: mdl-17495128
ABSTRACT
A novel high-affinity inhibitor of tumor necrosis factor (TNF) is described, which is created by the fusion of the extracellular domains of TNF-binding protein 1 (TBP-1) to both the alpha and beta chains of an inactive version of the heterodimeric protein hormone, human chorionic gonadotropin. The resulting molecule, termed TNF-soluble high-affinity receptor complex (SHARC), self-assembles into a heterodimeric protein containing two functional TBP-1 moieties. The TNF-SHARC is a potent inhibitor of TNF-alpha bioactivity in vitro and has a prolonged pharmacokinetic profile compared with monomeric TBP-1 in vivo. Consistent with the long half-life, the duration of action in an lipopolysaccharide-mediated proinflammatory mouse model is prolonged similarly. In a collagen-induced arthritis mouse model, this molecule demonstrates improved efficacy over monomeric TBP-1. Based on these results, we demonstrated that inactivated heterodimeric protein hormones are flexible and efficient scaffolds for the creation of soluble high-affinity receptor complexes.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Recombinantes de Fusão
/
Fator de Necrose Tumoral alfa
/
Receptores Tipo I de Fatores de Necrose Tumoral
/
Gonadotropina Coriônica
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article