PT  - JOURNAL ARTICLE
AU  - Sean D. McKenna
AU  - Georg Feger
AU  - Christie Kelton
AU  - Meijia Yang
AU  - Vittoria Ardissone
AU  - Rocco Cirillo
AU  - Pierre-Alain Vitte
AU  - Xuliang Jiang
AU  - Robert K. Campbell
TI  - Tumor Necrosis Factor (TNF)-Soluble High-Affinity Receptor Complex as a TNF Antagonist
AID  - 10.1124/jpet.107.119875
DP  - 2007 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 822--828
VI  - 322
IP  - 2
4099  - http://jpet.aspetjournals.org/content/322/2/822.short
4100  - http://jpet.aspetjournals.org/content/322/2/822.full
SO  - J Pharmacol Exp Ther2007 Aug 01; 322
AB  - 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 α and β 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-α 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. The American Society for Pharmacology and Experimental Therapeutics