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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 10, 2007; DOI: 10.1124/jpet.107.119875

0022-3565/07/3222-822-828$20.00
JPET 322:822-828, 2007
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NEUROPHARMACOLOGY

Tumor Necrosis Factor (TNF)-Soluble High-Affinity Receptor Complex as a TNF Antagonist

Sean D. McKenna, Georg Feger, Christie Kelton, Meijia Yang, Vittoria Ardissone, Rocco Cirillo, Pierre-Alain Vitte, Xuliang Jiang, and Robert K. Campbell

Serono Research Institute, Rockland, Massachusetts (S.D.M., C.K., M.Y., X.J., R.K.C.); Serono Pharmaceutical Research Institute, Plan-les-Ouates, Geneva, Switzerland (G.F., P.-A.V.); and Istituto di Ricerche Biomediche "A Marxer", Ivrea, Italy (V.A., R.C.)

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.

Received January 11, 2007; accepted May 9, 2007.

Address correspondence to: Sean D. McKenna, Serono Research Institute, One Technology Place, Rockland, MA 02370. E-mail: sean.mckenna{at}serono.com




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E. M. Grund, D. Kagan, C. A. Tran, A. Zeitvogel, A. Starzinski-Powitz, S. Nataraja, and S. S. Palmer
Tumor Necrosis Factor-{alpha} Regulates Inflammatory and Mesenchymal Responses via Mitogen-Activated Protein Kinase Kinase, p38, and Nuclear Factor {kappa}B in Human Endometriotic Epithelial Cells
Mol. Pharmacol., May 1, 2008; 73(5): 1394 - 1404.
[Abstract] [Full Text] [PDF]


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