Tumor necrosis factor (TNF)-soluble high-affinity receptor complex as a TNF antagonist.
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.
McKenna
Sean D
SD
Serono Research Institute, Rockland, Massachusetts 02370, USA. sean.mckenna@serono.com
Feger
Georg
G
Kelton
Christie
C
Yang
Meijia
M
Ardissone
Vittoria
V
Cirillo
Rocco
R
Vitte
Pierre-Alain
PA
Jiang
Xuliang
X
Campbell
Robert K
RK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000235:genetics*; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D015292:Glycoprotein Hormones, alpha Subunit / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008970:Molecular Weight; D010446:Peptide Fragments / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006063:Chorionic Gonadotropin; D018997:Chorionic Gonadotropin, beta Subunit, Human; D015292:Glycoprotein Hormones, alpha Subunit; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; C506235:TNFRSF1A protein, human; D014409:Tumor Necrosis Factor-alpha