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

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 ␣ and ␤ 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-␣ 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.

Tumor Necrosis Factor-α Regulates Inflammatory and Mesenchymal Responses via Mitogen-Activated Protein Kinase Kinase, p38, and Nuclear Factor κB in Human Endometriotic Epithelial Cells

“…The IKK2 inhibitor (AS602868) was synthesized at Serono (Frelin et al, 2003). TBP (Onercept) was produced at Serono and was used at 100 g/ml (D'Antonio et al, 2000;McKenna et al, 2007).…”

A Long-Acting Tumor Necrosis Factor α-Binding Protein Demonstrates Activity in Both In Vitro and In Vivo Models of Endometriosis

“…We recently described the development of novel TNF␣ antagonist by fusing TBP-1 to both the ␣ and ␤ subunits of an inactive hCG (McKenna et al, 2007). Removal of the last five amino acids from the C-terminal region of the ␣-subunit renders the hCG formed an inactive protein (McKenna et al, 2007). The resulting fusion protein, called TNF-soluble high-affinity receptor complex (TNF-SHARC), was described to have a prolonged pharmacokinetic profile compared with TBP-1 (McKenna et al, 2007).…”

“…The soluble form of human TNF␣ receptor-1, called TNF-binding protein (TBP)-1, was effective in inhibiting endometriosis in both rat and baboon animal models of endometriosis (D'Antonio et al, 2000;D'Hooghe et al, 2006). We recently described the development of novel TNF␣ antagonist by fusing TBP-1 to both the ␣ and ␤ subunits of an inactive hCG (McKenna et al, 2007). Removal of the last five amino acids from the C-terminal region of the ␣-subunit renders the hCG formed an inactive protein (McKenna et al, 2007).…”

“…Removal of the last five amino acids from the C-terminal region of the ␣-subunit renders the hCG formed an inactive protein (McKenna et al, 2007). The resulting fusion protein, called TNF-soluble high-affinity receptor complex (TNF-SHARC), was described to have a prolonged pharmacokinetic profile compared with TBP-1 (McKenna et al, 2007). This novel fusion protein, due to the dimeric nature of TNF␣ binding showed increased efficacy in vitro and was effective in inhibiting collagen-induced arthritis in mice (McKenna et al, 2007).…”

“…The resulting fusion protein, called TNF-soluble high-affinity receptor complex (TNF-SHARC), was described to have a prolonged pharmacokinetic profile compared with TBP-1 (McKenna et al, 2007). This novel fusion protein, due to the dimeric nature of TNF␣ binding showed increased efficacy in vitro and was effective in inhibiting collagen-induced arthritis in mice (McKenna et al, 2007). Engineering Fc-fusion proteins can also increase the half-life of newly formed proteins; however, they have the potential to lead to immunoglobulin-mediated effector functions such as antibody dependent cell cytotoxicity.…”