Trivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis.

Abstract

Tumor necrosis factor is a major pro-inflammatory cytokine which triggers various physiological consequences by binding to and trimerizing its receptors, and has been the single most sought-after drug target for intervening autoimmune diseases such as rheumatoid arthritis and psoriasis. However, current TNF-α blockers, including soluble receptor-Fc fusion and therapeutic antibodies, are all dimeric in structure, whereas their target TNF-α itself is homotrimeric in nature. Here we describe the development of a trivalent soluble TNF receptor and show that it is a more potent than the dimeric TNF receptor decoys in inhibiting TNF-α signaling both in vitro and in vivo. The process involves gene fusion between a soluble receptor TNFRII with a ligand binding domain and a trimerization tag from the C-propeptide of human collagen (Trimer-Tag), which is capable of self-assembly into a covalently linked trimer. We show that the homotrimeric soluble TNF receptor (TNFRII-Trimer) produced with such method is more potent in ligand binding kinetics and cell based bioassays, as well as more efficacious in attenuating collagen-induced arthritis (CIA) in a mouse model than its dimeric TNFRII-Fc counterpart. Thus, this work demonstrates the proof of concept of Trimer-Tag and provides a new platform for rational designs of next generation biologic drugs.

• Authors: Xiaofang Cui, Linmo Chang, Youwei Li, Qianrui Lv, Fei Wang, Yaxian Lin, Weiyang Li, Jonathan D Meade, Jamie C Walden, Peng Liang
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 7327 (05 09 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29743640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Tumor Necrosis Factor
• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha
• Collagen

Topics

• Animals
• Arthritis, Experimental (chemically induced, drug therapy)
• Collagen (pharmacology)
• Disease Models, Animal
• Humans
• Kinetics
• Mice
• Protein Domains
• Receptors, Tumor Necrosis Factor (chemistry, metabolism)
• Recombinant Fusion Proteins (chemistry, pharmacology, therapeutic use)
• Solubility
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)