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. How...

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Autores principales:	Xiaofang Cui, Linmo Chang, Youwei Li, Qianrui Lv, Fei Wang, Yaxian Lin, Weiyang Li, Jonathan D. Meade, Jamie C. Walden, Peng Liang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cc6ab514259e46329891bf7dc1a71817
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spelling	oai:doaj.org-article:cc6ab514259e46329891bf7dc1a718172021-12-02T12:32:35ZTrivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis10.1038/s41598-018-25652-w2045-2322https://doaj.org/article/cc6ab514259e46329891bf7dc1a718172018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25652-whttps://doaj.org/toc/2045-2322Abstract 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.Xiaofang CuiLinmo ChangYouwei LiQianrui LvFei WangYaxian LinWeiyang LiJonathan D. MeadeJamie C. WaldenPeng LiangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiaofang Cui Linmo Chang Youwei Li Qianrui Lv Fei Wang Yaxian Lin Weiyang Li Jonathan D. Meade Jamie C. Walden Peng Liang Trivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis
description	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.
format	article
author	Xiaofang Cui Linmo Chang Youwei Li Qianrui Lv Fei Wang Yaxian Lin Weiyang Li Jonathan D. Meade Jamie C. Walden Peng Liang
author_facet	Xiaofang Cui Linmo Chang Youwei Li Qianrui Lv Fei Wang Yaxian Lin Weiyang Li Jonathan D. Meade Jamie C. Walden Peng Liang
author_sort	Xiaofang Cui
title	Trivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis
title_short	Trivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis
title_full	Trivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis
title_fullStr	Trivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis
title_full_unstemmed	Trivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis
title_sort	trivalent soluble tnf receptor, a potent tnf-α antagonist for the treatment collagen-induced arthritis
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/cc6ab514259e46329891bf7dc1a71817
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Trivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis

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