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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| Format: | Article |
| Language: | English |
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Nature Portfolio
2018-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-018-25652-w |
| _version_ | 1818425281603436544 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T14:11:27Z |
| format | Article |
| id | doaj.art-cc6ab514259e46329891bf7dc1a71817 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T14:11:27Z |
| publishDate | 2018-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-cc6ab514259e46329891bf7dc1a718172022-12-21T22:58:17ZengNature PortfolioScientific Reports2045-23222018-05-018111110.1038/s41598-018-25652-wTrivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritisXiaofang Cui0Linmo Chang1Youwei Li2Qianrui Lv3Fei Wang4Yaxian Lin5Weiyang Li6Jonathan D. Meade7Jamie C. Walden8Peng Liang9Department of Biochemistry & Molecular Biology, College of Life Sciences, Sichuan UniversityDepartment of Biochemistry & Molecular Biology, College of Life Sciences, Sichuan UniversityDepartment of Biochemistry & Molecular Biology, College of Life Sciences, Sichuan UniversityDepartment of Biochemistry & Molecular Biology, College of Life Sciences, Sichuan UniversityDepartment of Biochemistry & Molecular Biology, College of Life Sciences, Sichuan UniversityDepartment of Biochemistry & Molecular Biology, College of Life Sciences, Sichuan UniversityJining Medical UniversityGenHunter CorporationGenHunter CorporationDepartment of Biochemistry & Molecular Biology, College of Life Sciences, Sichuan UniversityAbstract 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.https://doi.org/10.1038/s41598-018-25652-w |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-018-25652-w |
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