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タイトル: | Structural basis for tumor necrosis factor blockade with the therapeutic antibody golimumab |
著者: | Ono, Masatsugu Horita, Shoichiro Sato, Yumi Nomura, Yayoi Iwata, So Nomura, Norimichi https://orcid.org/0000-0002-6330-2239 (unconfirmed) |
著者名の別形: | 佐藤, 有美 野村, 弥生 岩田, 想 野村, 紀通 |
キーワード: | autoimmune disease competitive inhibition steric hindrance therapeutic antibody golimumab tumor necrosis factor α (TNFα) X‐ray crystallography |
発行日: | Jun-2018 |
出版者: | Wiley |
誌名: | Protein Science |
巻: | 27 |
号: | 6 |
開始ページ: | 1038 |
終了ページ: | 1046 |
抄録: | Tumor necrosis factor α (TNFα) is a proinflammatory cytokine, and elevated levels of TNFα in serum are associated with various autoimmune diseases, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis, and systemic lupus erythaematosus. TNFα performs its pleiotropic functions by binding to two structurally distinct transmembrane receptors, TNF receptor (TNFR) 1 and TNFR2. Antibody‐based therapeutic strategies that block excessive TNFα signaling have been shown to be effective in suppressing such harmful inflammatory conditions. Golimumab (Simponi®) is an FDA‐approved fully human monoclonal antibody targeting TNFα that has been widely used for the treatment of RA, AS, and CD. However, the structural basis underlying the inhibitory action of golimumab remains unclear. Here, we report the crystal structure of the Fv fragment of golimumab in complex with TNFα at a resolution of 2.73 Å. The resolved structure reveals that golimumab binds to a distinct epitope on TNFα that does not overlap with the binding residues of TNFR2. Golimumab exerts its inhibitory effect by preventing binding of TNFR1 and TNFR2 to TNFα by steric hindrance. Golimumab does not induce conformational changes in TNFα that could affect receptor binding. This mode of action is specific to golimumab among the four anti‐TNFα therapeutic antibodies currently approved for clinical use. |
著作権等: | This is the accepted version of the following article: [Masatsugu Ono, Shoichiro Horita, Yumi Sato, Yayoi Nomura, So Iwata, Norimichi Nomura. Structural basis for tumor necrosis factor blockade with the therapeutic antibody golimumab. Protein Science, 27(6), 1038-1046], which has been published in final form at https://doi.org/10.1002/pro.3407. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. The full-text file will be made open to the public on 28 May 2019 in accordance with publisher's 'Terms and Conditions for Self-Archiving'. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 This is not the published version. Please cite only the published version. |
URI: | http://hdl.handle.net/2433/231251 |
DOI(出版社版): | 10.1002/pro.3407 |
PubMed ID: | 29575262 |
出現コレクション: | 学術雑誌掲載論文等 |
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