Development of functional mutant protein with antagonistic activity as an anti-inflammatory drug

2009 Fiscal Year Final Research Report

• Project/Area Number: 20890300
• Research Category: Grant-in-Aid for Young Scientists (Start-up)
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: National Institute of Biomedical Innovation
• Principal Investigator: ABE Yasuhiro National Institute of Biomedical Innovation, 創薬基盤研究部バイオ創薬プロジェクト, 研究員 (20509898)
• Research Collaborator: 角田 慎一 ; 鎌田 春彦 ; 井上 雅己 ; 山根 美紀 ; 長野 一也 ; 野村 鉄也 ; 萱室 裕之 ; 河原 倫之 ; 有田 修平 ; 古屋 剛
• Project Period (FY): 2008 – 2009
• Keywords: 蛋白質 / 自己免疫疾患 / アンタゴニスト

Research Abstract

Blocking the binding of TNF to TNF receptor subtype 1 (TNFR1) is believed to be a promising strategy for the treatment of autoimmune disease. Recently, we generated the TNFR1-selective mutant TNF with antagonistic activity (R1antTNF) using phage display technique. In this study, the anti-inflammatory effects of R1antTNF have been investigated. First, to improve the in vivo stability, polyethylene glycol-modified R1antTNF (PEG-R1antTNF) was prepared. In the autoimmune disease model, the clinical score of the mice given PEG-R1antTNF was improved. These results suggest that selective blocking of TNFR1 by PEG-R1antTNF could be an effective therapeutic strategy against autoimmune disease.

Research Products

• [Journal Article] Creation of an improved mutant TNF with TNFR1-selectivity and antagonistic activity by phage display technology (2010)
  • Author(s): Nomura T., Abe Y., Kamada H., Inoue M., Kawara T., Arita S., Furuya T., Minowa K., Yoshioka Y., Shibata H., Kayamuro H., Yamashita T., Nagano K., Yoshikawa T., Mukai Y., Nakagawa S., Tsunoda S., Tsutsumi Y
  • Journal Title: Pharmazie 65(2) Pages: 93-96
  • Peer Reviewed
• [Journal Article] (2010)
  • Author(s): Nomura T., Abe Y., Yoshioka Y., Nakagawa S., Tsunoda S., Tsutsumi Y
  • Journal Title: Yakugaku Zasshi 130(1) Pages: 63-8
• [Journal Article] Development of novel DDS technologies for optimized protein therapy by creating functional mutant proteins with antagonistic activity (2009)
  • Author(s): Abe Y
  • Journal Title: Yakugaku Zasshi 129(8) Pages: 933-939
• [Journal Article] The treatment of established murine collagen-induced arthritis with a TNFR1-selective antagonistic mutant TNF (2009)
  • Author(s): Shibata H., Yoshioka Y., Abe Y., Ohkawa A., Nomura T., Minowa K., Mukai Y., Nakagawa S., Taniai M., Ohta T., Tsunoda S., Kamada H., Tsutsumi Y
  • Journal Title: Biomaterials 30(34) Pages: 6638-6647
  • Peer Reviewed
• [Journal Article] Novel protein engineering strategy for creating highly receptor-selective mutant TNFs (2009)
  • Author(s): Nomura T., Abe Y., Kamada H., Inoue M., Kawara T., Arita S., Furuya T., Yoshioka Y., Shibata H., Kayamuro H., Yamashita T., Nagano K., Yoshikawa T., Mukai Y., Nakagawa S., Taniai M., Ohta T., Tsunoda S., Tsutsumi Y
  • Journal Title: Biochem. Biophys. Res. Commun 388(4) Pages: 667-71
  • Peer Reviewed
• [Journal Article] The augmentation of intracellular delivery of peptide therapeutics by artificial protein transduction domains (2009)
  • Author(s): Yoshikawa T., Sugita T., Mukai Y., Abe Y., Nakagawa S., Kamada H., Tsunoda S., Tsutsumi Y
  • Journal Title: Biomaterials 30(19) Pages: 3318-23
  • Peer Reviewed
• [Journal Article] Structure-function relationship of tumor necrosis factor (TNF) and its receptor interaction based on 3D structural analysis of a fully active TNFR1-selective TNF mutant (2009)
  • Author(s): Mukai Y., Shibata H., Nakamura T., Yoshioka Y., Abe Y., Nomura T., Taniai M., Ohta T., Ikemizu S., Nakagawa S., Tsunoda S., Kamada H., Yamagata Y., Tsutsumi Y
  • Journal Title: J. Mol. Biol 385 Pages: 1221-1229
  • Peer Reviewed
• [Journal Article] The specific effect of 2-Methoxyestradiol on lymphatic vascular endothelial cells (2009)
  • Author(s): Imai S., Yoshida Y., Okamura T., Nagano K., Abe Y., Yoshikawa T., Kamada H., Nakagawa S., Tsunoda S., Tsutsumi Y
  • Journal Title: Pharmazie 64(3) Pages: 214-6
  • Peer Reviewed
• [Journal Article] The therapeutic effect of TNFR1-selective antagonistic mutant TNF-αin murine hepatitis models (2008)
  • Author(s): Shibata H., Yoshioka Y., Ohkawa A., Abe Y., Nomura T., Mukai Y., Nakagawa S., Taniai M., Ohta T., Mayumi T., Kamada H., Tsutsumi Y
  • Journal Title: Cytokine 44(2) Pages: 229-233
  • Peer Reviewed
• [Journal Article] Organelle-targeted delivery of biological macromolecules using the protein transduction domain: Potential applications for peptide aptamer delivery into the nucleus (2008)
  • Author(s): Yoshikawa T., Sugita T., Mukai Y., Yamanada N., Nagano K., Nabeshi H., Yoshioka Y., Nakagawa S., Abe Y., Kamada H., Tsunoda S., Tsutsumi Y
  • Journal Title: J. Mol. Biol 380(5) Pages: 777-782
  • Peer Reviewed
• [Journal Article] Simple and highly sensitive assay system for TNFR2-mediated soluble-and transmembrane-TNF activity (2008)
  • Author(s): Abe Y., Yoshikawa T., Kamada H., Shibata H., Nomura T., Minowa K., Kayamuro H., Katayama K., Miyoshi H., Mukai Y., Yoshioka Y., Nakagawa S., Tsunoda S., Tsutsumi Y
  • Journal Title: J. Immunol. Methods 335(1-2) Pages: 71-8
  • Peer Reviewed
• [Presentation] アンタゴニスト活性を有したTNFR1指向性変異体の新規自己免疫疾患治療薬としての有用性評価 (2009)
  • Author(s): 阿部康弘, 鎌田春彦, 角田慎一, 堤康央
  • Organizer: 第59回日本薬学会近畿支部総会・大会
  • Place of Presentation: 大阪
  • Year and Date: 20091000
• [Presentation] Creation and X-ray structural analysis of TNFR1-selective mutant TNF with antagonistic activity (2009)
  • Author(s): Abe Y., Nomura T., Kayamuro H., Yoshioka Y., Kamada H., Tsunoda S., Tsutsumi Y
  • Organizer: HUPO 8th Annual World Congress, Toronto 2009
  • Place of Presentation: Tronto (Canada)
  • Year and Date: 20090926-20090930
• [Presentation] Effective treatment of established murine collagen-induced arthritis with a novel TNFR1-selective antagonistic mutant TNF (2009)
  • Author(s): Tsunoda S., Abe Y., Nomura T., Kayamuro H., Shibata H., Yoshioka Y., Tsutsumi Y
  • Organizer: 12th International TNF Conference
  • Place of Presentation: Madrid (Spain)
  • Year and Date: 20090426-20090429
• [Presentation] Evaluation of safety and efficacy of TNFR1-selective antagonistic mutant TNF as a novel anti-inflammatory drug (2009)
  • Author(s): Abe Y., Shibata H., Nomura T., Kayamuro H., Yoshikawa T., Yoshioka Y., Nakagawa S., Kamada H., Tsunoda S., Tsutsumi Y
  • Organizer: Society of Toxicology 48th Annual Meeting, ToxExpo
  • Place of Presentation: Baltimore (U.S.A. )
  • Year and Date: 20090315-20090319
• [Presentation] 創薬プロテオミクス研究を有効活用したバイオ創薬 (2009)
  • Author(s): 阿部康弘, 角田慎一, 堤康央
  • Organizer: CphI Japan 2009
  • Place of Presentation: 東京
  • Year and Date: 2009-04-21
• [Presentation] Fine tuning of receptor-selectivity for tumor necrosis factor-□ using a phage display system with one-step competitive-subtractive panning (2008)
  • Author(s): Abe Y., Shibata H., Nomura T., Kayamuro H., Mukai Y., Yoshikawa T., Yoshioka Y., Taniai M., Ohta T., Nakagawa S., Kamada H., Tsunoda S., Tsutsumi Y
  • Organizer: 7th Joint Conference of the Intenational Society for Interderon and Cytokine Research and International Cytokine Society
  • Place of Presentation: Montreal/Quebec (CANADA)
  • Year and Date: 20081012-20081016
• [Presentation] アンタゴニスト活性を有したTNFR1指向性変異体の新規自己免疫疾患治療薬としての有用性評価 (2008)
  • Author(s): 阿部康弘, 野村鉄也, 柴田寛子, 吉岡靖雄, 中川晋作, 鎌田春彦, 角田慎一, 堤康央
  • Organizer: 第58回日本薬学会近畿支部総会・大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-10-25