Development of novel antibody drugs for inhibition of autoimmune diseases, based on integrin splicing variant functions

• Project/Area Number: 24590072
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Hokkaido University
• Principal Investigator: KON Shigeyuki 北海道大学, 薬学研究科(研究院), 准教授 (90344499)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: インテグリン / スプライシングバリアント / 細胞接着 / 酵素阻害剤 / 自己免疫疾患 / 抗体 / インテグリン変異体 / がん転移

Outline of Final Research Achievements

We reported that SFα9, α9 integrin splicing variant, is a functional modulator of wild-type α9 integrin. We identified a inhibitor, which inhibits α9 integrin function, by exploring SFα9-binding molecules. The inhibitor protects mice from various autoimmune diseases.
We identified α4 integrin splicing variant, α4B. Although cells expressing α4B only have little binding to ligands of wild-type, cells co-expressing wild-type α4 integrin and α4B exhibits inhibition of wild-type α4 integrin-dependent cell adhesion. Thus, α4B is a endogenous inhibitory molecule for wild-type α4 integrin.

Research Products

• [Journal Article] Tyk2 is a therapeutic target for psoriasis-like skin inflammation. (2014)
  • Author(s): Ishizaki M, Muromoto R, Akimoto T, Sekine Y, Kon S, Diwan M, Maeda, H, Togi S, Shimoda K, Oritani K, Matsuda T.
  • Journal Title: Int. Immunol. Volume: 26 Issue: 5 Pages: 257-267
  • DOI: 10.1093/intimm/dxt062
  • NAID: 120005522324
  • Peer Reviewed
• [Journal Article] Signal-transducing adaptor protein-2 controls the IgE-mediated, mast cell-mediated anaphylactic responses. (2014)
  • Author(s): Sekine Y, Nishida K, Yamasaki S, Muromoto R, Kon S, Kashiwakura J, Saitoh K, Togi S, Yoshimura A, Oritani K, Matsuda T
  • Journal Title: J Immunol Volume: 192 Issue: 8 Pages: 3488-3495
  • DOI: 10.4049/jimmunol.1300886
  • Peer Reviewed
• [Journal Article] Signal-transducing adaptor protein-2 regulates macrophage migration into inflammatory sites during dextran sodium sulfate induced colitis. (2014)
  • Author(s): Fujita N, Oritani K, Ichii M, Yokota T, Saitoh N, Okuzaki D, Sekine Y, Kon S, Muromoto R, Saitoh K, Yoshimura A, Matsuda T, Kanakura Y.
  • Journal Title: Eur J Immunol. Volume: 44 Issue: 6 Pages: 1791-1801
  • DOI: 10.1002/eji.201344239
  • Peer Reviewed / Open Access
• [Journal Article] The novel α4B murine α4 integrin splicing variant inhibits α4-dependent cell adhesion. (2014)
  • Author(s): Kouro H, Kon S, Matsumoto N, Miyashita T, Kakuchi A, Ashitomi D, Saito K, Nakatsuru T, Togi S, Muromoto R, Matsuda T.
  • Journal Title: J Biol Chem. Volume: 289 Issue: 23 Pages: 16389-16398
  • DOI: 10.1074/jbc.m114.553610
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel cryptic binding motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved osteopontin as a novel ligand for α9β1 integrin is involved in the anti-type II collagen antibody-induced arthritis. (2014)
  • Author(s): Kon S, Nakayama Y, Matsumoto N, Ito K, Kanayama M, Kimura C, Kouro H, Ashitomi D, Matsuda T, Uede T.
  • Journal Title: PLoS One. Volume: 9 Issue: 12 Pages: e116210-e116210
  • DOI: 10.1371/journal.pone.0116210
  • NAID: 120005540287
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] α9β1 integrin acts as a critical intrinsic regulator of human rheumatoid arthritis. (2014)
  • Author(s): α9β1 integrin acts as a critical intrinsic regulator of human rheumatoid arthritis.
  • Journal Title: Rheumatology (Oxford). Volume: 53 Issue: 3 Pages: 415-424
  • DOI: 10.1093/rheumatology/ket371
  • Peer Reviewed / Open Access
• [Journal Article] Y14 positively regulates TNF-α-induced NF-κB transcriptional activity via interacting RIP1 and TRADD beyond an exon junction complex protein. (2013)
  • Author(s): Togi S, Shiga K, Muromoto R, Kato M, Souma Y, Sekine Y, Kon S, Oritani K, Matsuda T.
  • Journal Title: J Immunol Volume: 191 Issue: 3 Pages: 1436-1444
  • DOI: 10.4049/jimmunol.1300501
  • Peer Reviewed
• [Journal Article] Jun activation domain-binding protein 1 (JAB1) is required for the optimal response to interferons. (2013)
  • Author(s): Muromoto R, Nakajima M, Hirashima K, Hirao T, Kon S, Shimoda K, Oritani K, Matsuda T.
  • Journal Title: J Biol Chem Volume: 288 Issue: 43 Pages: 30969-30979
  • DOI: 10.1074/jbc.m113.485847
  • NAID: 120005397865
  • Peer Reviewed
• [Journal Article] Signal-transducing adaptor protein-2 modulates Fas-mediated T cell apoptosis by interacting with caspase-8. (2012)
  • Author(s): Sekine Y, et al
  • Journal Title: J Immunol Volume: 188 Issue: 12 Pages: 6194-6204
  • DOI: 10.4049/jimmunol.1103467
  • Peer Reviewed
• [Presentation] 新規α9インテグリンリガンドLymphotactinの同定と機能解析 (2015)
  • Author(s): 中鶴 拓也, 松本 尚樹, 紅露 ひとみ, 松田 正, 今 重之
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] α4インテグリンスプライシングバリアントによるインテグリン機能調節機構の解明と創薬への発展 (2015)
  • Author(s): 今 重之, 紅露 ひとみ, 中鶴 拓也, 宮下 友惠, 松本 尚樹, 松田 正
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] 新規α４インテグリンバリアントはα４インテグリンの内在性機能阻害因子である (2014)
  • Author(s): 紅露ひとみ、松本尚樹、宮下友恵、中鶴拓也、今重之、松田正
  • Organizer: 第51回日本生化学会北海道支部例会
  • Place of Presentation: 札幌
  • Year and Date: 2014-07-18
• [Presentation] 新規変異型α４インテグリンの同定と機能解析 (2014)
  • Author(s): 宮下友惠、紅露ひとみ、松本尚樹、今重之、松田正
  • Organizer: 日本薬学会北海道支部第141回例会
  • Place of Presentation: 札幌
  • Year and Date: 2014-05-24
• [Presentation] Lymphotactinは新規α９インテグリンリガンドである (2014)
  • Author(s): 中鶴拓也、松本尚樹、紅露ひとみ、今重之、松田正
  • Organizer: 日本薬学会北海道支部第141回例会
  • Place of Presentation: 札幌
  • Year and Date: 2014-05-24
• [Presentation] 細胞内配列の異なる新規変異型α４インテグリンは α４インテグリン依存性細胞接着を抑制する (2013)
  • Author(s): 紅露 ひとみ、今 重之、松田 正
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸ポートアイランド、兵庫県
• [Presentation] A novel secreted alpha4 integrin variant inhibits alpa4 and alpha9 integrin-dependent cell adhesion (2013)
  • Author(s): Shigeyuki Kon and Tadashi Matsuda
  • Organizer: 第42回日本免疫学会
  • Place of Presentation: 千葉県幕張メッセ、千葉県
• [Presentation] Identification of a novel alpha9 integrin ligand, lymphotactin (2013)
  • Author(s): Naoki Matsumoto, Shigeyuki Kon, Tadashi Matsuda
  • Organizer: 第42回日本免疫学会
  • Place of Presentation: 千葉県幕張メッセ、千葉県
• [Presentation] 細胞内配列の異なる新規変異型α４インテグリンの機能 (2013)
  • Author(s): 紅露ひとみ、今重之、松田正
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] A novel murine α4 integrin splicing variant is a specific receptor for VCAM-1 (2012)
  • Author(s): Kon S, Kouro H, Matsuda T
  • Organizer: The 99th AAI Annual Meeting
  • Place of Presentation: Hynes Convention Center, Boston, USA
• [Remarks] がん細胞転移を抑制する新たな細胞接着制御メカニズムを解明
  • URL: http://www.hokudai.ac.jp/news/140428_pr_pharm.pdf