Therapeutic study of rheumatoid arthritis by humanized anti-PAD4 antibody

• Project/Area Number: 26461470
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Nagoya City University
• Principal Investigator: KANAZAWA Satoshi 名古屋市立大学, 大学院医学研究科, 助教 (90347401)
• Co-Investigator(Renkei-kenkyūsha): SATO Mamoru 横浜市立大学, 大学院生命医科学研究科, 教授 (60170784)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 関節リウマチ / 間質性肺炎 / PAD4 / 抗CCP抗体 / 炎症 / トランスレーショナルリサーチ / モデル動物 / 膠原病 / 病態モデル動物 / 動物 / 免疫学

Outline of Final Research Achievements

Peptidylarginine deiminase 4 (PAD4) that catalyzes the conversion of protein arginine residues to citrulline residues in the presence of Ca2+ is likely to be involved in rheumatoid arthritis (RA), because anti cyclic citrullinated protein antibodies against its catalytic modified peptides are associated with onset of RA disease. However, it is still not clear whether PAD4, in particular, its catalytic activity directly affects onset of RA symptoms.　To reveal this, we created that anti PAD4 monoclonal antibodies recognized catalytic cleft of PAD4. Antibodies were obtained by phage display technique to be combined with immunization in chick.　They were introduced by intraperitoneal administration in RA model mouse, called D1CC mouse, resulted in reduction of onset of inflammatory arthritis.　Anti PAD4 antibody reduces inflammatory arthritis in D1CC mouse. We therefore concluded that PAD4 played critical role in the pathogenesis of initial phase of RA.

Research Products

• [Journal Article] A diagnostic marker for superficial urothelial bladder carcinoma: lack of nuclear ATBF1 (ZFHX3) by immunohistochemistry suggests malignant progression. (2016)
  • Author(s): Kawaguchi M, Hara N, Bilim V, Koike H, Suzuki M, Kim TS, Gao N, Dong Y, Zhang S, Fujinawa Y, Yamamoto O, Ito H, Tomita Y, Naruse Y, Sakamaki A, Ishii Y, Tsuneyama K, Inoue M, Itoh J, Yasuda M, Sakata N, Jung CG, Kanazawa S, Akatsu H, Minato H, Nojima T, Asai K, Miura Y.
  • Journal Title: BMC Cancer. Volume: 16 Issue: 1 Pages: 805-805
  • DOI: 10.1186/s12885-016-2845-5
  • NAID: 120006814095
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel quinone derived from 5-hydroxyindoleacetic acid reacts with protein: Possible participation of oxidation of serotonin and its metabolite in the development of atherosclerosis (2016)
  • Author(s): Kato, Y., Oki, K., Suga, N., Ono, S., Ishisaka, A., Miura, Y., Kanazawa, S., Naito, M., Kitamoto, N., Kettle, A. J.
  • Journal Title: Free Radic Biol Med Volume: 101 Pages: 500-510
  • DOI: 10.1016/j.freeradbiomed.2016.11.023
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Chronic interstitial pneumonitis in D1CC/ D1BC mouse, animal model of rheumatoid arthritis (2017)
  • Author(s): Satoshi Kanazawa and Yoko Miura
  • Organizer: 19th Takeda Science Foundataion Symposium on Bioscience (Osaka)
  • Place of Presentation: 大阪府・吹田市 武田薬品研修所
  • Year and Date: 2017-01-20
  • Int'l Joint Research
• [Presentation] Ectopic expression of B7.1 (CD80) in chondrocytes leads to chronic inflammatory arthritis in mice (2017)
  • Author(s): Yoko Miura and Satoshi Kanazawa
  • Organizer: 19th Takeda Science Foundataion Symposium on Bioscience (Osaka)
  • Place of Presentation: 大阪府・吹田市 武田薬品研修所
  • Year and Date: 2017-01-20
  • Int'l Joint Research
• [Presentation] 関節リウマチモデル（D1CC, D1BCマウス）における関節炎発症重篤化のメカニズムについて (2016)
  • Author(s): 金澤 智
  • Organizer: 日本炎症・再生医学会
  • Place of Presentation: 京都府・京都市 京都市勧業館 みやこめっせ
  • Year and Date: 2016-06-16
• [Presentation] 関節リウマチマウスモデル(D1CCxD1BCマウス)における間質性肺炎誘導 (2016)
  • Author(s): 金澤 智
  • Organizer: 第60回日本リウマチ学会総会
  • Place of Presentation: 神奈川県・横浜市 パシフィコ横浜
  • Year and Date: 2016-04-21
• [Presentation] 間質性肺炎モデルマウスから単離した繊維芽細胞の解析 (2016)
  • Author(s): 金澤 智
  • Organizer: 第19回間質性肺炎細胞分子病態研究会
  • Place of Presentation: 東京都・千代田区 砂防会館
• [Presentation] Bleomycin投与により、間質性肺炎慢性化状態を示す新たなモデルマウス (2015)
  • Author(s): 金澤 智
  • Organizer: 第18回間質性肺炎細胞分子病態研究会
  • Place of Presentation: 砂防会館（東京都千代田区）
  • Year and Date: 2015-08-22
  • Invited
• [Presentation] 関節リウマチモデル（D1CCマウス）を用いたブレオマイシン誘導後に観察された慢性型の間質性肺炎の解析 (2015)
  • Author(s): 金澤 智
  • Organizer: 第36回日本炎症・再生医学会
  • Place of Presentation: 虎の門ヒルズフォーラム（東京都港区）
  • Year and Date: 2015-07-21
• [Presentation] 関節リウマチモデル（D1CCマウス）を用い“炎症～骨破壊～合併症”の連鎖を探る (2015)
  • Author(s): 金澤 智
  • Organizer: 免疫セミナー
  • Place of Presentation: ホテル日航プリンセス京都（京都府京都市）
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] D1CCマウス（RAモデル）における導入遺伝子量が関節炎および合併症、間質性肺炎の重篤度に及ぼす影響について (2015)
  • Author(s): 金澤 智
  • Organizer: 第59回日本リウマチ学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-23
• [Presentation] PAD4天然変性領域をターゲットとした抗PAD4抗体による関節リウマチモデル（D1CCマウス）における治療効果検討 (2014)
  • Author(s): 金澤 智
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 万国津梁館（沖縄）
  • Year and Date: 2014-07-01 – 2014-07-04
• [Presentation] PAD4天然変性領域をターゲットとした抗PAD4抗体による関節リウマチモデルマウス、D1CCマウスを用いた治療検討 (2014)
  • Author(s): 金澤 智
  • Organizer: 第58回日本リウマチ学会
  • Place of Presentation: グランドプリンスホテル高輪（東京都）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Remarks] 名古屋市立大学大学院医学研究科細胞分子生物学
  • URL: http://www.med.nagoya-cu.ac.jp/molgene.dir/
• [Patent(Industrial Property Rights)] 新規抗PAD4抗体 (2016)
  • Inventor(s): 金澤 智 他
  • Industrial Property Rights Holder: 金澤 智 他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-03-06
  • Overseas
• [Patent(Industrial Property Rights)] 間質性肺炎モデル動物及びその用途 (2015)
  • Inventor(s): 金澤 智
  • Industrial Property Rights Holder: 金澤 智
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-049568
  • Filing Date: 2015-09-26
• [Patent(Industrial Property Rights)] 新規抗PAD4抗体 (2015)
  • Inventor(s): 金澤 智 他
  • Industrial Property Rights Holder: 金澤 智 他
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-044518
  • Filing Date: 2015-03-06