Development of system for in situ and continuous production of antitumor molecules.

• Project/Area Number: 15K08022
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Shinshu University
• Principal Investigator: Taniguchi Shunichiro 信州大学, 医学部, 特任教授 (60117166)
• Co-Investigator(Kenkyū-buntansha): 肥田 重明 名古屋市立大学, 大学院薬学研究科, 教授 (10345762)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 低酸素環境 / 固形がん / ビフィズス菌 / 遺伝子組み換え / 単鎖抗体 / HER2 / 抗腫瘍性分子DDS / 安全性 / 固形がん治療 / DDS / 低酸素 / 抗腫瘍性抗体 / 抗腫瘍性サイトカイン / 発現分泌系 / サイトカイン / scFv / 炎症性サイトカイン / 固形がんの嫌気的環境 / 遺伝子組み替え / 抗腫瘍性物質

Outline of Final Research Achievements

We have established gene-engineered Bifidobacterium secreting biologically active anti-HER2 scFv. When the Bifidobacterium producing anti-HER2 scFv(B/anti-HER2) was iv injected to immunodeficient nude mice bearing HER2-positive tumor with hypoxic microenvironment, we confirmed the selective localization, growth of B/anti-HER2 in the tumor and the anti-HER2 scFv production in situ, furthermore, the tumor growth being consequently suppressed. In addition to anti HER2 scFv, we also have established Bifidobacterium secreting IFN-g.
On one hand, immunological aspects of Bifidobacterium were examined. When macrophages and dendritic cells were exposed to Bifidobacteirum, induction of inflammatory cytokines was very weak as compared with other bacteria, such as E. coli. In the dialyzed fraction of Bifidobacterium culture medium, however, several proteins inducing cytokines were identified, so that the analysis on the proteins is under way.

Research Products

• [Journal Article] In situ delivery and production system of trastuzumab scFv with Bifidobacterium (2017)
  • Author(s): Kikuchi Takeshi、Shimizu Hitomi、Akiyama Yasuto、Taniguchi Shun'ichiro
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 493 Issue: 1 Pages: 306-312
  • DOI: 10.1016/j.bbrc.2017.09.026
  • Peer Reviewed / Open Access
• [Journal Article] ASC induces apoptosis via activation of caspase-9 by enhancing gap junction-mediated intercellular communication. (2017)
  • Author(s): Kitazawa M, Hida S, Fujii C, Taniguchi S, Ito K, Matsumura T, Okada N, Sakaizawa T, Kobayashi A, Takeoka M, and Miyagawa SI
  • Journal Title: PLoS One Volume: 12 Issue: 1 Pages: e0169340-e0169340
  • DOI: 10.1371/journal.pone.0169340
  • Peer Reviewed / Open Access
• [Journal Article] The endothelial adrenomedullin-RAMP2 system regulates vascular integrity and suppresses tumour metastasis. (2016)
  • Author(s): Tanaka M, Koyama T, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, LiuT, Xian X, Imai A, Zhai L, Hirabayashi K, Owa S, Yamauchi A, Igarashi K, Taniguchi S, Shindo T.
  • Journal Title: Cardiovasc Res. Volume: 111 Pages: 398-409
  • Peer Reviewed / Open Access
• [Journal Article] Novel role of ASC as a regulator of metastatic phenotype. (2016)
  • Author(s): Okada N1, Fujii C1,2, Matsumura T, Kitazawa M, Okuyama R, Taniguchi S, and Hida S (1: Contributed equally, 2: Corresponding author)
  • Journal Title: Cancer Medicine Volume: 5 Issue: 9 Pages: 2487-2500
  • DOI: 10.1002/cam4.800
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] NFkB2 gene as anoble candidate epidemiologically responding to interval walking training. (2015)
  • Author(s): Zhang Y, Hashimoto S, Fujii C, Hida S, Ito K, Matsumura T, Sakaizawa T, Morikawa M, Masuki S, Nose H, Higuchi K, Nakajima K, Taniguchi S
  • Journal Title: Int. J. Sports. Med. Volume: in press Issue: 09 Pages: 769-775
  • DOI: 10.1055/s-0035-1547221
  • Peer Reviewed / Open Access
• [Journal Article] NLRP3 deficiency improves angiotensin II-induced hypertension but not fetal growth restriction during pregnancy. (2015)
  • Author(s): Shirasuna K, Karasawa T, Usui F, Kobayashi M, Komada T, Kimura A, Ohkuchi A, Taniguchi S, Takahashi M.
  • Journal Title: Endocrinology Volume: 156 Issue: 11 Pages: 4281-4292
  • DOI: 10.1210/en.2015-1408
  • Peer Reviewed / Open Access
• [Journal Article] Excess aldosterone is a critical danger signal for inflammasome activation in the development of renal fibrosis in mice. (2015)
  • Author(s): Kadoya H, Satoh M, Sasaki T, Taniguchi S, Takahashi M, Kashihara N.
  • Journal Title: FASEB J Volume: 29 Issue: 9 Pages: 3899-391
  • DOI: 10.1096/fj.15-271734
  • Peer Reviewed / Open Access
• [Journal Article] 固形がんの嫌気的微小環境を標的とした持続的抗腫瘍性物質産生系の開発 (2015)
  • Author(s): 谷口 俊一郎
  • Journal Title: 展望 Volume: 9 Pages: 37-42
• [Journal Article] Nanosilica-induced placental inflammation and pregnancy complications: Different roles of the inflammasome components NLRP3 and ASC. (2014)
  • Author(s): Shirasuna K, Usui F, Karasawa T, Kimura H, Kawashima A, Mizukami H, Ohkuchi A, Nishimura S, Sagara J, Noda T, Ozawa K, Taniguchi S, Takahashi M
  • Journal Title: Nanotoxicology Volume: 11 Issue: 5 Pages: 1-14
  • DOI: 10.3109/17435390.2014.956156
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inflammasome activation by mitochondrial oxidative stress in macrophages leads to the development of angiotensin II-induced aortic aneurysm (2014)
  • Author(s): Usui F, Shirasuna K, Kimura H, Tatsumi K, Kawashima A, Karasawa T, Yoshimura K, Aoki H, Tsutsui H, Noda T, Sagara J, Taniguchi S, Takahashi M
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 35 Issue: 1 Pages: 127-136
  • DOI: 10.1161/atvbaha.114.303763
  • Peer Reviewed / Open Access
• [Presentation] Enhanced antitumor effects by a combination approach of interferon-g producing recombinant Bifidobacterium and anti-mPD-1 antibody in CT26 syngeneic mouse model (2017)
  • Author(s): S Kobayashi,Y. Seki K Shioya, S Ktaoka, L, Wang, Y Shimatani, M Fujimori, S Taniguchi
  • Organizer: AACR
  • Int'l Joint Research
• [Presentation] インフラマソーム構成分子ASCの細胞運動における役割 (2016)
  • Author(s): 藤井千文、松村富穂、肥田重明、岡田なぎさ、谷口俊一郎
  • Organizer: 第75回日本癌学会学術集会
  • Place of Presentation: 横浜市
  • Year and Date: 2016-10-06
• [Presentation] がん細胞におけるアクチン束化タンパクfascin1による免疫制御機構 (2015)
  • Author(s): 松村富穂、谷口俊一郎、肥田重明
  • Organizer: 第７４回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] 固形がんへの抗 Immune Checkpoint 阻害分子デリバリーと持続的産生 (2015)
  • Author(s): 塩谷公一郎、谷口俊一郎 他
  • Organizer: 第７４回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] ヒト肺癌の悪性形質獲得におけるASCの役割 (2015)
  • Author(s): 境澤隆夫、松村富穂、藤井千文、肥田重明、谷口俊一郎
  • Organizer: 第24回日本がん転移学会学術集会・総会
  • Place of Presentation: シティプラザ大阪（大阪市）
  • Year and Date: 2015-07-23
• [Presentation] アクチン細胞骨格制御タンパクFascin1によるインターフェロン産生調節 機構の解析 (2015)
  • Author(s): 松村富穂、谷口俊一郎
  • Organizer: 第19回日本がん分子標的治療学会学術集会
  • Place of Presentation: 松山全日空ホテル（愛媛県松山市）
  • Year and Date: 2015-06-10
• [Book] Methods Mol Biol.（edited by R.M. Hoffman 分担執筆） (2016)
  • Author(s): Taniguchi S, Shimatani Y, Fujimori M
  • Total Pages: 186
  • Publisher: Humana Press
• [Book] Tumor-targeting therapy using gene-engineered anaerobic-nonpathogenic Bifidobacterium longum. Bacterial Therapy of Cancer Methods and Protocols edited by R. M. Hoffman (2016)
  • Author(s): Taniguchi S, Shimatani Y, Fujimori M
  • Total Pages: 186
  • Publisher: Humana Press
• [Remarks] 信州大学 研究者綜覧 SOAR
  • URL: http://soar-rd.shinshu-u.ac.jp/profile/ja.HCyUHCDV.html
• [Patent(Industrial Property Rights)] 抗体遺伝子の発現・分泌システム (2015)
  • Inventor(s): 谷口 俊一郎他
  • Industrial Property Rights Holder: 信州大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-04-17
  • Overseas