Development of all inclusive anti tumor immunotherapy based on engineered protein and nucleic acid

• Project/Area Number: 19390041
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kyoto University
• Principal Investigator: TAKAKURA Yoshinobu Kyoto University, 薬学研究科, 教授 (30171432)
• Co-Investigator(Kenkyū-buntansha): NISHIKAWA Makiya 京都大学, 薬学研究科, 准教授 (40273437)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2008: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2007: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
• Keywords: 抗原デリバリー / DNA ワクチン / 熱ショックタンパク質 / 抗原提示細胞 / CpGモチーフ / DNAワクチン

Research Abstract

機能改変タンパク質およびDNAワクチンの両アプローチを基盤とした包括的抗腫瘍免疫治療システムの開発を試みた。熱ショックタンパク質Hsp70 と卵白アルブミンの代表的な抗原エピトープから、新規Hsp70 融合タンパク質を設計した。Hsp70 融合タンパク質、あるいはこれを発現するプラスミドベクターを投与することで、高い抗原特異的免疫応答の誘導に成功した。Hsp70 融合タンパク質発現ベクター投与群では、腫瘍生着も効率的に拒絶され、抗腫瘍免疫治療システムとしての有用性が示された。

Research Products

• [Journal Article] Enhanced CTL response by controlled intracellular trafficking of antigen in dendritic cells following DNA vaccination (2009)
  • Author(s): Isaji K, Kawase A, Matono M, Guan X, Nishikawa M, Takakura Y.
  • Journal Title: Journal of Controlled Release 135 Pages: 227-233
  • Peer Reviewed
• [Journal Article] Quantitative and temporal analysis of gene silencing in tumor cells induced by small interfering RNA or short hairpin RNA expressed from plasmid vectors (2009)
  • Author(s): Takahashi Y, Yamaoka K, Nishikawa M, Takakura Y.
  • Journal Title: Journal of Pharmaceutical Sciences 98 Pages: 74-80
  • Peer Reviewed
• [Journal Article] Enhanced CTL response by controlled intracellular trafficking of antigen in dendritic cells following DNA vaccination (2009)
  • Author(s): Isaji K, et al.
  • Journal Title: Journal of Controlled Release 135(3) Pages: 227-233
  • Peer Reviewed
• [Journal Article] TLR9-depdendent systemic interferon-βproduction by intravenous injection of plasmid DNA/cationic liposome comolex in mice (2009)
  • Author(s): Yoshida H, et al.
  • Journal Title: Journal of Gene Medicine
  • Peer Reviewed
• [Journal Article] Quantitative and temporal analysis of gene silencing in tumor cells induced by small interfering RNA or short hairpin RNA expressed from plasmid (2009)
  • Author(s): Takahashi Y, et al.
  • Journal Title: Journal of Pharmaceutical Sciences 98 Pages: 74-80
  • Peer Reviewed
• [Journal Article] Nonviral vector-mediated RNA interference : its gene silencing characteristics and important factors to achieve RNAi-based gene therapy (2009)
  • Author(s): Takahashi Y, et al.
  • Journal Title: Advanced Drug Delivery Reviews
  • Peer Reviewed
• [Journal Article] Inhibition of tumor cell growth in the liver by RNA interference mediated suppression of HIF-1α expression in tumor cells and hepatocytes (2008)
  • Author(s): Takahashi Y, Nishikawa M, Takakura Y.
  • Journal Title: Gene Therapy 15 Pages: 572-582
  • Peer Reviewed
• [Journal Article] Gene silencing of ss-catenin in melanoma cells retards their growth but promotes the formation of pulmonary metastasis in mice (2008)
  • Author(s): Takahashi Y, Nishikawa M, Suehara T, Takiguchi N, Takakura Y.
  • Journal Title: International Journal of Cancer 123 Pages: 2315-2320
  • Peer Reviewed
• [Journal Article] Heat shock protein derivatives for delivery of antigens to antigen presenting cells (2008)
  • Author(s): Nishikawa M, Takemoto S, Takakura Y.
  • Journal Title: International Journal of Pharmaceutics 354 Pages: 23-27
  • Peer Reviewed
• [Journal Article] Enhanced immunostimulatory activity of oligodeoxynucleotides by Y-shape formation (2008)
  • Author(s): Nishikawa M, Matono M, Rattanakiat S, Matsuoka N, Takakura Y.
  • Journal Title: Immunology 124 Pages: 247-255
  • Peer Reviewed
• [Journal Article] Effects of inflammatory response on in vivo transgene expression by plasmid DNA in mice (2008)
  • Author(s): Kako K, Nishikawa M, Yoshida H, Takakura Y.
  • Journal Title: Journal of Pharmaceutical Sciences 97 Pages: 3074-3083
  • Peer Reviewed
• [Journal Article] Cellular activation by plasmid DNA in various macrophages in primary culture (2008)
  • Author(s): Yoshida H, Nishikawa M, Yasuda S, Mizuno Y, Takakura Y.
  • Journal Title: Journal of Pharmaceutical Sciences 97 Pages: 4575-4585
  • Peer Reviewed
• [Journal Article] Unique cytokine production profile following stimulation with DNA in macrophages from NZB/W F1 mice (2008)
  • Author(s): Ogawa Y, Yoshinaga T, Nishikawa M, Takakura Y.
  • Journal Title: Biological & Pharmaceutical Bulletin 31 Pages: 1244-1249
  • Peer Reviewed
• [Journal Article] Inhibition of tumor cell growth in the liver by RNA interference-mediated suppression of HIF-1α exoression in tumor cells and hppatocvtes (2008)
  • Author(s): Takahashi Y, et al.
  • Journal Title: Gene Therapy 15 Pages: 572-582
  • Peer Reviewed
• [Journal Article] Gene silencing of β-catenin in melanoma cells retards their growth but promotes the formation of pulmonary metastasis in mice (2008)
  • Author(s): Takahashi Y, et al.
  • Journal Title: International Journal of Cancer 123 Pages: 2315-2320
  • Peer Reviewed
• [Journal Article] Enhanced immunostimulatory activity of oligodeoxynucleotides by Y-shape formation (2008)
  • Author(s): Nishikawa M, et al.
  • Journal Title: Immunology 124 Pages: 247-255
  • Peer Reviewed
• [Journal Article] Cellular activation by plasmid DNA in various macrophages in primary culture (2008)
  • Author(s): Yoshida H, et al.
  • Journal Title: Journal of Pharmaceutical Sciences 97(10) Pages: 4575-4585
  • Peer Reviewed
• [Journal Article] Effects of inflammatory response on in vivo transgene expression by plasmid DNA in mice (2008)
  • Author(s): Kako K, et al.
  • Journal Title: Journal of Pharmaceutical Sciences 97(8) Pages: 3074-3083
  • Peer Reviewed
• [Journal Article] Unique cytokine production profile following stimulation with DNA in macrophages from NZB/W F1 mice (2008)
  • Author(s): Ogawa Y, et al.
  • Journal Title: Biological & Pharmaceutical Bulletin 31 Pages: 1244-1249
  • Peer Reviewed
• [Journal Article] Heat shock protein derivatives for delivery of antigens to antigen presenting cells. (2008)
  • Author(s): Nishikawa M, Takemoto S, Takakura Y.
  • Journal Title: International Journal of Pharmaceutics 354 Pages: 23-27
  • Peer Reviewed
• [Journal Article] Enhanced immunostimulatory activity of oligodeoxynucleotides by Y-shape formation. (2008)
  • Author(s): Nishikawa M, Matono M, Rattanakiat S, Matsuoka N,
  • Journal Title: Immunology
  • Peer Reviewed
• [Journal Article] Effects of inflammatory response on in vivo transgene expression by plasmid DNA in mice. (2008)
  • Author(s): Kako K, Nishikawa M, Yoshida H, Takakura Y.
  • Journal Title: Journal of Pharmaceutical Sciences
  • Peer Reviewed
• [Journal Article] Cellular activation by plasmid DNA in various macrophages in primary culture. (2008)
  • Author(s): Yoshida H, Nishikawa M, Yasuda S, Mizuno Y, Takakura Y.
  • Journal Title: Journal of Pharmaceutical Sciences
  • Peer Reviewed
• [Journal Article] Induction of antigen specific cytotoxic T lymphocytes by immunization with negatively charged soluble antigen through scavenger receptor mediated delivery (2007)
  • Author(s): Yamasaki Y, Ikenaga T, Ohtsuki T, Nishikawa M, Takakura Y.
  • Journal Title: Vaccine 25 Pages: 85-91
  • Peer Reviewed
• [Journal Article] Hsp-based tumor vaccines : state-of-the-art and future directions (2007)
  • Author(s): Takakura Y, Takemoto S, Nishikawa M.
  • Journal Title: Current Opinion in Molecular Therapeutics 9 Pages: 385-391
  • Peer Reviewed
• [Journal Article] Induction of antigen-specific cytotoxic T lymphocytes by immunization with negatively-charged soluble antigen through scavengreceptor-mediated delivery (2007)
  • Author(s): Yamasaki Y, Ikenaga T, Ohtsuki T, Nishikawa M, Takakura Y.
  • Journal Title: Vaccine 25 Pages: 85-91
  • Peer Reviewed
• [Journal Article] Hsp-based tumor vaccines: state-of-the-art and future directions. (2007)
  • Author(s): Takakura Y, Takemoto S, Nishikawa M.
  • Journal Title: Current Opinion in Molecular Therapeutics 9 Pages: 385-391
  • Peer Reviewed
• [Journal Article] TLR9-depdendent systemic interferon-ss production by intravenous injection of plasmid DNA/cationic liposome complex in mice
  • Author(s): Yoshida H, Nishikawa M, Yasuda S, Mizuno Y,Toyota H, Kiyota T, Takahashi R, Takakura Y.
  • Journal Title: Journal of Gene Medicine (in press)
  • Peer Reviewed
• [Journal Article] Nonviral vector-mediated RNA interference: its gene silencing characteristics and important factors to achieve RNAi-based gene therapy
  • Author(s): Takahashi Y, Nishikawa M, Takakura Y
  • Journal Title: Advanced Drug Delivery Reviews in press
  • Peer Reviewed
• [Presentation] Development of DNA Nano Assemblies with Enhanced Immunostimulatory Activity (2009)
  • Author(s): Rattanakiat S, Nishikawa M, Takakura Y.
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
• [Presentation] Development of DNA Nano-Assemblies with Enhanced Immunostimulatory Activity (2009)
  • Author(s): Rattanakiat S, et al.
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
• [Presentation] 導入遺伝子発現プロファイルの速度論解析に基づく遺伝子デリバリーシステムの最適化 (2008)
  • Author(s): 西川元也
  • Organizer: 遺伝子・デリバリー研究会第8回シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2008-05-09
• [Presentation] 導入遺伝子発現プロファイルの速度論解析に基づく遺伝子デジバリーシステムの最適化 (2008)
  • Author(s): 西川元也
  • Organizer: 遺伝子・デリバリー研究会第8回シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2008-05-09
• [Presentation] マウスにおけるDNAに対する免疫応答プロファイルの評価. (2008)
  • Author(s): 吉田寛幸、西川元也、安田幸代、水野友美子、豊田敬康、高倉喜信
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜市
  • Year and Date: 2008-03-26
• [Presentation] Enhanced immunostimulatory activity of oligodeoxynucleotides by cholesterol conjugation. (2008)
  • Author(s): Rattanakiat S, Nishikawa M, Takakura Y.
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜市
  • Year and Date: 2008-03-26
• [Presentation] DNAを基盤とする抗癌剤デリバリー・免疫活性化システムの開発. (2008)
  • Author(s): 水野友美子、西川元也、直井智幸、高倉喜信
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜市
  • Year and Date: 2008-03-26
• [Presentation] 免疫・化学療法に向けた短鎖DNA を基盤とするDNAナノ粒子・ハイドロゲル開発 (2008)
  • Author(s): 水野友美子、西川元也、的野光洋、Sakulrat Rattanakiat、Dan Luo、舟橋久景、高倉喜信
  • Organizer: 第18回アンチセンスシンポジウム
  • Place of Presentation: 岐阜
• [Presentation] Optimization of Design and Delivery of Plasmid Vector for Interferon Gene Therapy (2008)
  • Author(s): Takakura Y.
  • Organizer: 2008 KCRS Annual Conference : Research Networking for Future Therapy
  • Place of Presentation: Jeju Island, Korea
• [Presentation] DNA-based Nanoassembly Formation for Enhanced Immunostimulatory Activity of Oligodeoxynucleotides (2008)
  • Author(s): Rattanakiat S, Nishikawa M, Takakura Y.
  • Organizer: 第24回日本DDS学会学術集会
  • Place of Presentation: 東京
• [Presentation] ホスホロチオエートDNAの組み込みによるY型DNAの免疫賦活化能の増強 (2008)
  • Author(s): 松岡奈穂、西川元也、Sakulrat Rattanakiat、高倉喜信
  • Organizer: 第24回日本DDS学会学術集会
  • Place of Presentation: 東京
• [Presentation] 持続的インターフェロン遺伝子発現システムの開発による癌・アレルギー疾患治療 (2008)
  • Author(s): 西川元也
  • Organizer: 日本薬剤学会第23年会
  • Place of Presentation: 札幌
• [Presentation] DNA 刺激によるマクロファージ活性化に対するフィブロネクチンの細胞活性化抑制機構の解析 (2008)
  • Author(s): 吉田寛幸、西川元也、豊田敬康、安田幸代、水野友美子、高倉喜信
  • Organizer: 日本薬剤学会第23年会
  • Place of Presentation: 札幌
• [Presentation] β-catenin遺伝子発現抑制による癌細胞増殖抑制と肺転移の亢進 (2008)
  • Author(s): 末原徹也、高橋有己、西川元也、滝口直美、高倉喜信
  • Organizer: 日本薬剤学会第23年会
  • Place of Presentation: 札幌
• [Presentation] CpGモチーフを含まないプラスミドDNA/リポソーム複合体によるマクロファージからのサイトカイン産生機構の解析 (2008)
  • Author(s): 豊田敬康、安田幸代、西川元也、吉田寛幸、高倉喜信
  • Organizer: 日本薬剤学会第23年会
  • Place of Presentation: 札幌
• [Presentation] Unique Property of IFN-ss Production upon Intravenous Injection of CpG Plasmid DNA/Cationic Liposome Complex (2008)
  • Author(s): Yoshida H, Nishikawa M, Yasuda S, Mizuno Y, Toyota H, Takakura Y
  • Organizer: The 4th Seoul Kyoto Osaka Joint Symposium on Pharmaceutical Sciences for Young Scientists
  • Place of Presentation: Kyoto
• [Presentation] マウスにおけるDNAに対する免疫応答プロファイルの評価 (2008)
  • Author(s): 吉田寛幸、西川元也、安田幸代、水野友美子、豊田敬康、高倉喜信
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜市
• [Presentation] Enhanced immunostimulatory activity of oligodeoxynucleotides by cholesterol conjugation (2008)
  • Author(s): Rattanakiat S, Nishikawa M, Takakura Y.
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜市
• [Presentation] DNAを基盤とする抗癌剤デリバリー・免疫活性化システムの開発 (2008)
  • Author(s): 水野友美子、西川元也、直井智幸、高倉喜信
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜市
• [Presentation] 免疫・化学療法に向けた短鎖DNAを基盤とするDNAナノ粒子・ハイドロゲル開発 (2008)
  • Author(s): 水野友美子, ほか
  • Organizer: 第18回アンチセンスシンポジウム
  • Place of Presentation: 岐阜
• [Presentation] ホスホロチオェートDNAの組み込みによるY型DNAの免疫賦活化能の増強 (2008)
  • Author(s): 松岡奈穂, ほか
  • Organizer: 第24回日本DDS学会学術集会
  • Place of Presentation: 東京
• [Presentation] DNA刺激によるマクロファージ活性化に対するフイブロネクチンの細胞活性化抑制機構の解析 (2008)
  • Author(s): 吉田寛幸, ほか
  • Organizer: 日本薬剤学会第23年会
  • Place of Presentation: 札幌
• [Presentation] CpGモチーフを含まないプラスミドDNA/リボソーム複合体によるマクロファージからのサイトカイン産生機構の解析 (2008)
  • Author(s): 豊田敬康, ほか
  • Organizer: 日本薬剤学会第23年会
  • Place of Presentation: 札幌
• [Presentation] Unique Property of IFN-β Production upon Intravenous Injection of CpG Plasmid DNA/Cationic Liposome Complex (2008)
  • Author(s): Yoshida H, et al.
  • Organizer: The 4th Seoul-Kyoto-Osaka Joint Symposium on Pharmaceutical Sciences for Young Scientists
  • Place of Presentation: Kyoto
• [Presentation] Development of DNA-based nanosized DDS. (2007)
  • Author(s): Nishikawa M.
  • Organizer: BioJapan2007
  • Place of Presentation: 横浜市
  • Year and Date: 2007-09-19
• [Presentation] Enhanced immunostimulatory activity of oligodeoxynucleotides by Y-shape formation. (2007)
  • Author(s): Rattanakiat S, Matono M, Nishikawa M, Takakura Y.
  • Organizer: 第23回日本DDS学会学術集会
  • Place of Presentation: 熊本市
  • Year and Date: 2007-06-15
• [Presentation] MHCクラスI・II両エピトープ搭載型Hsp70抗原デリバリーシステムの開発. (2007)
  • Author(s): 関心、竹本誠二、西川元也、太田淳、高倉喜信
  • Organizer: 第23回日本DDS学会学術集会
  • Place of Presentation: 熊本市
  • Year and Date: 2007-06-14
• [Presentation] DNAワクチンの投与部位依存的免疫応答の誘導. (2007)
  • Author(s): 矢田智也、西川元也、大野祐司、関心、竹本誠二、高倉喜信
  • Organizer: 第23回日本DDS学会学術集会
  • Place of Presentation: 熊本市
  • Year and Date: 2007-06-14
• [Presentation] プラスミドDNAに対する炎症応答の評価とその制御. (2007)
  • Author(s): 吉田寛幸、西川元也、安田幸代、水野友美子、光井優、高倉喜信
  • Organizer: 日本薬剤学会第22年会
  • Place of Presentation: さいたま市
  • Year and Date: 2007-05-21
• [Presentation] Development of DNA-based nanosized DDS (2007)
  • Author(s): Nishikawa M.
  • Organizer: BioJapan2007
  • Place of Presentation: 横浜市
• [Presentation] Enhanced immunostimulatory activity of oligodeoxynucleotides by Y-shape formation (2007)
  • Author(s): Rattanakiat S, Matono M, Nishikawa M, Takakura Y.
  • Organizer: 第23回日本DDS学会学術集会
  • Place of Presentation: 熊本市
• [Presentation] MHCクラスI・II両エピトープ搭載型Hsp70抗原デリバリーシステムの開発 (2007)
  • Author(s): 関心、竹本誠二、西川元也、太田淳、高倉喜信
  • Organizer: 第23回日本DDS学会学術集会
  • Place of Presentation: 熊本市
• [Presentation] DNA ワクチンの投与部位依存的免疫応答の誘導 (2007)
  • Author(s): 矢田智也、西川元也、大野祐司、関心、竹本誠二、高倉喜信
  • Organizer: 第23回日本DDS学会学術集会
  • Place of Presentation: 熊本市
• [Presentation] プラスミドDNA に対する炎症応答の評価とその制御 (2007)
  • Author(s): 吉田寛幸、西川元也、安田幸代、水野友美子、光井優、高倉喜信
  • Organizer: 日本薬剤学会第22年会
  • Place of Presentation: さいたま市