Development of designed TLR2 ligand as antitumor immunoadjuvant

• Project/Area Number: 24590500
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Research Institute, Osaka Medical Center for Cancer and Cardiovascular Disaeses
• Principal Investigator: Takashi Akazawa 地方独立行政法人大阪府立病院機構大阪府立成人病センター(研究所), その他部局等, 主任研究員 (80359299)
• Co-Investigator(Renkei-kenkyūsha): INOUE Norimitsu 地方独立行政法人大阪府立病院機構・大阪府立成人病センター(研究所), 研究所, 部門長(腫瘍免疫学部門) (80252708) ; SUGIURA Kikuya 大阪府立大学, 生命環境科学研究科, 准教授 (30171143)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 腫瘍免疫 / アジュバント / ワクチン / 人工設計 / Toll-like receptor / 癌 / 免疫 / リポペプチド / toll－like receptor / 薬学 / 免疫学 / TLR

Outline of Final Research Achievements

We have developed adjuvant engineering strategy to design the TLR2 ligand with new ability by replacing the peptide of bacterial origin with a functional motif. We designed a new dendritic cell (DC)-targeting lipopeptide, h11c (P2C-ATPEDNGRSFS), which uses the CD11c-binding sequence of ICAM-1 to selectively and efficiently activate DCs but not other immune cells. Although P2C-SKKKK is well known as artificial lipopeptide and has strong immunostimulatory activity, h11c induces stronger antitumor activity at low doses without local inflammation at vaccination site of skin. The h11c is the ideal antitumor immunoadjuvant that improvement of the efficiency and the evasion of the adverse effects were realized by functional design.

Research Products

• [Journal Article] PolyI:C-induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector-Mediated Tumor Elimination In Vivo (2015)
  • Author(s): Ryo Takemura, Hiromi Takaki, Seiji Okada, Hiroaki Shime, Takashi Akazawa, Hiroyuki Oshiumi, Misako Matsumoto, Takanori Teshima, and Tsukasa Seya
  • Journal Title: Cancer Immunology Research Volume: 3 Issue: 8 Pages: 902-914
  • DOI: 10.1158/2326-6066.cir-14-0219
  • NAID: 120005820710
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] PolyI:C-induced, TLR3/RIP3-dependent necroptosis backs up immune effector-mediated tumor elimination in vivo. (2015)
  • Author(s): Takemura R, Takaki H, Okada S, Shime H, Akazawa T, Oshiumi H, Matsumoto M, Teshima T, Seya T.
  • Journal Title: Cancer Immunol Res Volume: -
  • NAID: 120005820710
  • Peer Reviewed
• [Journal Article] Development of a dendritic cell-targeting lipopeptide as an immunoadjuvant that inhibits tumor growth without inducing local inflammation. (2014)
  • Author(s): Akazawa T, Ohashi T, Nakajima H, Nishizawa Y, Kodama K, Sugiura K, Inaba T, Inoue N.
  • Journal Title: Int. J. Cancer. Volume: 135 Issue: 12 Pages: 2847-2856
  • DOI: 10.1002/ijc.28939
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A possible abscopal effect of post-irradiation immunotherapy in two patients with metastatic lung tumors. (2014)
  • Author(s): 4.Kodama, K., Higashiyama, M., Okami, J., Tokunaga, T., Fujiwara, A., Inoue, N., Akazawa, T. and Seya, T.
  • Journal Title: In. Canc. Conf. J. Volume: 3 Issue: 2 Pages: 122-127
  • DOI: 10.1007/s13691-013-0130-x
  • Peer Reviewed / Open Access
• [Journal Article] Production of canine soluble CD40 ligand to induce maturation of monocyte derived dendritic cells for cancer immunotherapy. (2013)
  • Author(s): Wijewardana, V., Sugiura, K., Yahata, M., Akazawa, T., Wijesekera, D. P., Imamoto, S., Hatoya, S., Inoue, N., Inaba, T.
  • Journal Title: Vet. Immunol. Immunopathol. Volume: 156 Issue: 1-2 Pages: 121-127
  • DOI: 10.1016/j.vetimm.2013.09.016
  • Peer Reviewed
• [Journal Article] Dichroloacetate improves immune dysfunction caused by tumor-secreted lactic acid and increases antitumor immunoreactivity (2013)
  • Author(s): Ohashi, T., Akazawa, T., Aoki, M., Kuze, B., Mizuta, K., Ito, Y., Inoue, N.
  • Journal Title: Int. J. Cancer Volume: 133 Issue: 5 Pages: 1107-1118
  • DOI: 10.1002/ijc.28114
  • Peer Reviewed
• [Presentation] Development of bacteria-mimicked tumor cell vaccine modified with engineered TLR2 ligands (2015)
  • Author(s): Takashi Akazawa and Norimitsu Inoue
  • Organizer: International Conference of Cancer Immunotherapy and Macrophage 2015（第１９回日本がん免疫学会）
  • Place of Presentation: 東京
  • Year and Date: 2015-07-09
  • Int'l Joint Research
• [Presentation] Modification of tumor cells with bacterial components and application to vaccine. (2014)
  • Author(s): Akazawa T, Inoue N
  • Organizer: The 73rd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] アジュバントの人工設計：樹状細胞標的化リポペプチドは局所炎症を起こさない理想的なアジュバントとして働く (2013)
  • Author(s): 赤澤 隆、大橋 敏充、井上 徳光
  • Organizer: 第72回日本癌学会
  • Place of Presentation: 横浜
• [Presentation] CR4サブユニットを標的とした抗がん免疫アジュバント (2013)
  • Author(s): 赤澤 隆、井上徳光
  • Organizer: 第５０回補体シンポジウム
  • Place of Presentation: 旭川
• [Presentation] Improvement of dendritic cell-based immunotherapy for enhancing systemic immune responses against cancer (2013)
  • Author(s): Viskam Wijewardana, Kikuya Sugiura, Takashi Akazawa, Dalthgamage-Pathy Wijesekera, Shigeki Imamoto, Norimitu Inoue, Toshio Inaba
  • Organizer: 第４２回日本免疫学会
  • Place of Presentation: 幕張
• [Presentation] 免疫細胞標的化トル様受容体２リガンドの人工設計と抗がんアジュバントへの応用 (2012)
  • Author(s): 赤澤 隆、大橋 敏充、井上 徳光
  • Organizer: 日本がん免疫学会
  • Place of Presentation: 札幌
• [Presentation] Adjuvant engineering for caner immunotherapy: Improved synthetic TLR2 ligand with DC targeting ability (2012)
  • Author(s): Takashi Akazawa, Toshimitu Ohashi, Norimitsu Inoue
  • Organizer: 日本癌学会
  • Place of Presentation: 札幌
• [Remarks] 大阪府立成人病センター 研究所 腫瘍免疫学部門
  • URL: http://www.mc.pref.osaka.jp/laboratory/department/shuyou/
• [Remarks] 大阪府立成人病センター 研究所 分子遺伝学部門
  • URL: http://www.mc.pref.osaka.jp/omc2/category/genetics.html
• [Remarks] 大阪府立成人病センター・研究所・分子遺伝学部門
  • URL: http://www.mc.pref.osaka.jp/omc2/genetics.html
• [Patent(Industrial Property Rights)] 新規人工設計リポペプチド (2014)
  • Inventor(s): 赤澤 隆，井上 徳光
  • Industrial Property Rights Holder: 地方独立行政法人 大阪府立病院機構
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-508043
  • Filing Date: 2014-09-12
• [Patent(Industrial Property Rights)] 新規人工設計リポペプチド (2013)
  • Inventor(s): 赤澤 隆、井上 徳光
  • Industrial Property Rights Holder: 地方独立行政法人大阪府立病院機構
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-03-28
  • Acquisition Date: 2015-12-04
• [Patent(Industrial Property Rights)] 新規人工設計リポペプチド (2013)
  • Inventor(s): 赤澤 隆、井上 徳光
  • Industrial Property Rights Holder: 地方独立行政法人大阪府立病院機構
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-03-28
  • Overseas