Development of cell preparations and high/low molecular-weight therapeutics that exhibit synergistic effects with PD-1 immune checkpoint antibodies

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16K08844
• Research Institution: Nagasaki University
• Principal Investigator: 田中 義正 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (90280700)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: PD-1 / PD-L1 / 免疫チェックポイント / シグナル / BcL-XL / ミトコンドリア / ビスホスホン酸 / 抗腫瘍作用

Outline of Annual Research Achievements

PD-1免疫チェックポイント阻害剤と相乗作用を示す低分子製剤の探索を行った。まず、ヒト末梢血に第4世代ビスホスホン酸を作用させ、γδ型Ｔ細胞を増殖誘導し、エフェクター細胞として用いた。一方、PD-L1を強制発現させたヒトDaudiバーキットリンパ腫細胞に、テルピリジン誘導体を25μMで作用させ、FPMI1640培地で洗浄した細胞を標的細胞として用いた。アッセイ系としては、標的細胞105個に対して、エフェクター細胞105個を作用させ、60分後に細胞培養上清を回収した。ここに、ユーロピウムを添加することによりキレートを形成させた。この系に低分子化合物ライブラリーを添加することにより、細胞障害性を亢進する化合物の探索を行った。具体的には、天然物エキストラクトとして長崎大学に保有されている2万種の海洋微生物ライブラリーをスクリーニングすることにより、PD-1免疫チェックポイント阻害剤と併用効果が期待される化合物を取得した。その後、最適化合成を試み、6つの化合物を得た。
以上のようにして、PD-1免疫チェックポイント阻害剤と相乗作用を示す細胞製剤、高分子製剤、低分子製剤が取得できた。次に、種々のがん患者の末梢血から第4世代ビスホスホン酸によりγδ型T細胞を増殖誘導し、対応するがん細胞ラインに作用させ、その際、PD-1免疫チェックポイント阻害剤と本研究により取得された化合物を用いて相乗効果を検討した。その結果、低分子化合物の中に、抗PD-L1抗体と同程度の抗腫瘍作用亢進能のある化合物が見出された。

Research Products

• [Int'l Joint Research] University of Iowa(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: University of Iowa
• [Journal Article] Identification and structure of an MHC class I-encoded protein with the potential to present N-myristoylated 4-mer peptides to T cells (2019)
  • Author(s): Yukie Yamamoto, Daisuke Morita, Yoko Shima, Akihiro Midorikawa, Tatsuaki Mizutani, Juri Suzuki, Naoki Mori, Takashi Shiina, Hidetoshi Inoko, Yoshimasa Tanaka, Bunzo Mikami and Masahiko Sugita
  • Journal Title: Journal of Immunology Volume: In press Pages: In press
  • Peer Reviewed / Open Access
• [Journal Article] Determination of human gammadelta T cell-mediated cytotoxicity using a non-radioactive assay system (2019)
  • Author(s): Mohammed S. O. Tagod, Satoshi Mizuta, Yuki Sakai, Masashi Iwasaki, Kengo Shiraishi, Hiroaki Senju, Hiroshi Mukae, Craig T. Morita, Yoshimasa Tanaka
  • Journal Title: Journal of Immunological Methods Volume: 466 Pages: 32-40
  • DOI: 10.1016/j.jim.2019.01.003
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis and immunomodulatory activity of fluorine-containing bisphosphonates (2019)
  • Author(s): Satoshi Mizuta, Mohammed S. O. Tagod, Masashi Iwasaki, Yoichi Nakamura, Hiroaki Senju, Hiroshi Mukae, Craig T. Morita and Yoshimasa Tanaka
  • Journal Title: ChemMedChem Volume: 14 Pages: 462-468
  • DOI: 10.1002/cmdc.201800764
  • Peer Reviewed / Open Access
• [Journal Article] Methylcelluloses end-functionalized with peptides as thermoresponsive supramolecular hydrogelators (2019)
  • Author(s): Ryo Suhara, Mao Yamagami, Hiroshi Kamitakahara, Arata Yoshinaga, Yoshimasa Tanaka and Toshiyuki Takano
  • Journal Title: Cellulose Volume: 26 Pages: 355-382
  • DOI: 10.1007/s10570-018-2027-5
  • Peer Reviewed / Open Access
• [Journal Article] Prediction model for anti-malarial activities of hemozoin inhibitors using physicochemical properties (2018)
  • Author(s): Farhana Mosaddeque, Shusaku Mizukami, Mohamed Gomaa Kamel, Awet Alem Teklemichael, Truong Van Dat, Satoshi Mizuta, Dinh Van Toan, Ali Mahmoud Ahmed, Nguyen Lam Vuong, Mohamed Tamer Elhady, Hoang Thi Nam Giang, Tran Ngoc Dang, Michiko Fukuda, Lam K. Huynh, Yoshimasa Tanaka, et al.
  • Journal Title: Antimicrobial Agents and Chemotherapy Volume: 62 Pages: e02424-17
  • DOI: 10.1128/AAC.02424-17
  • Peer Reviewed / Open Access
• [Journal Article] IL-18 primes murine NK cells for proliferation by promoting protein synthesis, survival, and autophagy (2018)
  • Author(s): Yosif El-Darawish, Wen Li, Kyosuke Yamanishi, Magdalena Pencheva, Naoto Oka, Hiromichi Yamanishi, Tomohiro Matsuyama, Yoshimasa Tanaka, Nagahiro Minato and Haruki Okamura
  • Journal Title: Journal of Leukocyte Biology Volume: 104 Pages: 253-264
  • DOI: 10.1002/JLB.1HI1017-396RR
  • Peer Reviewed / Open Access
• [Journal Article] Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug (2018)
  • Author(s): Yoshimasa Tanaka, Kaoru Murata-Hirai, Masashi Iwasaki, Kenji Matsumoto, Kosuke Hayashi, Asuka Kumagai, Mohanad H. Nada, Hong Wang, Hirohito Kobayashi, Hiroshi Kamitakahara, Haruki Okamura, Tomoharu Sugie, Nagahiro Minato, Masakazu Toi and Craig T. Morita
  • Journal Title: Cancer Science Volume: 109 Pages: 587-599
  • DOI: 10.1111/cas.13491
  • Peer Reviewed / Open Access
• [Journal Article] The effects of zoledronic acid on gammadelta T cells in postmenopausal women with early-stage breast cancer undergoing neoadjuvant endocrine therapy (2018)
  • Author(s): Tomoharu Sugie, Eiji Suzuki, Akira Yamauchi, Kazuhiko Yamagami, Norikazu Masuda, Hiroji Iwata, Eriko Sumi, Takafumi Ikeda, Harue Tada, Ryuji Uozumi, Shotaro Kanao, Yoshimasa Tanaka, Yoko Hamazaki, Nagahiro Minato and Masakazu Toi
  • Journal Title: Breast Volume: 38 Pages: 114-119
  • DOI: 10.1016/j.breast.2017.12.017
  • Peer Reviewed / Open Access
• [Journal Article] Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: Application to Cancer Immunotherapy (2018)
  • Author(s): Hiroaki Senju, Asuka Kumagai, Yoichi Nakamura, Hiroyuki Yamaguchi, Katsumi Nakatomi, Shota Fukami, Kengo Shiraishi, Yuka Harada, Mitsuhiro Nakamura, Haruki Okamura, Yoshimasa Tanaka and Hiroshi Mukae
  • Journal Title: International Journal of Biological Sciences Volume: 14 Pages: 331-340
  • DOI: 10.7150/ijbs.22809
  • Peer Reviewed / Open Access
• [Presentation] Expansion of human gammadelta T cells for adoptive immunotherapy using a novel bisphosphonate prodrug (2018)
  • Author(s): Yoshimasa Tanaka, Masashi Iwasaki, Kosuke Hayashi, Kenji Matsumoto, Yuki Sakai, Mohammed S. O. Tagod, Asuka Kumagai and Craig T. Morita
  • Organizer: The 8th gammadelta T Cell Conference
  • Int'l Joint Research
• [Presentation] Immuno-modulatory effects of zoledronic acid on gammadelta T cells in postmenopausal women undergoing neoadjuvant endocrine therapy for early-stage breast cancer (2018)
  • Author(s): Tomoharu Sugie, Eiji Suzuki, Akira Yamauchi, Kazuhiko Yamagami, Norikazu Masuda, Naomi Gondo, Eriko Sumi, Takafumi Ikeda, Harue Tada, Ryuji Uozumi, Shotaro Kanao, Yoshimasa Tanaka, Yoko Hamazaki, Nagahiro Minato, Masakazu Toi
  • Organizer: The 45th Naito Conference: Immunological and Molecular Bases for Cancer Immunotherapy
  • Int'l Joint Research
• [Presentation] KID-001, a novel TDO/IDO inhibitor, suppresses the AHR-TIPARP pathway to reduce HBV replication in human hepatocytes (2018)
  • Author(s): Seiichi Sato, Taisho Yamada, Kenji Matsuno, Kai Li, Koichi Watashi, Takaji Wakita, Yoshimasa Tanaka, Yasuhito Tanaka, and Akinori Takaoka
  • Organizer: 6th Japan-Taiwan-Korea HBV Research Symposium 2018
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 免疫チェックポイント阻害剤の効果予測方法 (2018)
  • Inventor(s): 田中義正、千住博明、迎寛、福島雅典
  • Industrial Property Rights Holder: 田中義正、千住博明、迎寛、福島雅典
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2018-187856
• [Patent(Industrial Property Rights)] γδ型T細胞への遺伝子導入方法 (2018)
  • Inventor(s): 珠玖 洋、宮原 慶裕、奥村 悟司、加藤 琢磨、林 妙、田中 義正
  • Industrial Property Rights Holder: 珠玖 洋、宮原 慶裕、奥村 悟司、加藤 琢磨、林 妙、田中 義正
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2018-143207