Development of therapeutic antibodies based on the elevated S100A8/A9 in tumor microenvironment

• Project/Area Number: 20K07636
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Okayama University
• Principal Investigator: Kinoshita Rie 岡山大学, 医歯薬学域, 助教 (40518297)
• Co-Investigator(Kenkyū-buntansha): 阪口 政清 岡山大学, 医歯薬学域, 教授 (70379840) ; 小林 和子 岡山大学, 医歯薬学域, 助教 (20304298)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: antibody / inflammation / cancer / metastasis / がん / がん転移 / 抗体医薬品 / S100A8/A9

Outline of Research at the Start

S100A8/A9は、好中球の細胞内タンパク質の約50%を占めるタンパク質であり、炎症環境において強く発現が誘導され、がん微小環境の構築に重要な役割を果たす。
申請者らは、S100A8/A9のヘテロダイマー構造特異的なモノクローナル抗体および複数のS100A8/A9受容体の細胞外領域と抗体のFc領域を融合させたタンパク質をがん転移治療薬として開発した。
本申請では、がん転移前微小環境の悪性化におけるS100A8/A9の役割を解明し、S100A8/A9抗体治療薬の実用化に向けて研究を進める。

Outline of Final Research Achievements

S100A8/A9 (S100A8 and A9 heterodimer) is an inflammatory factor engaged in the onset of chronic inflammatory diseases. We analyzed patient plasma of several kinds of cancer and discovered excessive expression of S100A8/A9. Using RNA-seq analysis, we confirmed that stimulation of S100A8/A9 on macrophages induced upregulation of many types of cancer-associated cytokines and chemokines. Therefore, we have developed prominent new anti-human S100A8/A9 monoclonal antibody for treatment of cancer. We confirmed the therapeutic effect of our developed S100A8/A9 neutralizing antibody in subcutaneous pancreatic tumor mouse model. The antibody can terminate the negative spiral of aggravated inflammation induced by S100A8/A9, which in turn alleviates cancer progression.

Academic Significance and Societal Importance of the Research Achievements

開発した抗S100A8/A9抗体は、強力な抗炎症作用をもち、様々な炎症性疾患治療薬として実用化される可能性をもつ。先行してIPF(特発性肺線維症)およびIPF急性増悪について有意な治療効果を示し、ヒト化抗体を作製している。本研究成果により、RNA-seq解析の手法を用いて、S100A8/A9が炎症性疾患を増悪するメカニズムの一端が解明され、マウスモデルの実験データからがん転移治療薬としての開発抗体の可能性が示された。

Research Products

• [Journal Article] Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells. (2023)
  • Author(s): Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Junichiro Futami, Lena Audebert, Youyi Chen, Ni Luh Gede Yoni Komalasari, Fan Jiang, Chikako Yoshizawa, Hitoshi Murata, Ken-Ichi Yamamoto, Masami Watanabe, Hiromi Kumon, Masakiyo Sakaguchi
  • Journal Title: Journal of molecular medicine (Berlin, Germany) Volume: 101 Issue: 4 Pages: 431-447
  • DOI: 10.1007/s00109-023-02292-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toll-like receptor 4 promotes bladder cancer progression upon S100A8/A9 binding, which requires TIRAP-mediated TPL2 activation (2022)
  • Author(s): Acosta Gonzalez Herik Rodrigo, Nahoko Tomonobu, Haruka Yoneda, Rie Kinoshita, ..., Hitoshi Murata, Ken-ichi Yamamoto, Junichiro Futami, Akira Yamauchi, Futoshi Kuribayashi, Yusuke Inoue, Eisaku Kondo, Shinichi Toyooka, Masahiro Nishibori, Masami Watanabe, Yasutomo Nasu, Masakiyo Sakaguchi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 634 Pages: 83-91
  • DOI: 10.1016/j.bbrc.2022.09.116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Engineering Cancer/Testis Antigens With Reversible S-Cationization to Evaluate Antigen Spreading (2022)
  • Author(s): Miyamoto Ai、Honjo Tomoko、Masui Mirei、Kinoshita Rie、Kumon Hiromi、Kakimi Kazuhiro、Futami Junichiro
  • Journal Title: Frontiers in Oncology Volume: 12 Pages: 869393-869393
  • DOI: 10.3389/fonc.2022.869393
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional Blockage of S100A8/A9 Ameliorates Ischemia Reperfusion Injury in the Lung (2022)
  • Author(s): Nakata Kentaro、Okazaki Mikio、Sakaue Tomohisa、Kinoshita Rie、Komoda Yuhei、Shimizu Dai、Yamamoto Haruchika、Tanaka Shin、Suzawa Ken、Shien Kazuhiko、Miyoshi Kentaroh、Yamamoto Hiromasa、Ohara Toshiaki、Sugimoto Seiichiro、Yamane Masaomi、Matsukawa Akihiro、Sakaguchi Masakiyo、Toyooka Shinichi
  • Journal Title: Bioengineering Volume: 9 Issue: 11 Pages: 673-673
  • DOI: 10.3390/bioengineering9110673
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibiting S100A8/A9 attenuates airway obstruction in a mouse model of heterotopic tracheal transplantation (2022)
  • Author(s): Shimizu Dai、Okazaki Mikio、Sugimoto Seiichiro、Kinoshita Rie、Nakata Kentaro、Tanaka Shin、Hashimoto Kohei、Miyoshi Kentaroh、Yamane Masaomi、Matsukawa Akihiro、Sakaguchi Masakiyo、Toyooka Shinichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 629 Pages: 86-94
  • DOI: 10.1016/j.bbrc.2022.08.087
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells (2022)
  • Author(s): Nahoko Tomonobu, Rie Kinoshita, Hidenori Wake, Yusuke Inoue, ..., Hitoshi Murata, Ken-ichi Yamamoto, I Wayan Sumardika, Youyi Chen, Junichiro Futami, Akira Yamauchi, Futoshi Kuribayashi, Eisaku Kondo, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 18 Pages: 10300-10300
  • DOI: 10.3390/ijms231810300
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 軸索変性誘導分子 SARM1の阻害剤開発 (2022)
  • Author(s): 村田 等、安藤 隆幸、大磯 和真、友信 奈保子、山本 健一、木下 理恵、阪口 政清
  • Organizer: NEURO2022
• [Presentation] 炎症性疾患に対する抗S100A8/A9抗体療法におけるマクロファージの役割 (2022)
  • Author(s): 木下理恵、小林和子、荒木恒太、佐藤博紀、友信奈保子、村田等、許南浩、豊岡伸一、阪口政清
  • Organizer: 日本組織培養学会第94回大会
• [Presentation] REIC protein suppresses tumor progression through PD-L1 regulation in cancer cells (2022)
  • Author(s): Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Hitoshi Murata, Ken-ichi Yamamoto, Masayoshi Namba, Nam-ho Huh, Hiromi Kumon, Masakiyo Sakaguchi
  • Organizer: 日本組織培養学会第94回大会
• [Presentation] 腫瘍微小環境を悪性化する S100A8/A9 を標的としたがん治療薬の開発 (2022)
  • Author(s): 木下 理恵、友信 奈保子、山内 明、二見 淳一郎、近藤 英作、豊岡 伸一、阪口 政清
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] REIC/Dkk-3の受容体への結合はトリプルネガティブ乳がんのPD-L1の発現を抑制する (2022)
  • Author(s): 吉澤 智香子、合原 勇馬、友信 奈保子、木下 理恵、二見 淳一郎、村田 等、山本 健一、阪口 政清
  • Organizer: 第45回日本分子生物学会年会