Development of Intracellular Molecularly Targeted Therapy Targeting E7 Protein of HPV that Initiates Cervical Cancer

• Project/Area Number: 17K11301
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Aichi Medical University
• Principal Investigator: Yoshikawa Kazuhiro 愛知医科大学, 研究創出支援センター, 特務研究教授 (60109759)
• Co-Investigator(Kenkyū-buntansha): 藪下 廣光 愛知医科大学, 医学部, 教授 (00140046) ; 鈴木 進 愛知医科大学, 加齢医科学研究所, 准教授 (70518422)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: HPV / 抗体 / 免疫治療 / 膜貫通 / cell-penetrating peptide / HPV16-E7 / HPV18-E7 / antibody / scFv / 子宮がん / ペプチド / 子宮頸がん / 組換え型抗体 / HPV-E7 / 細胞膜透過性ペプチド / 子宮頚がん / 組み換え型抗体 / ファージ抗体

Outline of Final Research Achievements

The purpose of this study was to generate antibodies against the E7 gene product of HPV, which is considered to be the cause of cervical cancer, and to apply them to uterine cancer treatment. The gene construction for the antibody-producing phage library was completed. We also attempted to generate mouse monoclonal antibodies by producing antigens with E. coli. However, no antibody that could specifically stain virus-infected cells was obtained. In addition, for the construction of the evaluation system, we screened commercially available antibodies, but were unable to obtain antibodies that could specifically stain viral antigens. Therefore, the desired antibodies could not be obtained.

Academic Significance and Societal Importance of the Research Achievements

本研究は、子宮頸がんの発生原因として考えられているHPVのE7遺伝子産物に対する抗体を作製し、子宮がん治療に応用する事を目的として実施した。HPV16、18の感染が認められた子宮がん患者より採取されたリンパ節細胞から抗体産生ファージライブラリー作成のための遺伝子構築ができたことから、子宮がんだけでなく、その他のがんにおいても同様の抗体作成のためのライブラリー作成の可能性が示された。このことは、それらのライブラリーのスクリーニングより、がん治療用の抗体を得る可能性が示されたということも意義として大きく、今後も研究を続けていく意味のある事と思われた。

Research Products

• [Journal Article] Establishment of Mucoepidermoid Carcinoma Cell Lines from Surgical and Recurrence Biopsy Specimens (2023)
  • Author(s): Yamanaka S, Suzuki S, Ito H, Sivasundaram K, Hanamura I, Okubo I, Yoshikawa K, Ono S, Takahara T, Satou A, Tsuzuki T, Ueda R, Ogawa T, Fujimoto Y.
  • Journal Title: International journal of molecular sciences Volume: 24 Issue: 2 Pages: 1722-1722
  • DOI: 10.3390/ijms24021722
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Trametinib improves Treg selectivity of anti-CCR4 antibody by regulating CCR4 expression in CTLs in oral squamous cell carcinoma (2022)
  • Author(s): Ono S, Suzuki S, Kondo Y, Okubo I, Goto M, Ogawa T, Kato H, Ito H, Takahara T, Satou A, Tsuzuki T, Yoshikawa K, Nagao T, Ueda R.
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 21678-21678
  • DOI: 10.1038/s41598-022-22773-1
  • Peer Reviewed / Open Access
• [Journal Article] An In Vivo Study of Local Administration of Low-dose Anti-PD-1 Antibody Using an Oral Cancer Cell Line. (2022)
  • Author(s): Sakuma K, Kii T, Takahashi H, Suzuki S, Yoshikawa K, Ogawa T, Tanaka A.
  • Journal Title: Ainticancer Research Volume: 42 Issue: 9 Pages: 4293-4303
  • DOI: 10.21873/anticanres.15929
  • Peer Reviewed
• [Journal Article] Immune-checkpoint molecules on regulatory T-cells as potential therapeutic target in head and neck squamous cell cancers. (2020)
  • Author(s): Suzuki S, Ogawa T, Sano R, Takahara T, Inukai D, Satou A, Tsuchida H, Yoshikawa K, Ueda R, Tsuzuki T
  • Journal Title: Cancer Sci. Volume: in press Issue: 6 Pages: 1943-1957
  • DOI: 10.1111/cas.14422
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combining T‐cell‐based immunotherapy with venetoclax elicits synergistic cytotoxicity to B‐cell lines in vitro (2020)
  • Author(s): Murakami Satsuki、Suzuki Susumu、Hanamura Ichiro、Yoshikawa Kazuhiro、Ueda Ryuzo、Seto Masao、Takami Akiyoshi
  • Journal Title: Hematological Oncology Volume: 38 Issue: 5 Pages: 705-714
  • DOI: 10.1002/hon.2794
  • Peer Reviewed / Open Access
• [Journal Article] Increased infiltration of CCR4-positive regulatory T cells in prostate cancer tissue is associated with a poor prognosis. (2019)
  • Author(s): Watanabe M, Kanao K, Suzuki S, Muramatsu H, Morinaga S, Kajikawa K, Kobayashi I, Nishikawa G, Kato Y, Zennami K, Nakamura K, Tsuzuki T, Yoshikawa K, Ueda R, Sumitomo M.
  • Journal Title: Prostate Volume: 79(14) Issue: 14 Pages: 1658-1665
  • DOI: 10.1002/pros.23890
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CCR4 expression in tumor-infiltrating regulatory T cells in patients with squamous cell carcinoma of the lung: A prognostic factor for relapse and survival (2019)
  • Author(s): Kubo A, Asai N, Suzuki S, Murotani K, Numanami H, Yoshikawa K, Ueda R, Yamaguchi E
  • Journal Title: Cancer Invest Volume: 37 Issue: 3 Pages: 163-73
  • DOI: 10.1080/07357907.2019.1582848
  • Peer Reviewed
• [Journal Article] Targeting lactate dehydrogenase-A promotes docetaxe-induced cytotoxicity predominantly in castration-resistant prostate cancer cells. (2019)
  • Author(s): Muramatsu H, Sumitomo M, Morinaga S, Kajikawa K, Kobayashi I, Nishikawa G, Kato Y, Watanabe M, Zennami K, Kanao K, Nakamura K, Suzuki S, Yoshikawa K.
  • Journal Title: Oncol Rep. Volume: 42(1) Pages: 224-230
  • DOI: 10.3892/or.2019.7171
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HOXA10 expression profiling in prostate cancer (2019)
  • Author(s): Hatanaka Yuji、de Velasco Marco A.、Oki Takashi、Shimizu Nobutaka、Nozawa Masahiro、Yoshimura Kazuhiro、Yoshikawa Kazuhiro、Nishio Kazuto、Uemura Hirotsugu
  • Journal Title: The Prostate Volume: 79 Issue: 5 Pages: 554-563
  • DOI: 10.1002/pros.23761
  • Peer Reviewed / Open Access
• [Journal Article] Systemic transduction of p16INK4a antitumor peptide inhibits lung metastasis of the MBT-2 bladder tumor cell line in mice (2018)
  • Author(s): Shimazui Toru、Yoshikawa Kazuhiro、Ishitsuka Ryutaro、Kojima Takahiro、Kandori Shuya、Yoshino Takayuki、Miyazaki Jun、Uchida Kazuhiko、Nishiyama Hiroyuki
  • Journal Title: Oncology Letters Volume: 17 Pages: 1203-1210
  • DOI: 10.3892/ol.2018.9655
  • NAID: 120007128291
  • Peer Reviewed
• [Journal Article] Generation of PTEN?knockout (-/-) murine prostate cancer cells using the CRISPR/Cas9 system and comprehensive gene expression profiling (2018)
  • Author(s): Takao Akiko、Yoshikawa Kazuhiro、Karnan Sivasundaram、Ota Akinobu、Uemura Hirotsugu、De Velasco Marco、Kura Yurie、Suzuki Susumu、Ueda Ryuzo、Nishino Tokiko、Hosokawa Yoshitaka
  • Journal Title: Oncology Reports Volume: 40 Pages: 2455-2466
  • DOI: 10.3892/or.2018.6683
  • Peer Reviewed
• [Journal Article] Adoptive immunotherapy combined with FP treatment for head and neck cancer: An in vitro study (2017)
  • Author(s): Nishio-Nagai Mayako、Suzuki Susumu、Yoshikawa Kazuhiro、Ueda Ryuzo、Kazaoka Yoshiaki
  • Journal Title: International Journal of Oncology Volume: 51 Issue: 5 Pages: 1471-1481
  • DOI: 10.3892/ijo.2017.4142
  • Peer Reviewed
• [Presentation] Transforming growth factor-beta inhibitor is a candidate drug for immunotherapy of oral squamous cell carcinoma (2022)
  • Author(s): Yutaro Kondo, Taishi Takahara, Shoya Ono, Mitsuo Goto, Tetsuya Ogawa, Hideaki Ito, Akira Sato, Toyonori Tsuzuki, Kazuhiro Yoshikawa, Ryuzo Ueda, Susumu Suzuki
  • Organizer: 日本癌学会
• [Presentation] Establishment passive culture cells derived from mucoepidermoid carcinoma (2022)
  • Author(s): Shunpei Yamanaka, Susumu Suzuki, Hideaki Ito, Shoya Ono, Yutaro Kondo, Daisuke Inukai, Hiroki Okamoto, Taishi Takahara, Toyonori Tsuzuki, Kazuhiro Yoshikawa, Ryuzo Ueda, Tetsuya Ogawa
  • Organizer: 日本癌学会
• [Presentation] Characterization of immune-suppressive microenvironment in head & neck cancer (2018)
  • Author(s): 佐野 塁,鈴木 進, 小川 徹也, 犬飼 大輔, 岡本 啓希, 高原 大志, 佐藤 啓, 吉川 和宏, 都築 豊徳, 上田 龍三
  • Organizer: 日本癌学会
• [Presentation] Interrogating genetically engineered mouse models of prostate cancer to aid in immunotherapy development (2018)
  • Author(s): デベラスコ・マルコ, 倉 由吏恵, 森 康範, 清水 信貴, 大關 孝之, 坂井 和子, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受
  • Organizer: 日本癌学会
• [Presentation] 頭頸部がん外科免疫治療の開発 手術検体を用いた腫瘍局所における免疫関連細胞・分子の解析から考える (2018)
  • Author(s): 小川 徹也, 犬飼 大輔, 岡本 啓希, 山中 俊平, 佐野 塁, 植田 広海, 都築 豊徳, 鈴木 進, 吉川 和宏, 上田 龍三
  • Organizer: 日本頭頸部癌学会
• [Presentation] 頭頸部がん手術検体を用いたeffector Tregの腫瘍内発現の解析 (2017)
  • Author(s): 鈴木 進, 西村 邦宏, 小川 徹也, 都築 豊徳, 吉川 和宏, 上田 龍三
  • Organizer: 日本癌学会
• [Patent(Industrial Property Rights)] エフェクター制御性T細胞の検出と調整 (2018)
  • Inventor(s): 鈴木進、吉川和宏
  • Industrial Property Rights Holder: 愛知医科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Acquisition Date: 2022