Development of highly specific oncolytic herpes virus vectors by modification of two envelope glycoproteins

• Project/Area Number: 15K15144
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Virology
• Research Institution: The University of Tokyo
• Principal Investigator: Uchida Hiroaki 東京大学, 医科学研究所, 講師 (20401250)
• Co-Investigator(Kenkyū-buntansha): KOJIMA MASAKI 東京薬科大学, 生命科学部, 教授 (90277252) ; TAHARA HIDEAKI 東京大学, 医科学研究所, 教授 (70322071)
• Project Period (FY): 2015-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 遺伝子治療 / 腫瘍溶解性ウイルス療法 / ヘルペスウイルス / 抗体 / がん

Outline of Final Research Achievements

Herpes simplex virus (HSV) vectors are promising agents for oncolytic virotherapy. We have recently reported a fully retargeted HSV platform that incorporates single-chain antibodies (scFv) into gD to mediate entry exclusively via tumor-associated antigens, including epidermal growth factor receptor (EGFR). In this study, we sought to examine whether another envelope glycoprotein, gB, could also be genetically re-engineered to interact with tumor-associated antigens. We inserted an anti-EGFR scFv or the EGF ligand into a number of different portions of gB, and found that many, but not all, of the mutated gB proteins were expressed on the cell surface. We also found that the viruses incorporating some of the mutated gB proteins retained the capability of entering cells, suggesting the potential feasibility of gB retargeting.

Research Products

• [Int'l Joint Research] University of Pittsburgh(米国)
• [Journal Article] Development of an oncolytic HSV vector fully retargeted specifically to cellular EpCAM for virus entry and cell-to-cell spread. (2016)
  • Author(s): Shibata T, Uchida H, Shiroyama T, Okubo Y, Suzuki T, Ikeda H, Yamaguchi M, Miyagawa Y, Fukuhara T, Cohen JB, Glorioso JC, Watabe T, Hamada H, Tahara H.
  • Journal Title: Gene Therapy. Volume: 印刷中 Issue: 6 Pages: 479-488
  • DOI: 10.1038/gt.2016.17
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A newly developed anti-Mucin 13 monoclonal antibody targets pancreatic ductal adenocarcinoma cells. (2015)
  • Author(s): Nishii Y, Yamaguchi M, Kimura Y, Hasegawa T, Aburatani H, Uchida H, Hirata K, Sakuma Y.
  • Journal Title: International Journal of Oncology. Volume: 46 Issue: 4 Pages: 1781-1787
  • DOI: 10.3892/ijo.2015.2880
  • Peer Reviewed
• [Journal Article] 大腸癌の遺伝子治療・ウイルス療法 (2015)
  • Author(s): 内田宏昭, 田原秀晃
  • Journal Title: 日本臨床 Volume: 1077 Pages: 569-573
• [Presentation] がん細胞のみに侵入可能な標的化改変ヘルペスウイルスの開発 (2016)
  • Author(s): 内田宏昭
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2016-04-14
• [Presentation] 腫瘍細胞表面抗原を介して侵入する標的化単純ヘルペスウイルスベクターの開発 (2015)
  • Author(s): 城山智貴, 内田宏昭, 大久保優, 柴田智子, 福原武志, 山口美樹, Justus B. Cohen, Joseph C. Glorioso, 渡部徹郎, 濱田洋文, 田原秀晃
  • Organizer: 第7回血液疾患免疫療法研究会
  • Place of Presentation: 東京大学本郷キャンパス（東京都文京区）
  • Year and Date: 2015-09-26
• [Presentation] Exploration of cancer-targeting antibodies using an HSV-based screening system for development of novel HSV vectors fully retargeted to cancer cells. (2015)
  • Author(s): 内田宏昭
  • Organizer: The 21th Annual Meeting of Japan Society of Gene Therapy.
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2015-07-24
• [Presentation] がん細胞表面抗原を介して細胞内侵入する標的化改変単純ヘルペスウイルスベクターの開発 (2015)
  • Author(s): 内田宏昭
  • Organizer: 第56回日本臨床ウイルス学会
  • Place of Presentation: 岡山大学鹿田キャンパス（岡山県岡山市）
  • Year and Date: 2015-06-13
  • Invited
• [Remarks] 東京大学医科学研究所先端医療研究センター臓器細胞工学分野ホームページ
  • URL: http://www.ims.u-tokyo.ac.jp/sur+trans/sur+be/index.html