Generation of immunotoxins with super-targeting mAb in the acute myelocytic leukemia

• Project/Area Number: 23501309
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: Sapporo Medical University
• Principal Investigator: YAMAGUCHI MIKI 札幌医科大学, 医学部, 助教 (10530454)
• Co-Investigator(Kenkyū-buntansha): HAMADA Hirofumi 東京薬科大学, 生命科学部, 教授 (00189614) ; HIRAI Sachie 札幌医科大学, 医学部, 助手 (20218754) ; UCHIDA Hiroaki 東京薬科大学, 生命科学部, 准教授 (20401250)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: AML / 標的治療 / イミュノトキシン / モノクローナル抗体 / DT3C / ADC

Research Abstract

We generated a recombinant fusion protein DT3C, which contained the catalytic and translocation domain of the truncated diphtheria toxin (DT) as well as the three IgG-binding C domains of streptococcal protein G (3C). Fc of MoAb binds with DT3C, resulting in a MoAb-DT3C complex (two DT3C molecules conjugated with one IgG molecule). The MoAb-DT3C complex binds with the surface Ag, being followed by internalization and translocation into the cytoplasm, leads to the cytocydal effect by protein synthesis inhibition of DT. By using these, we developed a unique screening system to establish cancer-targetable antigens/antibodies sets. In total 224 MoAb clones were obtained which performed immunotoxin cytocydal on leukemic cells. Our method provide an excellent way to obtain promising superior mAbs for antibodies drug conjugation(ADC) therapy.

Research Products

• [Journal Article] Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV (2013)
  • Author(s): Wang PY, Currier MA, Hansford L, Kaplan D, Chiocca EA, Uchida H, Goins WF, Cohen JB, Glorioso JC, van Kuppevelt TH, Mo X, Cripe TP
  • Journal Title: Gene Ther Volume: 20(7) Pages: 761-769
  • Peer Reviewed
• [Journal Article] Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus (2013)
  • Author(s): Uchida H, Marzulli M, Nakano K, Goins WF, Chan J, Hong CH, Mazzacurati L, Yoo JY, Haseley A, Nakashima H, Baek H, Kwon H, Kumagai I, Kuroki M, Kaur B, Chiocca EA, Grandi P, Cohen JB, Glorioso JC
  • Journal Title: Mol Ther Volume: 21(3) Pages: 561-569
  • Peer Reviewed
• [Journal Article] Novel mutations in gB and gH circumvent the requirement for known gD receptors in HSV-1 entry and cell-to-cell spread (2013)
  • Author(s): Uchida H, Chan J, Shrivastava I, Reinhart B, Grandi P, Glorioso JC, Cohen JB
  • Journal Title: J Virol Volume: 87(3) Pages: 1430-1442
  • Peer Reviewed
• [Journal Article] IKAROS isoform 6 enhances BCR-ABL1-mediated proliferation of human CD34+ hematopoietic cells on stromal cells (2012)
  • Author(s): Suzuki K, et al
  • Journal Title: Int J Oncol Volume: 40 Pages: 53-62
  • DOI: 10.3892/ijo.2011.1192
  • Peer Reviewed
• [Journal Article] Epigenetic modulation enhances the therapeutic effect of anti-IL-13R(alpha)2 antibody in human mesothelioma xenografts (2011)
  • Author(s): Takenouchi M, Hirai S, Sakuragi N, Yagita H, Hamada H, Kato K
  • Journal Title: Clin Cancer Res Volume: 17(9) Pages: 2819-2829
  • Peer Reviewed
• [Journal Article] Bone marrow stromal cell line promotes the proliferation of mast cell progenitors derived from cord blood CD34+ cells under serum-free conditions with a combination of both cell-cell interaction and soluble factors. (2011)
  • Author(s): Fujihara M, Azuma H, Ikeda H, Yamaguchi M, Hamada H.
  • Journal Title: Artif Cells Blood Substit Immobil Biotechnol Volume: Apr;39(2) Issue: 2 Pages: 51-58
  • DOI: 10.3109/10731199.2010.501754
  • Peer Reviewed
• [Journal Article] EpCAM- and EGFR-targeted selective gene therapy for biliary cancers using Z33-fiber-modified adenovirus (2011)
  • Author(s): Kawashima R, Abei M, Fukuda K, Nakamura K, Murata T, Wakayama M, Seo E, Hasegawa N, Mizuguchi H, Obata Y, Hyodo I, Hamada H, Yokoyama KK.
  • Journal Title: INTERNATIONAL JOURNAL OF CANCER Volume: Sep;129(5) Issue: 5 Pages: 1244-1253
  • DOI: 10.1002/ijc.25758
  • Peer Reviewed
• [Journal Article] E1A, E1B double-restricted adenovirus enhances the cytotoxicity and antitumor activity of gemcitabine to renal cell carcinoma. (2011)
  • Author(s): Wang H, Satoh M, Chen GP, Li DC, Hamada H, Arai Y.
  • Journal Title: CHINESE MEDICAL JOURNAL Volume: APR;124(7) Pages: 1082-1087
  • Peer Reviewed
• [Presentation] 急性骨髄性白血病に対するスーパー標的化抗体を用いたイミュノトキシンの開発 (2013)
  • Author(s): 山口美樹、西井ゆかり、濱田洋文
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-12
• [Presentation] 白血病/リンパ腫に対するスーパー標的化抗体を用いたイムノトキシンの開発 (2013)
  • Author(s): 西井ゆかり、山口美樹、平井幸恵、内田宏昭、濱田洋
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03
• [Presentation] Generation of immunotoxins with super-targeting mAb in acute myeloid leukemia (2013)
  • Author(s): Miki Yamaguchi1, Yukari Nishii1, Hirofumi Hamada1,2
  • Organizer: 第７５回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Generation of Immunotoxins against AML: Cytocidal activities with anti-CD71 mAb (2013)
  • Author(s): Yukari Nishii1, Miki Yamaguchi1, Hirofumi Hamada1,2
  • Organizer: 第７５回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Generation of immunotoxins with super-targeting mAb in the leukemia/lymphoma (2013)
  • Author(s): Yukari Nishii1, Miki Yamaguchi1, Hiroaki Uchida2, Hirofumi Hamada1,2
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Application of in-house monoclonal antibody resources to a fully retargeted oncolytic herpes simplex virus platform (2013)
  • Author(s): Yu Okubo1, Takuma Suzuki1, Tomoko Shibata1, Mao Komai1, Takeshi Fukuhara1, Miki Yamaguchi2, Sachie Hirai2, Yoshitaka Miyagawa3, Justus B. Cohen3, Joseph C. Glorioso3, Hirofumi Hamada1, and Hiroaki Uchida1
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Development of fully retargeted oncolytic herpes simplex virus vectors by insertion of tumor-specific single-chain antibodies into viral envelope glycoprotein D (2013)
  • Author(s): Takuma Suzuki1, Tomoko Shibata1, Yu Okubo1, Takeshi Fukuhara1, Yoshitaka Miyagawa2, Justus B. Cohen2, Joseph C. Glorioso2, Kenji Nakano3, Izumi Kumagai4, Masahide Kuroki5, Miki Yamaguchi6, Sachie Hirai6, Hirofumi Hamada1, and Hiroaki Uchida1
  • Organizer: 第６１回日本ウイルス学会学術集会
  • Place of Presentation: 神戸
• [Presentation] Application of monoclonal antibody resources to a fully retargeted HSV platform (2013)
  • Author(s): Tomoko Shibata1, Takuma Suzuki1, Yu Okubo1, Mao Komai1, Takeshi Fukuhara1, Miki Yamaguchi2, Sachie Hirai2, Yoshitaka Miyagawa3, Justus B. Cohen3, Joseph C. Glorioso3, Hirofumi Hamada1, and Hiroaki Uchida1
  • Organizer: 第６１回日本ウイルス学会学術集会
  • Place of Presentation: 神戸
• [Presentation] Establishment of highly functional monoclonal antibodies through novel screening methods for targeted cancer therapy (2013)
  • Author(s): Moegi Sato1, Miki Yamaguchi2, Hitomi Ikeda1, Yuta Matsuura1, Takeshi Fukuhara1, Hirofumi Hamada1, and Hiroaki Uchida1
  • Organizer: 第81回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] スーパー標的化抗体を用いたimmunotoxin の開発:AML に対する抗CD71 抗体を用いた抗腫瘍活性 (2012)
  • Author(s): 西井ゆかり、山口美樹、平井幸恵、濱田洋文
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-20
• [Presentation] メラノーマ標的化新規モノクローナル抗体の網羅的解析 (2012)
  • Author(s): 平井幸恵、山口美樹、濱田洋文
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-19
• [Presentation] Systematic screening of novel monoclonal antibodies targeting human melanoma cells (2012)
  • Author(s): Hirai S, Yamaguchi M, Hamada H
  • Organizer: The 71st Annual Meeting of Japanese Cancer Association
  • Place of Presentation: 札幌
• [Presentation] Generation of immunotoxins with super-targeting mAb: superior antitumor activities with anti-CD71 mAb agenst AML (2012)
  • Author(s): Nishii Y, Yamaguchi M, Hirai S, Hamada H
  • Organizer: The 71st Annual Meeting of Japanese Cancer Association
  • Place of Presentation: 札幌
• [Presentation] メラノーマに対する新規標的化抗体の樹立と機能解析 (2011)
  • Author(s): 平井幸恵、山口美樹、濱田洋文
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] スーパー標的化抗体を用いたImmunotoxin の開発:非小細胞肺癌に対するCD59 抗体を用いた抗腫瘍活性 (2011)
  • Author(s): 山口美樹、西井ゆかり、平井幸恵、濱田洋文
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] Generation of immunotoxins with super-targeting mAb: superior antitumor activities with anti-TROP2 mAb against NSCLC
  • Author(s): 山口美樹、西井ゆかり、平井幸恵、加藤和則、濱田洋文
  • Organizer: 第15回日本がん免疫学会総会
  • Place of Presentation: 大阪府
• [Presentation] Generation of immunotoxins with super-targeting monoclonal antibodies (mAb): superior antitumor activities with anti-CD59 mAb against non-small cell lung cancers (NSCLC).
  • Author(s): 山口美樹、西井ゆかり、平井幸恵、濱田洋文
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知県名古屋市
• [Presentation] メラノーマに対する新規標的化抗体の樹立と機能解析
  • Author(s): 平井幸恵、山口美樹、濱田洋文
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知県名古屋市
• [Remarks]
  • URL: http://web.sapmed.ac.jp/molm/
• [Patent(Industrial Property Rights)] 抗Trop-2 抗体 (2011)
  • Inventor(s): 山口美樹、加藤和則、濱田洋文、他
  • Industrial Property Rights Holder: 札幌医科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2011-06-09