Development of specific anti-mutated IDH monoclonal antibodies for diagnosis of gliomas

• Project/Area Number: 16K10748
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Tohoku University
• Principal Investigator: Kato Yukinari 東北大学, 未来科学技術共同研究センター, 教授 (00571811)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: IDH / イソクエン酸デヒドロゲナーゼ / IDH1 / IDH2 / モノクローナル抗体 / グリオーマ / 脳腫瘍 / 特異的抗体 / 予後 / 免疫組織染色 / 診断 / glioma / glioblastoma / monoclonal antibody / IDH1-R132L / immunohistochemistry / 抗体 / IDH1-R132H

Outline of Final Research Achievements

A point mutation in IDH1/2 is linked to the pathogenesis of gliomas. Several antibodies that can distinguish between mutant and wild-type enzymes have been established to detect this mutation. MsMab-1 has a unique multi-specific character against several types of mutated IDH1/2. This promiscuous character is in remarkable contrast to the highly specific antigen recognition typically observed with a monoclonal antibody. We solved the crystal structure of MsMab-1 Fab fragment in complex with either IDH1/IDH2-derived peptides. Based on the structure, it became clear that the peptide-binding pocket of the antibody is highly complementary to the core determinant shared between the IDH1 and IDH2, while leaving just enough space for the side chain of the pathogenic but not the wild-type amino acids located in the mutation position. Clarification of the molecular basis for the peculiar binding characteristics of MsMab-1 in atomic detail will help facilitating its diagnostic application.

Academic Significance and Societal Importance of the Research Achievements

脳腫瘍の中でも、グリオーマには複数の種類があるが、患者さんの予後は簡単には推測ができない。そこで、グリオーマにおいて見られる遺伝子変異を標的にモノクローナル抗体を作製し、患者さんの予後の診断を行うことは臨床的にとても重要である。我々が注目した変異型IDH1/2はグリオーマにおいて予後診断マーカーとして有用である。本研究では、変異型IDH1/2に対する特異的抗体を樹立しグリオーマの臨床診断に応用すると共に、その作用メカニズムの解明を目指した。その結果、変異型IDH1/2に対する特異的抗体の認識メカニズムが明らかとなり、今後の診断法のさらなる開発につながる成果となった。

Research Products

• [Journal Article] Epitope mapping of an anti-alpha thalassemia/mental retardation syndrome X-linked monoclonal antibody AMab-6 (2018)
  • Author(s): Kaneko MK, Yamada S, Itai S, Furusawa Y, Nakamura T, Yanaka M, Handa S, Hisamatsu K, Nakamura Y, Fukui M, Harada H, Kato Y
  • Journal Title: Biochem. Biophys. Rep. Volume: 15 Pages: 52-56
  • DOI: 10.1016/j.bbrep.2018.07.003
  • Peer Reviewed / Open Access
• [Journal Article] Epitope mapping of anti-telomerase reverse transcriptase (TERT) monoclonal antibodies (2018)
  • Author(s): Furusawa Y, Itai S, Yamada S, Kaneko MK, Kato Y
  • Journal Title: Monoclon. Antib. Immunodiagn. Immunother. Volume: 37 Issue: 4 Pages: 185-187
  • DOI: 10.1089/mab.2018.0019
  • Peer Reviewed
• [Journal Article] Immunohistochemical ATRX expression is not a surrogate for 1p19q codeletion (2018)
  • Author(s): Yamamichi Akane、Ohka Fumiharu、Aoki Kosuke、Suzuki Hiromichi、Kato Akira、Hirano Masaki、Motomura Kazuya、Tanahashi Kuniaki、Chalise Lushun、Maeda Sachi、Wakabayashi Toshihiko、Kato Yukinari、Natsume Atsushi
  • Journal Title: Brain Tumor Pathology Volume: - Issue: 2 Pages: 106-113
  • DOI: 10.1007/s10014-018-0312-5
  • NAID: 120006496406
  • Peer Reviewed
• [Journal Article] Elevated TERT Expression in TERT-Wildtype Adult Diffuse Gliomas: Histological Evaluation with a Novel TERT-Specific Antibody. (2018)
  • Author(s): Masui K, Komori T, Kato Y, Masutomi K, Ichimura K, Ogasawara S, Kaneko MK, Oki H, Suzuki H, Nitta M, Maruyama T, Muragaki Y, Kawamata T, Sawada T, and Shibata N
  • Journal Title: BioMed Research International Volume: - Pages: 95-99
  • DOI: 10.1155/2018/7945845
  • Peer Reviewed / Open Access
• [Journal Article] A novel all-in-one intraoperative genotyping system for IDH1-mutant glioma. (2017)
  • Author(s): Ohka F, Yamamichi A, Kurimoto M, Motomura K, Tanahashi K, Suzuki H, Aoki K, Deguchi S, Chalise L, Hirano M, Kato A, Nishimura Y, Hara M, Kato Y, Wakabayashi T, Natsume A.
  • Journal Title: Brain Tumor Pathol. Volume: 印刷中 Issue: 2 Pages: 91-97
  • DOI: 10.1007/s10014-017-0281-0
  • NAID: 120006331835
  • Peer Reviewed
• [Journal Article] Immunohistochemistry Using Monoclonal Antibody MsMab-2 Is Useful to Detect IDH1 R132L in Intrahepatic Cholangiocarcinoma. (2016)
  • Author(s): Hayashi A, Misumi K, Shibahara J, Kokudo N, Kato Y and Fukayama M.
  • Journal Title: Pathology international Volume: 66 Issue: 10 Pages: 578-582
  • DOI: 10.1111/pin.12459
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structural basis for multi-specific peptide recognition by the anti-IDH1/2 monoclonal antibody, MsMab-1. (2016)
  • Author(s): Kitago Y, Kaneko MK, Ogasawara S, Kato Y, Takagi J.
  • Journal Title: Biochem Biophys Res Commun Volume: 478 Issue: 3 Pages: 1274-1279
  • DOI: 10.1016/j.bbrc.2016.08.110
  • Peer Reviewed / Open Access
• [Journal Article] mmunohistochemistry on IDH 1/2, ATRX, p53 and Ki-67 substitute molecular genetic testing and predict patient prognosis in grade III adult diffuse gliomas. (2016)
  • Author(s): Takano S, Ishikawa E, Sakamoto N, Matsuda M, Akutsu H, Noguchi M, Kato Y, Yamamoto T, Matsumura A
  • Journal Title: Brain Tumor Pathology Volume: 33 Issue: 2 Pages: 107-116
  • DOI: 10.1007/s10014-016-0260-x
  • Peer Reviewed / Acknowledgement Compliant
• [Remarks] 抗体創薬研究分野のホームページ
  • URL: http://www.med-tohoku-antibody.com/index.htm
• [Remarks] 東北大学大学院医学系研究科抗体創薬研究分野
  • URL: http://www.med-tohoku-antibody.com/index.htm