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

2018 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

抗体創薬

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。