Targeting surface antigens for intraoperative treatment of IDH mutant gliomas

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16632
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: Niigata University
• Principal Investigator: Natsumeda Manabu 新潟大学, 脳研究所, 助教 (00515728)
• Research Collaborator: KATO Yukinari ; ABE Hideaki ; OKADA Masayasu ; WATANABE Jun
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: グリオーマ / 神経膠腫 / NIR-PIT / 光線免疫療法 / 術中療法 / ポドプラニン

Outline of Final Research Achievements

The present research was devoted to looking at the potential application of intraoperative antibody treatment targeting isocitrate dehydrogenase (IDH) mutant protein. We tested 4 IDH1-mutant antibodies (HMab1, HMab-2, H09, and MsMab-1) against 2 IDH-mutant glioma cell lines (MGG152, BT142) by flowcytometry and found that only 10-20% of cells stained weakly positive. These results suggested that IDH1-mutant protein was not a good target for near infrared photoimmunotherapy (NIR-PIT) in gliomas, probably because IDH1 mutation is expressed in the cytoplasm of IDH1-mutant gliomas and not the cell surface.
Next, we targeted podoplanin, a membrane bound antigen highly expressed in malignant gliomas by using 4 podoplanin antibodies against 2 podoplanin expressing cell lines, and found an almost 100% positivity by flow cytometry. NIR-PIT using podoplanin-IR700 conjugate induced blebbing and cell death in glioblastoma cell lines in vitro.

Free Research Field

脳腫瘍

Academic Significance and Societal Importance of the Research Achievements

悪性神経膠腫は極めて予後の悪い脳腫瘍であり、その治療法の確立は急務である。周囲脳に細胞が浸潤し、手術で取り切れない。本研究は悪性神経膠腫に対して、近赤外線光線免疫療法（NIR-PIT）という、腫瘍細胞の表面抗原を標的し腫瘍細胞のみを破壊する抗原特異的免疫療法の確立を目指した。腫瘍特異抗体を蛍光標識することで術中の残存腫瘍の評価にも利用できることから、NIR-PITの実現は神経膠腫に革命的な治療の進歩をもたらす可能性を秘めている。細胞表面ではなく細胞質に発現するIDH1抗体によるNIR-PITは上手く行かなかったが、その後、ポドプラニンという細胞膜蛋白に対するNIR-PITの有効性が示唆された。