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Specific monoclonal antibodies against IDH1/2 mutations as diagnostic tools for gliomas

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Abstract

Mutations of isocitrate dehydrogenase 1/2 (IDH1/2) have been reported in gliomas and other types of tumors, such as acute myeloid leukemias, cartilaginous tumors, intrahepatic cholangiocarcinomas, osteosarcomas, and giant cell tumors of bone. In gliomas, IDH mutations uniformly occur in the functionally critical arginine 132 residue (R132) of IDH1 and arginine 172 residue (R172) of IDH2. IDH1 and IDH2 catalyze the oxidative carboxylation of isocitrate to α-ketoglutarate (α-KG) in the cytosol and mitochondria, respectively. In contrast, mutated IDH1/2 proteins possess a neomorphic enzymatic function that changes α-KG into the oncometabolite, R(–)-2-hydroxyglutarate, resulting in genomic hypermethylation, histone methylation, genetic instability, and malignant transformation. To date, several monoclonal antibodies (mAbs) specific for IDH1/2 mutations such as anti-IDH1-R132H mAbs (clone H09, clone IMab-1, and clone HMab-1) or an anti-IDH1-R132S mAb (clone SMab-1) have been established. Furthermore, one of multi-specific mAbs, MsMab-1, recognizes IDH1 mutants (R132H, R132S, R132G) and IDH2 mutants (R172S, R172G), which are observed in gliomas. Another mAb, MsMab-2, recognizes IDH1-R132L and IDH2-R172M. These IDH1/2 mutation-specific mAbs are useful for the immunohistochemical determination of IDH1/2 mutation-bearing gliomas.

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Fig. 1

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Abbreviations

IDH1/2:

Isocitrate dehydrogenase 1/2

mAb:

Monoclonal antibody

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Acknowledgments

We thank Mika Kato Kaneko, Satoshi Ogasawara, Yuta Tsujimoto, Hiroharu Oki, Xing Liu, Takuro Nakamura, and Noriko Saidoh (Tohoku University) for their helpful suggestion and excellent technical assistance. We also thank Mitsutoshi Nakada and Hemragul Sabit (Kanazawa University) for their immunohistochemical data. This work was supported in part by the Platform for Drug Discovery, Informatics, and Structural Life Science (PDIS) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; by the Regional Innovation Strategy Support Program from MEXT of Japan; and by a Grant-in-Aid for Scientific Research (C) from MEXT of Japan.

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The authors have no conflict of interest to declare.

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  1. Department of Regional Innovation, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Yukinari Kato

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Kato, Y. Specific monoclonal antibodies against IDH1/2 mutations as diagnostic tools for gliomas. Brain Tumor Pathol 32, 3–11 (2015). https://doi.org/10.1007/s10014-014-0202-4

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