Anti-IDH1 (Human) mAb

Isocitrate dehydrogenase 1 (IDH1) mutations, which have been identified as early and frequent genetic alterations in astrocytomas, oligodendrogliomas, and oligoastrocytomas, as well as in secondary glioblastomas, might be the initiating event in these glioma subtypes. In contrast, primary glioblastomas, as well as other systemic cancers, rarely contain IDH1 mutations. The IDH1 mutations are remarkably specific to a single codon in the conserved and functionally important Arginine 132 residue (R132) in IDH1. Mutations in the analogous IDH2-R172 codon also occur at a lower rate in these cancers. IDH1/2 mutations were observed subsequently in 22% of acute myeloid leukemias. IDH1 mutations were found to result in the ability of the enzyme to catalyze the reduced NADP-dependent reduction of alpha-ketoglutarate to R(?)-2-hydroxyglutarate (2-HG). Reduction of alpha-ketoglutarate by 2-HG or mutant IDH1 results in a lower level of prolyl hydroxylases and promotes the accumulation of hypoxia-inducible factor (HIF) 1alpha. HIF-1alpha levels were greater in human gliomas harboring an IDH1 mutation than in tumors without the mutation. IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway.