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Overview
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Background
Indoximod is an Indoleamine 2,3-dioxygenase (IDO) pathway inhibitor. IDO is a tryptophan-catabolizing enzyme that tumors use to create a state of immunosuppression. [1]The immunosuppressive activity of IDO leads to an increase in the number of T-regulatory cells, as measured by their Foxp3+/CD4+/CD25+ phenotype. Indoximod has also been shown to reduce the number of T-regulatory cells [2]. In MMTV-Neu mice, researchers looked at the activity of indoximod with and without paclitaxel [3]. The combination of docetaxel and indoximod is more toxic than docetaxel monotherapy. A single 1200 mg dose of indoximod almost totally saturates the gut, and higher doses do not significantly increase peak serum levels. The single-agent phase I trial of indoximod demonstrated very good oral bioavailability and a mild toxicity profile with no significant myelosuppression, and no maximally tolerated dose was identified up to 2000 mg orally twice daily [1]. Blockade of IDO with indoximod enhanced the adoptive immunologic response to antigens and dendritic cell (DC) vaccines in LLC mouse models.
[1]. Soliman HH, Jackson E, Neuger T et al. A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors. Oncotarget. 2014 Sep 30;5 (18):8136-46.
[2]. Munn DH. Blocking IDO activity to enhance anti-tumor immunity. Front Biosci (Elite Ed). 2012 Jan 1;4:734-45.
[3]. Muller AJ, DuHadaway JB, Donover PS et al.Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med. 2005 Mar;11(3):312-9. Epub 2005 Feb 13.
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Overview