Anti-IDO1 monoclonal antibody, clone 2B4

Cancers express tryptophan catabolising enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) to produce immunosuppressive tryptophan metabolites that undermine patients' immune systems, leading to poor disease outcomes. Both enzymes are validated targets for cancer immunotherapy but there is a paucity of potent TDO2 and dual IDO1/TDO2 inhibitors. To identify novel dual IDO1/TDO2 scaffolds, 3D shape similarity and pharmacophore in silico screening was conducted using TDO2 as a model for both systems. The obtained hits were tested in cancer cell lines expressing mainly IDO1 (SKOV3-ovarian), predominantly TDO2 (A172-brain), and both IDO1 and TDO2 (BT549-breast). Three virtual screening hits were confirmed as inhibitors (TD12, TD18 and TD34). Dose response experiments showed that TD34 is the most potent inhibitor capable of blocking both IDO1 and TDO2 activity, with the IC50 value for BT549 at 3.42 mu M. This work identified new scaffolds able to inhibit both IDO1 and TDO2, thus enriching the collection of dual IDO1/TDO2 inhibitors and providing chemical matter for potential development into future anticancer drugs.

Indoleamine 2,3-dioxygenase 1(IDO1) is an enzyme known to suppress immune responses, and several reports have showed that it is associated with psoriasis.IDO2is an isoform ofIDO1, recently identified as a catalytic enzyme in the tryptophan-kynurenine pathway, which is expressed in dendritic cells and monocytes. The expression ofIDO2in immune cells suggests thatIDO2may contribute to immune functions. However, the role ofIDO2in the pathogenesis of psoriasis remains unclear. In this study, to elucidate the role ofIDO2in psoriasis, we assessed imiquimod (IMQ)-induced psoriasis-like dermatitis inIDO2knockout (KO) mice. Skin inflammation, evaluated by scoring erythema, scaling, and ear thickness, was significantly worse in theIDO2KO mice than in the wild-type (WT) mice. The mRNA expression levels of TNF-alpha, IL-23p19, and IL-17A, key cytokines involved in the development of psoriasis, were also increased in theIDO2KO mice. Furthermore, immunohistochemistry revealed that the number of Ki67-positive cells in the epidermis and CD4-, CD8-, and IL-17-positive lymphocytes infiltrating the dermis were significantly increased in theIDO2KO mice. These results suggest thatIDO2might decrease IL-17 expression, thereby resulting in the suppression of skin inflammation in IMQ-induced psoriasis-like dermatitis.