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Background IDO1 inhibition with a 1st-generation inhibitor has shown promising clinical benefit in melanoma patients, as well as exacerbated toxicity, when combined with ipilimumab. We have identified a novel class of IDO1 inhibitors (IDO1i), which surpass the potency, selectivity and pharmacokinetic parameters of 1st-generation IDO1i. Methods IDO1 inhibition was assessed from kynurenine (kyn) levels produced by stimulated HeLa or dendritic cell cultures or recombinant IDO1. T-cell proliferation was measured using eFluor®670 dye. CT26 tumours were grown SC in Balb/c mice. IDO1i and kyn levels were measured by LC/MS/MS. Assessment of immune parameters was performed on tumour-infiltrating leucocytes by FACS. Findings These IDO1i potently inhibit cellular IDO1 with IC50 ≤ 10 nM, retain their potency in human serum (IC50 ≤ 10 nM) and restore T-cell proliferation, which is inhibited by allogeneic IDO1 + DC (EC50 = 2–5 nM). They exhibit PK characteristics consistent with once-daily dosing in humans. One of these molecules, selected for clinical evaluation, has undergone extensive characterisation, including the relationship between plasma levels of compound and kyn, and its impact on tumour growth and immune parameters in mouse syngeneic tumours, as single agent and in combination with various immune checkpoint inhibitors. Discussion This study provides the preclinical basis for clinical evaluation of a 2nd-generation IDO1i in combination with other immunotherapies. |
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