Introduction:

Indoleamine 2,3-dioxygenase (IDO) was a potential tumor immunotherapy target. IDO inhibitors showed inconsistent results in clinical trials, but no preclinical comparative study was reported. The purpose of this study was to evaluate the differences of representative IDO inhibitors (PCC0208009, INCB024360, NLG919) from the pharmacological perspective.

Methods:

In vitro experiments included: inhibition effects on IDO activity in cell and enzyme-based assay, effects on IDO expression in HeLa cells, and enhancement of proliferation and activation of peripheral blood mononuclear cell (PBMC). In vivo experiments included: pharmacokinetics and tumor distribution in CT26-bearing mice, effects on Kyn/Trp and anti-tumor effect and immunological mechanism in CT26 and B16F10 tumor-bearing mice.

Results:

Compared with INCB024360 and NLG919, PCC0208009 effectively inhibited IDO activity at lower dose 2 nM and longer duration more than 72 h, had higher enhancements on PBMC proliferation and activation, and could inhibit the IDO expression in Hela cells. The pharmacokinetics characteristics of three IDO inhibitors were similar in CT26-bearing mice. In CT26 and B16F10 tumor-bearing mice, PCC0208009 and INCB024360 had similar effects in Kyn/Trp reduction, and more potent than NLG919; three IDO inhibitors had similar effects in tumor suppression, changes of the percentages of CD3⁺CD8⁺ and CD3⁺CD4⁺ T cells, and activation of tumor infiltrating lymphocytes, while PCC0208009 had a better tendency than INCB024360 and NLG919.

Conclusion:

PCC0208009, INCB024360, and NLG919 were all effective IDO inhibitors, but the comprehensive pharmacological activity of PCC0208009 was better than INCB024360 and NLG919, which was basically consistent with the results or progresses of clinical trials.

中文翻译：

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从药效学角度比较不同吲哚胺-2,3双加氧酶抑制剂。

介绍：

吲哚胺 2,3-双加氧酶 (IDO) 是一种潜在的肿瘤免疫治疗靶点。IDO 抑制剂在临床试验中显示出不一致的结果，但没有报告临床前比较研究。本研究的目的是从药理学角度评估代表性IDO抑制剂（PCC0208009、INCB024360、NLG919）的差异。

方法：

体外实验包括：对细胞和酶测定中IDO活性的抑制作用，对HeLa细胞中IDO表达的影响，以及增强外周血单个核细胞（PBMC）的增殖和活化。体内实验包括：CT26荷瘤小鼠的药代动力学和肿瘤分布、对Kyn/Trp的影响以及CT26和B16F10荷瘤小鼠的抗肿瘤作用和免疫机制。

结果：

与 INCB024360 和 NLG919 相比，PCC0208009 在低剂量 2 nM 和更长的持续时间超过 72 h 时有效抑制 IDO 活性，对 PBMC 增殖和活化有更高的增强作用，并且可以抑制 Hela 细胞中 IDO 的表达。三种 IDO 抑制剂的药代动力学特征在携带 CT26 的小鼠中相似。在 CT26 和 B16F10 荷瘤小鼠中，PCC0208009 和 INCB024360 在降低 Kyn/Trp 方面具有相似的作用，并且比 NLG919 更有效；三种IDO抑制剂在肿瘤抑制、CD3 ⁺ CD8 ⁺和CD3 ⁺ CD4 ⁺ T细胞百分比的变化、肿瘤浸润淋巴细胞的活化方面具有相似的作用，而PCC0208009的趋势优于INCB024360和NLG919。

结论：

PCC0208009、INCB024360和NLG919均为有效的IDO抑制剂，但PCC0208009的综合药理活性优于INCB024360和NLG919，与临床试验结果或进展基本一致。