Molecure S.A., Warsaw, Poland.
Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
Mol Cancer Ther. 2023 Jul 5;22(7):807-817. doi: 10.1158/1535-7163.MCT-22-0721.
Pharmacologic inhibition of the controlling immunity pathway enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacologic properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance, which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed nonclinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in patients with cancer.
We have developed an orally available, small-molecule intracellular arginase 1 and 2 inhibitor as a potential enhancer in cancer immunotherapy. Because of its favorable pharmacologic properties shown in nonclinical studies, OATD-02 abolishes tumor immunosuppression induced by both arginases, making it a promising drug candidate entering clinical trials.
抑制控制免疫途径酶精氨酸酶 1 和 2（ARG1 和 ARG2）的药理学抑制剂是癌症免疫治疗的一种有前途的策略。在这里，我们报告了 OATD-02 的发现和开发，这是一种口服生物利用度高、有效的精氨酸酶抑制剂。OATD-02 的独特药理特性表现为靶向细胞内 ARG1 和 ARG2，以及较长的药物靶标停留时间、中等至高的分布容积和低清除率，这可能共同提供了一种对抗精氨酸酶相关肿瘤免疫抑制和 ARG2 依赖性肿瘤细胞生长的武器。OATD-02 单药治疗在多种肿瘤模型中具有抗肿瘤作用，并增强了其他免疫调节剂的疗效。已完成的非临床研究和人体药代动力学预测表明存在可行的治疗窗，并允许为癌症患者的首次人体临床研究提出剂量范围。
我们已经开发出一种可口服的、小分子的细胞内精氨酸酶 1 和 2 抑制剂，作为癌症免疫治疗的潜在增强剂。由于其在非临床研究中表现出的有利药理特性，OATD-02 消除了精氨酸酶引起的肿瘤免疫抑制，使其成为一种很有前途的候选药物，即将进入临床试验。
