PO.CL05.10 · 临床研究
新型口服高选择性PTPN2/1抑制剂（ZE00-0388）的疗效、体内安全性及PK/PD研究
Efficacy, in vivo safety, and PK/PD studies for novel, oral, highly selective PTPN2/1 inhibitor (ZE00-0388)
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
抑制PTPN2是一种新型免疫肿瘤学方法：通过释放一个细胞内的"刹车"，它增加了细胞因子反应性（例如IFN-gamma/JAK-STAT），增强抗原提呈，并增强T细胞细胞毒性，有助于克服对PD-1阻断耐药的肿瘤中的免疫逃逸。
我们的开发候选药物ZE00-0388展现出潜在的同类最佳特性：纳摩尔级效力，对PTPN2/1相较于其他磷酸酶具有高选择性，可预测的PK/PD且持续暴露高于EC50，以及经证实的靶点结合。ZE00-0388在所有物种中均显示良好的生物利用度，预期从犬到人的转化效果最佳。
anti-mPD-1与ZE00-0388的联合应用对皮下MC38结肠模型展现出显著的剂量依赖性抗肿瘤疗效。ZE00-0388单药治疗表现出81%的肿瘤生长抑制，与anti-mPD-1联合应用时50%的动物实现肿瘤完全消退。ZE00-0388具有非常良好的安全性，其耐受剂量显著高于临床前概念验证的有效剂量，这表明ZE00-0388应具有非常宽的治疗窗。
查看英文原文 English abstract
PTPN2 inhibition is a novel immuno-oncology approach: by releasing an intracellular “brake” it increases cytokine responsiveness (e.g., IFN-gamma/JAK-STAT), boosts antigen presentation, and enhances T-cell cytotoxicity, helping to overcome immune evasion in tumors resistant to PD-1 blockade.
Our development candidate ZE00-0388 demonstrates potential best-in-class profile: Nanomolar potency with high selectivity for PTPN2/1 over other phosphatases, predictable PK/PD with sustained exposure above EC50, and proven target engagement. ZE00-0388 shows favorable bioavailability in all species, with best translation expected from dog to human.
The combination of anti-mPD-1 and ZE00-0388 exhibited remarkable dose-dependent anti-tumor efficacy against the subcutaneous MC38 colon model. Solo treatments with ZE00-0388 demonstrated tumor growth inhibition of 81% and in combination with anti-mPD-1 complete regression of tumor in 50% of animals. ZE00-0388 has a very favorable safety profile with tolerated doses significantly above pre-clinical proof-of-concept efficacious doses, which indicates that ZE00-0388 should have a very broad therapeutic window.
利益披露 Disclosure
A. Pushechnikov, None..
R. Karapetian, None..
S. Mochalov, None..
S. Baumann Tomovska, None..
N. Savchuk, None..
I. Dukes, None..
R. Abagyan, None.