PO.ET04.01 · 实验与分子治疗
NRT-YHD_001（一种用于肝癌的巨噬细胞检查点抑制剂）IND申报支持研究的完成
Completion of IND-enabling studies for NRT-YHD_001, a macrophage checkpoint inhibitor in liver cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
NRT-YHD_001是一种靶向let-7i-5p的修饰型反义microRNA，作为肝细胞癌（HCC）的新型治疗候选药物而开发。该化合物作为肿瘤微环境内巨噬细胞激活的关键调节因子发挥作用。在体外吞噬测定中，NRT-YHD_001（GalNAc偶联形式）表现出比NRT-YHD（GalNAc未偶联形式）更强的巨噬细胞激活。在小鼠单次静脉注射后，NRT-YHD_001选择性抑制let-7i-5p而不影响let-7家族的其他成员，证实了其高靶标特异性。为评估NRT-YHD_001对晚期HCC的体内疗效，使用了约15-20周龄自发形成肝肿瘤的Ras转基因小鼠。通过超声检查确认肿瘤形成（约5 mm2）后，以5 mg/kg每周一次静脉给予NRT-YHD_001。与索拉非尼治疗组相比，NRT-YHD_001治疗小鼠表现出更强的肿瘤抑制，展示出优越的治疗疗效。NRT-YHD_001制剂满足所有CMC质量控制标准。冻干后，制剂复溶为澄清、无色溶液，含量测定值为标示量的105.1%（规格范围：90.0-110.0%）。所有其他参数，包括杂质水平、pH（7.5）、渗透压（324 mOsm/kg）、内毒素（<2.0 EU/mg）和无菌性，均符合规格限值，证实了优异的质量属性。在小鼠和食蟹猴中开展了药代动力学和ADME研究、血清及肝匀浆中的代谢稳定性评估以及代谢物分析。在4周重复剂量毒性研究中未观察到治疗相关异常。原料药（DS）和药品（DP）均由具有FDA批准制造经验的全球CDMO制造并经分析验证。总之，这些结果表明NRT-YHD_001是一种强效且选择性的let-7i-5p反义治疗药物，具有巨噬细胞调节活性和在晚期HCC模型中优越的体内抗肿瘤疗效。已完成一套完整的非临床IND申报资料包，并确保了FTO许可和全面知识产权保护。计划于2026年向MFDS（韩国）和FDA（美国）提交IND申请。
查看英文原文 English abstract
NRT-YHD_001 is a modified antisense microRNA targeting let-7i-5p, developed as a novel therapeutic candidate for hepatocellular carcinoma (HCC). This compound functions as a key regulator of macrophage activation within the tumor microenvironment. In in vitro phagocytosis assays, NRT-YHD_001 (GalNAc-conjugated form) demonstrated stronger macrophage activation than NRT-YHD (GalNAc-unconjugated form). Following a single intravenous injection in mice, NRT-YHD_001 selectively inhibited let-7i-5p without affecting other members of the let-7 family, confirming its high target specificity.To evaluate the in vivo efficacy of NRT-YHD_001 against advanced HCC, Ras-transgenic mice that spontaneously develop hepatic tumors at approximately 15-20 weeks of age, were used. After confirming tumor formation (~5 mm2) by ultrasonography, NRT-YHD_001 was administered intravenously once weekly at 5 mg/kg. Compared with the sorafenib-treated group, NRT-YHD_001-treated mice exhibited greater tumor suppression, demonstrating superior therapeutic efficacy.The NRT-YHD_001 formulation satisfied all CMC quality control criteria. After lyophilization, the formulation was reconstituted into a clear, colorless solution, with an assay value of 105.1% of the label claim (specification range: 90.0-110.0%). All other parameters, including impurity levels, pH (7.5), osmolality (324 mOsm/kg), endotoxin (<2.0 EU/mg), and sterility, met specification limits, confirming excellent quality attributes.Pharmacokinetic and ADME studies, metabolic stability assessments in serum and liver homogenates, and metabolite profiling were conducted in mice and cynomolgus monkeys. No treatment-related abnormalities were observed in the 4-week repeated-dose toxicity study. The drug substance (DS) and drug product (DP) were both manufactured and analytically validated by a global CDMO with FDA-approved manufacturing experience.Collectively, these results demonstrate that NRT-YHD_001 is a potent and selective let-7i-5p antisense therapeutic with macrophage-modulating activity and superior in vivo antitumor efficacy in an advanced HCC model. A complete nonclinical IND submission package has been finalized, with FTO clearance and full intellectual property protection secured. IND submissions to the MFDS (Korea) and FDA (U.S.) are planned for 2026.
利益披露 Disclosure
S. Nam, None..
I. Yoon, None..
M. Na, None..
J. Ha, None..
S. Jeon, None..
H. Lee, None..
S. Mun, None..
C. Park, None.