Abstract 279: Completion of IND-enabling studies for NRT-YHD₀01, a macrophage checkpoint inhibitor in liver cancer.

Abstract NRT-YHD₀01 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-YHD₀01 (GalNAc-conjugated form) demonstrated stronger macrophage activation than NRT-YHD (GalNAc-unconjugated form). Following a single intravenous injection in mice, NRT-YHD₀01 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-YHD₀01 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-YHD₀01 was administered intravenously once weekly at 5 mg/kg. Compared with the sorafenib-treated group, NRT-YHD₀01-treated mice exhibited greater tumor suppression, demonstrating superior therapeutic efficacy. The NRT-YHD₀01 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-YHD₀01 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. Citation Format: Suk Woo Nam, In Seop Yoon, Sang Yean Kim, Minjeong Na, Jin Woong Ha, Soyoung Jeon, Hyunmin Lee, Seo Hyeon Mun, Chang Won Park. Completion of IND-enabling studies for NRT-YHD₀01, a macrophage checkpoint inhibitor in liver cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (7 Suppl): Abstract nr 279.