Abstract 3209: IND enabling study of NRT-YHD_001, a macrophage immune checkpoint inhibitor in liver cancer
Abstract
NRT-YHD_001, a modified antisense miRNA targeting let-7i-5p for liver cancer therapy, acts as a key regulator of macrophage activity within the tumor microenvironment. Through in vitro pharmacology studies, we identified anticancer effects not only on cell growth, proliferation, viability, migration, and invasion but also through the enhancement of macrophage phagocytosis. To evaluate the in vivo efficacy of NRT-YHD_001, we used a Ras-transgenic mouse liver cancer model which develops spontaneous liver cancer mass after 15 ∼ 20 weeks of birth. Based on dose-dependent and injection interval studies, the optimal regimen was determined to be 1 mg/kg administered weekly. We confirmed that weekly intravenous injections of 1mg/kg NRT-YHD_001 showed significantly greater therapeutic efficacy than the sorafenib-treated group. Additionally, xenograft assay using human liver cancer cells in athymic-nude mice showed that weekly injection of NRT-YHD_001 led to improved survival and tumor growth inhibition compared to the untreated group. We performed Absorption, Metabolism, Distribution, and Excretion studies for NRT-YHD_001, stability studies in serum and liver homogenate, and metabolite identification and profiling analysis were completed in mice and cynomolgus monkeys. In maximum tolerated dose (MTD) studies conducted in mice and cynomolgus monkeys, no toxicity of NRT-YHD_001 was observed at doses up to 500 mg/kg administered intravenously. Furthermore, comprehensive evaluations…
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