Abstract 7520: NRT-YHD₀01, targeting CD47 for liver cancer immunotherapy

Abstract Previously, we demonstrated that recovery of histone deacetylase 6 (HDAC6) suppressed let-7i-5p expression to de-repress the thrombospondin-1 (TSP1) expression, and thereby it occupied CD47 receptor to block CD47-SIRPα mediated anti-phagocytosis of macrophage in liver cancer. NRT-YHD₀01 is a modified antisense miRNA of let-7i-5p for liver cancer treatment. In addition, N-acetylgalactosamine was attached to NRT-YHD₀01 for specific delivery to the liver. In vitro phagocytosis assay showed better macrophage phagocytosis activity than non-modified antisense let-7i-5p. To investigate the in vivo efficacy of NRT-YHD₀01, spontaneous (Ras-transgenic) mouse liver cancer model was used and compared with that of sorafenib treatment. This mouse liver cancer model usually develops spontaneous liver cancer mass after 15 ~ 20 weeks of birth. We confirmed that both weekly i. v. injection of 1mg/kg and biweekly i. v. injection of 2mg/kg NRT-YHD₀01 showed more significant therapeutic efficacy than the sorafenib-treated group. Furthermore, xenograft assay with Hep3B human liver cancer cells in athymic-nude mouse also showed that weekly i. v. injection of 1mg/kg NRT-YHD₀01 exhibited better survival and tumor growth inhibition compared to non-treated group. In mouse and cynomolgus monkey maximum tolerated dose (MTD) studies, no toxicity of NRT-YHD₀01 was found at doses up to 500 mg/kg intravenously. These results showed that NRT-YHD₀01 had a robust anticancer effect by converting the macrophage of “don't eat me” into “eat me signal” in the tumor microenvironment of liver cancer, thereby removing or inhibiting liver cancer cells. Keywords: let-7i-5p, macrophage, phagocytosis, liver cancer, CD47 Citation Format: Suk Woo Nam, Sangyean Kim, Minjeong Na, Eunbi Shin, Jin Woong Ha, Soyoung Jeon, Sungpil Yoon. NRT-YHD₀01, targeting CD47 for liver cancer immunotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7520.