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KR-20260067468-A - Co-administered pharmaceutical composition for the prevention or treatment of cancer comprising HN1 shRNA and an anti-PD-1 antibody

KR20260067468AKR 20260067468 AKR20260067468 AKR 20260067468AKR-20260067468-A

Abstract

The present invention relates to a molecular mechanism for regulating tumor PD-L1 levels and a combined therapeutic approach for managing hepatocellular carcinoma (HCC). The invention confirmed that the combined treatment of HN1 inhibition and an anti-PD-1 antibody enhances tumor suppression and therapeutic effects on cancer cells, and that this combined treatment can be usefully employed to effectively inhibit the proliferation of HCC.

Inventors

  • 김수미
  • 호단
  • 이총삼
  • 맹약우

Assignees

  • 전북대학교산학협력단

Dates

Publication Date
20260513
Application Date
20241105

Claims (7)

  1. HN1 shRNA composed of the nucleotide sequences of SEQ ID NOs 1 to 3; and A pharmaceutical composition for the prevention or treatment of cancer comprising one or more anti-PD-1 antibodies selected from the group consisting of dostalimab, pembrolizumab, nivolumab, and spartalizumab.
  2. In paragraph 1, A pharmaceutical composition for the prevention or treatment of cancer, characterized in that the above composition is administered simultaneously or sequentially in the form of a single formulation in which HN1 shRNA and an anti-PD-1 antibody are mixed, or in the form of multiple formulations in which HN1 shRNA and an anti-PD-1 antibody are each separately formulated.
  3. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by increasing the expression of PD-L1 in cancer cells.
  4. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by inhibiting proteasomes to increase the expression of PD-L1.
  5. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by promoting the phosphorylation of GSK3β to increase the stability of PD-L1.
  6. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer characterized by increasing the infiltration of CD8+ T cells.
  7. In paragraph 1 or 2, A pharmaceutical composition for the prevention or treatment of cancer, characterized in that the cancer is hepatocellular carcinoma (HCC).

Description

Co-administered pharmaceutical composition for the prevention or treatment of cancer comprising HN1 shRNA and an anti-PD-1 antibody The present invention relates to a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC) for combination administration comprising HN1 shRNA and an anti-PD-1 antibody. Liver cancer, consisting of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), ranked sixth among malignant tumors worldwide, with approximately 870,000 new cases and 760,000 deaths reported in 2022. Among these, hepatocellular carcinoma, which originates from hepatocytes, accounts for 80–90% of all liver cancers, and factors such as alcohol abuse and hepatitis B and C infections are known to have a significant impact. Despite advancements in early detection and treatment methods, the 5-year survival rate remains low at 15–38%, and high mortality rates are observed in East Asia, Western Europe, and the United States due to factors such as late diagnosis, multidrug resistance, frequent recurrence, and metastasis. Immune checkpoint inhibitors are expected to be promising therapeutic agents in various cancer fields, and Programmed death-ligand 1 (PD-L1) is a representative protein. PD-L1, also known as B7-H1 and CD274, interacts with its receptor, Programmed cell death protein 1 (PD-1), to promote T-cell apoptosis, loss of function, and immunosuppression. Increased expression of PD-L1 leads to tumor development by allowing cancer cells to evade the T-cell-mediated immune system. Neutralizing antibodies that block this PD-L1/PD-1 pathway have shown significant clinical efficacy in certain cancers, including HCC. However, PD-1 antibody therapy was effective in less than 20% of HCC patients, and there have been reports that it induces increased resistance to first- or second-line anti-tumor immunotherapy. According to previous studies, PD-L1 protein levels are closely related to the therapeutic effects of anti-PD-L1/PD-1 antibodies in various types of malignant cells, and treatment with PD-1-blocking antibodies following increased PD-L1 expression resulted in higher response rates and patient survival. Several regulatory factors important for post-translational alterations of PD-L1 expression have been identified, including AMPK, JAK1-STT3A, B3GNT3, and glycogen synthase kinase 3 beta (GSK3β). Understanding the molecular mechanisms controlling PD-L1 expression, including these regulatory factors, can facilitate the development of combination therapies to enhance the therapeutic effects of anti-PD-1/PD-L1 in HCC. Hematological and neurological expressed 1 (HN1), located on human chromosome 17q25.2, was first discovered in mouse embryos and subsequently identified as JPT1 (Jupiter microtubule-associated homolog 1). HN1 is often overexpressed in malignant tumors, including melanoma, non-small cell lung cancer (NSCLC), and epithelial ovarian cancer. While the precise role of HN1 in human cells is not yet fully understood, several studies have reported that its overexpression promotes cancer cell proliferation, metastasis, and progression, and is positively correlated with metastatic status, advanced cancer stage, and poor prognosis. Increased HN1 expression has been shown to influence breast tumorigenesis by inducing Myc activity. Furthermore, HN1 is highly conserved and expressed throughout human cells, suggesting that it plays an important role in human health. In previous studies, the inventors confirmed that increased expression of HN1 is correlated with reduced overall survival in HCC patients and the demethylation of HN1 promoters. HN1 interacts with mTOR (mammalian target of rapamycin), and inhibition of HN1 expression suppresses mTOR activation, thereby increasing the nuclear translocation of TFEB (Transcription factor EB) and inducing autophagy in HCC. Furthermore, previous studies showed that HN1 enhances the degradation of STMN130 and HMGB131 mediated by ubiquitination in thyroid carcinoma and HCC cells, respectively, suggesting that HN1 plays a fundamental role in the post-translational regulation of PD-L1. Dysregulation of post-translational processes leads to significant changes in protein expression, intracellular localization, and activity. However, the precise role of HN1 in cancer immune resistance remains unknown. Figure 1 shows the inhibition of tumor growth and the increase in PD-L1 expression following the inhibition of HN1 expression in an immune mouse model. Figure 2 shows the pattern in which inhibition of HN1 expression inhibits the activity of cytotoxic CD8+ T lymphocytes in HCC cells. Figure 3 shows the pattern of PD-L1 expression control in HCC cells following the inhibition of HN1 expression. Figure 4 shows that inhibition of HN1 expression increases PD-L1 expression by inhibiting proteasome-mediated degradation of PD-L1 in HCC cells. Figure 5 shows that inhibition of HN1 expression regulates the interaction between Gsk3β and PD-L1