Hepatocellular carcinoma antigen peptide and application thereof
By systematically mining shared neoantigens in HCC, designing hepatocellular carcinoma antigen peptide vaccines, and utilizing mRNA technology to activate T cells to kill tumor cells, this approach solves the problems of limited efficacy of existing hepatocellular carcinoma treatment drugs and complex vaccine preparation, achieving highly efficient immunotherapy for hepatocellular carcinoma.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- GZ RUNSHENG CYTOMED TECH CO LTD
- Filing Date
- 2026-02-13
- Publication Date
- 2026-05-29
AI Technical Summary
Existing drugs for treating hepatocellular carcinoma have limited efficacy, and traditional tumor antigen vaccines have problems such as immune tolerance, high cost, and complex preparation, making it difficult to effectively elicit a strong and lasting immune response in most HCC patients.
A hepatocellular carcinoma antigen peptide was developed. By systematically mining shared neoantigens generated in HCC by aberrant splicing, long fragment insertions and deletions, and gene fusions, a vaccine containing this antigen peptide was designed and administered using mRNA vaccine technology to activate specific T cells to kill tumor cells.
Hepatocellular carcinoma antigen peptides have high immunogenicity and shareability, can significantly activate T cells, and specifically kill tumor cells, providing a highly efficient hepatocellular carcinoma vaccine development program suitable for large-scale production and application.
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Figure CN122103305A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of immunobiology, specifically relating to a hepatocellular carcinoma antigen peptide and its applications. Background Technology
[0002] Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, mainly developing from chronic liver diseases such as hepatitis B, hepatitis C, and cirrhosis. HCC is characterized by its insidious onset, rapid progression, early recurrence, and poor prognosis; most cases are diagnosed at an advanced stage. With ongoing research into the molecular signaling pathways of HCC, targeted therapies have shown significant advantages in treating advanced HCC. By specifically targeting tumor cells, these drugs increase drug concentration at the tumor site, reducing damage to normal tissues and achieving better therapeutic effects.
[0003] Patent document CN112143805A discloses the application of RIT1 in the diagnosis and treatment of hepatocellular carcinoma, specifically providing the application of RIT1 gene, mRNA, cDNA, or protein, or its detection reagent, in the diagnosis of hepatocellular carcinoma. The inhibitor of this RIT1 gene or protein can effectively treat hepatocellular carcinoma, and the inhibitor of this RIT1 gene or protein can optionally be used in combination with tyrosine kinase inhibitors and / or optional other drugs for the prevention and / or treatment of hepatocellular carcinoma, showing a significant synergistic effect in the treatment of hepatocellular carcinoma.
[0004] Patent document CN118792402A discloses the application of PCSK9 in the diagnosis and treatment of hepatocellular carcinoma, specifically providing the application of a PCSK9 gene, mRNA, cDNA, or protein, or its detection reagent, in the diagnosis of hepatocellular carcinoma. The inhibitor of this PCSK9 gene or its protein can effectively treat hepatocellular carcinoma. Patent document CN114106097A discloses a polypeptide for treating hepatocellular carcinoma and its application. This polypeptide has a significant inhibitory effect on the proliferation of liver cancer cells, and animal experiments have demonstrated its effective inhibition of tumor growth.
[0005] However, the efficacy of drugs currently used to treat hepatocellular carcinoma is limited and cannot meet clinical requirements. In addition, in the field of tumor immunotherapy, vaccines developed based on tumor-specific antigens have good effects on tumor treatment. At present, the research and development of antigen vaccines related to HCC mainly focuses on the following categories: (1) Tumor-associated antigen (TAAs) vaccines. These antigens have the characteristic of high expression in tumor cells. TAAs for HCC that have been studied more include alpha-fetoprotein and phosphatidylinositol proteoglycan-3 (GPC3). However, the inherent autoantigen properties of TAAs may lead to immune tolerance, and their immunogenicity is relatively weak, making it difficult to stimulate strong and durable T cell responses, and the clinical efficacy is not significant. (2) Personalized neoantigen vaccines. These vaccines have the advantages of high tumor specificity and extremely low risk of autoimmune toxicity. However, these vaccines have the disadvantages of high cost, long preparation cycle and complex process, making it difficult to promote on a large scale. (3) Virus-associated antigen vaccines. These vaccines are designed to control viral replication and reduce liver inflammation. They are ineffective against non-viral HCC and have limited anti-tumor effects.
[0006] Therefore, researching and developing a treatment solution for HCC that is highly compatible with a large proportion of HCC patients, has strong immunogenicity, and can avoid the risks of autoimmune diseases remains a challenge for current research. Summary of the Invention
[0007] To address the shortcomings of existing technologies, this invention proposes for the first time a hepatocellular carcinoma antigen peptide and a vaccine containing this antigen peptide. The hepatocellular carcinoma antigen peptide provided by this invention has advantages such as good safety, high shareability, strong immunogenicity, and high tumor specificity. It is suitable for the development of universal vaccines and can be mass-produced, overcoming the current treatment bottlenecks for hepatocellular carcinoma and providing a new antigen resource for its treatment.
[0008] To achieve the above objectives, the technical solution of the present invention is as follows: The present invention provides a hepatocellular carcinoma antigen peptide, wherein the amino acid sequence of the antigen peptide is at least one of SEQ ID NO.1, SEQ ID NO.2, SEQ ID NO.3, SEQ ID NO.4, SEQ ID NO.5, SEQ ID NO.6, SEQ ID NO.7 and SEQ ID NO.8.
[0009] Further, the amino acid sequence of the antigenic peptide is at least one of SEQ ID NO.1, SEQ ID NO.3, SEQ ID NO.5, SEQ ID NO.6 and SEQ ID NO.8.
[0010] The present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding the aforementioned hepatocellular carcinoma antigen peptide, wherein the nucleic acid molecule is double-stranded DNA.
[0011] In addition, the present invention provides an mRNA comprising an mRNA encoding a hepatocellular carcinoma antigen peptide as described above.
[0012] Further, the nucleotide sequence of the mRNA is at least one of SEQ ID NO.9, SEQ ID NO.10, SEQ ID NO.11, SEQ ID NO.12, SEQ ID NO.13, SEQ ID NO.14, SEQ ID NO.15 and SEQ ID NO.16.
[0013] Further, the nucleotide sequence of the mRNA is at least one of SEQ ID NO.9, SEQ ID NO.11, SEQ ID NO.13, SEQ ID NO.14 and SEQ ID NO.16.
[0014] Furthermore, the present invention also provides an mRNA vaccine comprising lipid nanoparticles and the aforementioned mRNA.
[0015] Furthermore, the vaccine preparation can be administered via intramuscular injection, intradermal injection, intravenous injection, arterial injection, or through a mucosal route.
[0016] In addition, the present invention provides a pharmaceutical composition comprising the above-described mRNA and a pharmaceutically acceptable carrier.
[0017] In addition, the present invention also provides the use of the hepatocellular carcinoma antigen peptide, the nucleic acid molecule, the mRNA, the mRNA vaccine, or the pharmaceutical composition in the preparation of drugs for the prevention and / or treatment of hepatocellular carcinoma.
[0018] Hepatocellular carcinoma (HCC) is a tumor closely related to chronic inflammation, viral infection, and metabolic abnormalities. HCC exhibits poor genomic stability, manifesting as more complex variants such as gene fusions, aberrant splicing events, and long-segment insertions and deletions. These variants can also generate novel immunogenic peptides. Current routine analytical procedures are insufficient in identifying and predicting the antigenicity of these variants, leading to the omission of many potential shared neoantigens and potentially insufficient coverage of HCC-specific characteristics.
[0019] To address the aforementioned issues, this invention develops a novel set of antigenic peptide sequences derived from high-frequency shared variants in HCC, effectively overcoming the shortcomings of traditional neoantigen screening, which often misses splicing mutations and long insertion / deletion mutations. This invention systematically mines mutant peptides in HCC resulting from aberrant splicing, long insertion / deletion (≥50 bp), and gene fusion, providing eight candidate antigenic peptides for the development of a universal HCC vaccine.
[0020] Furthermore, the hepatocellular carcinoma antigen peptides provided by this invention are a group of shared neoantigens derived from splicing abnormalities, long fragment insertions / deletions, or gene fusion mutations. Immunological enzyme-linked immunospot assays confirmed that the number of spots generated by the hepatocellular carcinoma antigen peptides provided by this invention showed statistically significant differences, indicating that the hepatocellular carcinoma antigen peptides possess strong immunogenicity. Tumor cell killing experiments confirmed that the hepatocellular carcinoma antigen peptides can specifically activate and induced T cells to kill tumor cells with an efficiency ≥30%, demonstrating significant tumor-killing effects. The hepatocellular carcinoma antigen peptides provided by this invention have significant market value for the development of vaccines for the prevention and / or treatment of hepatocellular carcinoma.
[0021] In summary, compared with existing technologies, this invention provides an optimal hepatocellular carcinoma antigen peptide. Immunogenicity testing has demonstrated that this hepatocellular carcinoma antigen peptide possesses excellent immunogenicity and immunoprotective efficacy, capable of inducing the formation of specific T cells in the body, enhancing the immune response, maintaining long-term immune memory, and forming a public neoantigen library for application in hepatocellular carcinoma immunotherapy. It also has significant pharmaceutical value for the development of vaccines for the prevention and / or treatment of hepatocellular carcinoma. Attached Figure Description
[0022] Figure 1 This is a flowchart for the prediction and screening of neoantigen peptides for hepatocellular carcinoma.
[0023] Figure 2 This is a graph showing the number of IFN-γ spots generated by hepatocellular carcinoma antigen peptides.
[0024] Figure 3 This diagram illustrates the cytotoxic activity of T cells induced by specific activation and expansion of hepatocellular carcinoma antigen peptides against tumor cells. Detailed Implementation
[0025] The present invention will be further described below through specific embodiments, but this is not intended to limit the invention. Those skilled in the art can make various modifications or improvements based on the basic idea of the invention, but as long as they do not depart from the basic idea of the invention, they are all within the scope of the invention. The reagents involved in the present invention can all be obtained through commercially available or conventional techniques in the art.
[0026] Example 1: Prediction and Screening of Neoantigen Peptides for Hepatocellular Carcinoma 1. Experimental objective: Using an established next-generation sequencing data analysis pipeline, the system systematically mines mutant peptides in hepatocellular carcinoma (HCC) generated by aberrant splicing, long InDel (≥50 bp in length), and gene fusion, providing candidate antigen peptides for the development of a universal HCC vaccine.
[0027] 2. Experimental methods: 2.1 Data Source: Whole-exome sequencing (WES) and RNA-seq data of paired peripheral blood and tumor tissue samples from approximately 250 hepatocellular carcinoma (HCC) patients were obtained from public databases (the Cancer Genome Atlas Hepatocellular Carcinoma (TCGA-LIHC) database or the International Cancer Genome Consortium (ICGC) database).
[0028] 2.2 Neoantigen Prediction and Screening: The prediction and screening process for neoantigen peptides in hepatocellular carcinoma is as follows: Figure 1 As shown, the process utilizes bioinformatics workflows, including tools such as GATK, MuTect2, STAR, and RSEM, to identify somatic mutations. The focus is on analyzing neoantigen peptides generated by aberrant splicing and long-fragment insertions / deletions. NetMHCpan v4.1 is used to predict their binding affinity to common Chinese HLA subtypes such as HLA-A*02:01 and HLA-A*24:02 (IC50 < 50 nM is considered strong binding), and mutant peptides shared in at least 80% of patients are screened.
[0029] 3. Experimental Results: The experimental results are shown in Tables 1 and 2.
[0030] This invention, through a systematic analysis process, successfully identified a group of shared neoantigens derived from hepatocellular carcinoma (HCC) genomic data, derived from splicing abnormalities, long-fragment insertions / deletions, or gene fusion mutations, and ultimately selected eight core candidate antigen peptides. The amino acid and nucleotide sequences of these eight core candidate antigen peptides are shown in Table 1. The key bioinformatics characteristics of these eight core candidate antigen peptides are shown in Table 2.
[0031] Table 1. Amino acid and nucleotide sequence information of candidate antigen peptides. serial number Mutation type amino acid sequence Nucleotide sequence (5'→3') 1 Abnormal splicing (exon skipping) PHIATLRKYTYGKHILAKLEKYYMKNGVDL (SEQ IDNO.1) CCTCACATAGCTACTCTGAGAAAATATACATATGGTAAACACATCTTGGCCAAGCTAGAGAAGTACTATATGAAAAATGGTGTCGACTTG (SEQ ID NO.9) 2 Long segment insertion leads to code shift RDQRVAAENALSVAEEQIRRLEHSEWDSSR (SEQ IDNO.2) CGTGACCAACGGGTTGCAGCCGAAAATGCCCTTTCCGTTGCCGAAGAGCAAATACGACGCCTTGAACATTCAGAGTGGGATTCGTCAAGA (SEQ ID NO. 10) 3 Aberrant splicing (intron preservation) DRESQTHKPQTLSSFYSSSRPTTASQRSPS (SEQ IDNO.3) GATCGCGAATCGCAAACCCACAAGCCCCAAACGCTATCCTCTTTCTACTCAAGCTCTCGACCAACGACCGCAAGTCAGCGTTCACCCTCC (SEQ ID NO.11) 4 Long fragment missing leads to missing frame EAKTPAKEEARSPADKFPEKAKSPVKEEVK (SEQ IDNO.4) GAAGCTAAGACTCCGGCAAAAGAAGAGGCACGATCCCCGGCGGATAAGTTTCCAGAAAAGGCCAAGTCCCCGGTTAAAGAGGAGGTAAAG (SEQ ID NO. 12) 5 Gene fusion CCSTPVICCCRRTCSSCGCGYGKGCCQQKG (SEQ IDNO.5) TGTTGCTCAACACCTGTGATATGTTGCTGCAGACGAACCTGCTCGTCTTGCGGATGCGGTTACGTAAAGGCTGCTGCCAGCAGAAAGGA (SEQ ID NO. 13) 6 Aberrant splicing (alternate donor site) QPGRQEKMSIYQAMWKGVLRPGTALVLLEA (SEQ IDNO.6) CAGCCAGGCAGGCAGGAAAAGATGAGTATATACCAAGCGATGTGGAAGGGCGTACTAAGGCCAGGTACGGCTCTAGTCCTACTCGAGGCC (SEQ ID NO.14) 7 Long segment insertion leads to code shift WWASFFFGKSTLPFMATVLESAEHSEPPQA (SEQ IDNO.7) TGGTGGGCTAGCTTCTTTTTTGGTAAAAGCACTCTGCCTTTTATGGCCACGGTTCTAGAGTCAGCCGAGCACTCCGAGCCACCGCAAGCC (SEQ ID NO.15) 8 Abnormal splicing (exon skipping) QAQAHDLVIKSLDKLKEVKEFLGENISNFL(SEQ IDNO.8) CAAGCGCAAGCCCATGACCTCGTAATAAAAAGCTTAGATAAGTTAAAGGAAGTTAAAGAGTTCCTAGGGGAAAACATTTCGAATTTCCTT (SEQ ID NO.16) Table 2 Key Bioinformatics Characteristics of Candidate Antigenic Peptides sequence HLA-restrictive (predictive) Binding affinity (IC50 nM) Predicted immunogenicity score (0-1) Frequency of occurrence in the verification queue (%) SEQ ID NO.1 HLA-A*02:01 12.3 0.92 100% SEQ ID NO.2 HLA-A*24:02 8.7 0.95 95% SEQ ID NO.3 HLA-A*11:01 22.5 0.88 100% SEQ ID NO.4 HLA-B*40:01 35.1 0.84 98% SEQ ID NO.5 HLA-A*02:01 5.2 0.96 89% SEQ ID NO.6 HLA-B*46:01 18.9 0.90 100% SEQ ID NO.7 HLA-A*24:02 42.3 0.82 93% SEQ ID NO.8 HLA-B*58:01 29.8 0.86 100%
[0032] Example 2: Immunological Enzyme-Linked Immunodot Assay Validation Experiment 1. Experimental Method: 1.1 Collection of peripheral blood mononuclear cells (PBMCs): Peripheral blood samples were collected from four patients with hepatocellular carcinoma (HCC) at the hospital. The collected blood was gently mixed with an equal volume of PBS buffer. Then, four centrifuge tubes containing Ficoll lymphocyte separation medium were prepared, and the diluted blood samples were slowly added to them. After centrifugation, the supernatant plasma was removed, and the PBMCs in the middle were carefully collected. The four collected PBMCs were then frozen.
[0033] 1.2 T cell incubation: Frozen PBMC cells were retrieved, thawed, and centrifuged to remove the supernatant. Cells were resuspended in culture medium containing 5% serum to obtain two culture systems. The first culture system was then supplemented with the synthetic peptides of SEQ ID NO. 1-8 selected in Example 1, along with cell growth factors IL-2 and IL-7, to achieve a working concentration of 50 ng / mL; it was then cultured at 37 °C. The second culture system was supplemented with the synthetic peptides of SEQ ID NO. 1-8 selected in Example 1, and the same procedure was performed. Ten days later, cells were collected and washed to prepare for subsequent experiments.
[0034] 1.3. Enzyme-linked immunospot assay (ELISPOT) detection and counting: First, 100 μL of pre-coated IFN-γ antibody was added to each well of an ELISPOT plate and incubated overnight at 4 °C. The next day, 200 μL of 1640 culture medium was added and incubated at room temperature for a period of time. Next, the synthetic peptides selected from SEQ ID NO. 1-8 in Example 1 were added to a working concentration of 5 μg / mL, with positive and negative control groups set up. PBS was used as the peptide dilution buffer. The plate was incubated in a 5% CO2 incubator. After incubation, detection antibody and streptavidin were added for color development, and the number of IFN-γ spots was determined using an automated ELISPOT plate reader (AID iSpot).
[0035] 2. Experimental Results: Experimental results are as follows Figure 2 As shown in Table 3.
[0036] in: Figure 2 The diagram shows the number of IFN-γ spots generated by hepatocellular carcinoma antigen peptides (SEQ ID NO.1~8). Table 3 shows the number of IFN-γ spots generated by hepatocellular carcinoma antigen peptides (SEQ ID NO.1~8).
[0037] Table 3. Spot Count Table for Enzyme-Linked Immunosorbent Assay (ELISA) sequence Number of IFN-γ spots Significance (vs PBS) SEQ ID NO.1 131 p < 0.01 SEQ ID NO.2 246 p < 0.001 SEQ ID NO.3 496 p < 0.0001 SEQ ID NO.4 538 p < 0.0001 SEQ ID NO.5 380 p < 0.001 SEQ ID NO.6 330 p < 0.001 SEQ ID NO.7 310 p < 0.001 SEQ ID NO.8 296 p < 0.001 Positive control group 118 \ negative control group 0 \ Depend on Figure 2 As shown in Table 3, the number of IFN-γ spots generated by the hepatocellular carcinoma antigen peptides (SEQ ID NO.1~8) provided by the present invention showed statistically significant differences, indicating that the hepatocellular carcinoma antigen peptides have strong immunogenicity.
[0038] Example 3: Tumor Cell Killing Effect Experiment 1. Experimental Method: The killing activity of specific T cells activated by the neoantigens SEQ ID NO. 1-8 selected in Example 1 against tumor cells was detected to assess whether the neoantigens could effectively activate an immune response. This experiment used the ACEA xCELLigence RTCA MP instrument to detect the immune response.
[0039] First, tumor tissue was collected from one patient at the hospital. Tumor cells were then isolated and cultured. Peripheral blood mononuclear cells (PBMCs) were also isolated from the patient's peripheral blood. T cells were activated using the peptides SEQ ID NO. 1-8 selected in Example 1. Tumor cells in the logarithmic growth phase were then collected as target cells and their density was adjusted to 1×10⁻⁶. 5 Cells / mL; 50 μL of target cancer cell culture medium was added to each well of a 96-well E-Plates. Background impedance was measured and showed to be stable and at baseline. Then, isolated and activated T cells were co-cultured with tumor cells (experimental group) under the following conditions: 37 ℃, 5% CO2. Data was recorded every 15 minutes throughout the experiment, and monitored for 16–24 h. Effector cells were added when the CI value was ≥1. Cells activated and expanded under non-specific stimulation (non-specific activation of T cells) served as the control group, with the same culture conditions. Cell killing activity was calculated as follows: Cell killing activity = (1 - CI value of effector / target cell well / CI value of target cell well) × 100%. A killing efficiency ≥30% was considered to have significant killing efficiency.
[0040] 2. Experimental Results: Experimental results are as follows Figure 3 As shown in Table 4.
[0041] in: Figure 3 This diagram illustrates the cytotoxic activity of T cells induced by hepatocellular carcinoma antigen peptide-specific activation against tumor cells. Table 4 shows the inhibition rate of tumor cells by T cells induced by hepatocellular carcinoma antigen peptide-specific activation.
[0042] Table 4. Inhibition rate of tumor cells by T cells induced by hepatocellular carcinoma antigen peptide-specific activation. Group CI value 24 h after adding T cells Inhibition rate (100%) 24 h after T cell addition Is it ≥30%? Primary cells (target cell control group) 1.235 - - negative control group 0.732 73.48（1-0.732 / 1.235） yes SEQ ID NO.1 activated T cell group 0.247 60.97（1-0.247 / 1.235） yes SEQ ID NO.3 activated T cell group 0.509 39.76（1-0.509 / 1.235） yes SEQ ID NO.5 activated T cell group 0.3795 50.24（1-0.3795 / 1.235） yes SEQ ID NO.6 activated T cell group 0.199 64.86（1-0.199 / 1.235） yes SEQ ID NO.8 activated T cell group 0.3541 52.29（1-0.3541 / 1.235） yes Depend on Figure 3As shown in Table 4, the hepatocellular carcinoma antigen peptides provided by this invention: SEQ ID NO.1, SEQ ID NO.3, SEQ ID NO.5, SEQ ID NO.6 and SEQ ID NO.8 specifically activate and induce the expansion of T cells, which have significant tumor-killing effects.
[0043] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.
Claims
1. A hepatocellular carcinoma antigen peptide, characterized in that, The amino acid sequence of the antigenic peptide is at least one of SEQ ID NO.1, SEQ ID NO.2, SEQ ID NO.3, SEQ ID NO.4, SEQ ID NO.5, SEQ ID NO.6, SEQ ID NO.7 and SEQ ID NO.
8.
2. The hepatocellular carcinoma antigen peptide as described in claim 1, characterized in that, The amino acid sequence of the antigenic peptide is at least one of SEQ ID NO.1, SEQ ID NO.3, SEQ ID NO.5, SEQ ID NO.6 and SEQ ID NO.
8.
3. A nucleic acid molecule, characterized in that, The nucleic acid molecule contains a nucleotide sequence encoding the hepatocellular carcinoma antigen peptide of claim 1, and the nucleic acid molecule is double-stranded DNA.
4. An mRNA, characterized in that, The mRNA comprises an mRNA encoding the hepatocellular carcinoma antigen peptide as described in claim 1.
5. The mRNA as described in claim 4, characterized in that, The nucleotide sequence is at least one of SEQ ID NO.9, SEQ ID NO.10, SEQ ID NO.11, SEQ ID NO.12, SEQ ID NO.13, SEQ ID NO.14, SEQ ID NO.15 and SEQ ID NO.
16.
6. The mRNA as described in claim 5, characterized in that, The nucleotide sequence is at least one of SEQ ID NO.9, SEQ ID NO.11, SEQ ID NO.13, SEQ ID NO.14 and SEQ ID NO.
16.
7. An mRNA vaccine, characterized in that, The mRNA vaccine comprises lipid nanoparticles and mRNA as described in any one of claims 4 to 6.
8. The mRNA vaccine as described in claim 7, characterized in that, The vaccine preparation can be administered via intramuscular injection, intradermal injection, intravenous injection, arterial injection, or through mucosal route.
9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the mRNA as described in any one of claims 4 to 6 and a pharmaceutically acceptable carrier.
10. The use of the hepatocellular carcinoma antigen peptide of claim 1, the nucleic acid molecule of claim 3, the mRNA of claim 4, the mRNA vaccine of claim 7, or the pharmaceutical composition of claim 9 in the preparation of a medicament for the prevention and / or treatment of hepatocellular carcinoma.