CN116870150A - Application of PNU112455A inhibitor and PD-1 antibody in preparation of hepatocellular carcinoma immunotherapy medicament - Google Patents
Application of PNU112455A inhibitor and PD-1 antibody in preparation of hepatocellular carcinoma immunotherapy medicament Download PDFInfo
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- CN116870150A CN116870150A CN202310886953.1A CN202310886953A CN116870150A CN 116870150 A CN116870150 A CN 116870150A CN 202310886953 A CN202310886953 A CN 202310886953A CN 116870150 A CN116870150 A CN 116870150A
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- 101710089372 Programmed cell death protein 1 Proteins 0.000 title claims abstract description 54
- XBXQRCJKDCEQBS-UHFFFAOYSA-N 4-[(6-aminopyrimidin-3-ium-4-yl)amino]benzenesulfonamide;chloride Chemical compound Cl.C1=NC(N)=CC(NC=2C=CC(=CC=2)S(N)(=O)=O)=N1 XBXQRCJKDCEQBS-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 239000003112 inhibitor Substances 0.000 title claims abstract description 33
- 206010073071 hepatocellular carcinoma Diseases 0.000 title claims abstract description 27
- 231100000844 hepatocellular carcinoma Toxicity 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 102100023990 60S ribosomal protein L17 Human genes 0.000 title claims abstract 15
- 238000009169 immunotherapy Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 241000699670 Mus sp. Species 0.000 abstract description 30
- 238000011282 treatment Methods 0.000 abstract description 21
- 206010028980 Neoplasm Diseases 0.000 abstract description 14
- 230000004083 survival effect Effects 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 238000011081 inoculation Methods 0.000 abstract description 6
- 230000036039 immunity Effects 0.000 abstract description 3
- 230000002035 prolonged effect Effects 0.000 abstract description 2
- 230000002195 synergetic effect Effects 0.000 abstract description 2
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 39
- 102000008096 B7-H1 Antigen Human genes 0.000 description 22
- 108010074708 B7-H1 Antigen Proteins 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000011284 combination treatment Methods 0.000 description 7
- 208000014018 liver neoplasm Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 102000001398 Granzyme Human genes 0.000 description 4
- 108060005986 Granzyme Proteins 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 239000006143 cell culture medium Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000002055 immunohistochemical effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 102000013717 Cyclin-Dependent Kinase 5 Human genes 0.000 description 2
- 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
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- 101100495314 Caenorhabditis elegans cdk-5 gene Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 230000001419 dependent effect Effects 0.000 description 1
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- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003684 drug solvent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention provides an application of PNU112455A inhibitor and PD-1 antibody combination in preparing a hepatocellular carcinoma immune medicament. The PNU112455A inhibitor and the PD-1 antibody are used in combination, so that the PNU112455A inhibitor and the PD-1 antibody have good synergistic effect on the treatment of hepatocellular carcinoma immunity, and the effect of PD-1 antibody treatment is obviously improved and the survival period of mice is prolonged by the combination of the PNU112455A inhibitor and the PD-1 antibody in mice. PD-1 antibody-treated mice had only 37.5% survival 60 days post tumor inoculation, while PNU112455a inhibitor-treated mice had 87.5% survival 60 days post PD-1 antibody.
Description
Technical Field
The invention belongs to the technical field of tumor treatment, and particularly relates to application of PNU112455A inhibitor and PD-1 antibody in preparation of medicines for treating hepatocellular carcinoma immunity.
Background
Liver cancer is one of the most frequently occurring malignant tumors in the world, and occupies the 6 th site of all malignant tumors and the 3 rd site of death related to malignant tumors. Hepatocellular carcinoma is a major type of liver cancer, accounting for about 90% of all liver cancers. However, more than 70% of hepatocellular carcinoma patients are in progress at the time of diagnosis, and have lost surgical indications of partial resection or liver transplantation.
Since 2017, as the U.S. FDA successively approves the anti-PD-1 medicine nivolumab, pembrolizumab for treating advanced hepatocellular carcinoma, obvious progress is made on the curative effect of advanced hepatocellular carcinoma, and the treatment aiming at the immune-checkpoint PD-1/PD-L1 is one of a few effective treatment means, but the objective remission rate of the PD-1/PD-L1 immune-checkpoint blocking therapy on hepatocellular carcinoma patients is still insufficient to 20%. Therefore, the treatment of hepatocellular carcinoma remains a clinical challenge, and there is an urgent need to find effective therapeutic drugs.
Disclosure of Invention
In view of the above problems, the present invention provides the use of a PNU112455a inhibitor in combination with a PD-1 antibody in the preparation of an immune medicament for hepatocellular carcinoma. The combination of the two significantly improves the treatment effect and prolongs the survival period of mice in the mouse experiment.
The invention is realized by the following technical scheme:
the invention provides an application of PNU112455A inhibitor and PD-1 antibody combination in preparing a hepatocellular carcinoma immune medicament.
Further, the mass ratio of the PNU112455A inhibitor to the PD-1 antibody is (10-20): 1. Preferably, the mass ratio of the PNU112455A inhibitor to the PD-1 antibody is 15:1.
The invention also provides an immune pharmaceutical composition for treating hepatocellular carcinoma, which consists of a PNU112455A inhibitor and a PD-1 antibody.
Further, the weight ratio of the PNU112455A inhibitor to the PD-1 antibody is (10-20): 1. preferably, the mass ratio of the PNU112455A inhibitor to the PD-1 antibody is 15:1.
The invention also provides a preparation method of the immune pharmaceutical composition, which comprises the following steps: taking the PNU112455A inhibitor and the PD-1 antibody according to the weight ratio, and then mixing.
The invention also provides an immune pharmaceutical preparation for treating hepatocellular carcinoma, which is prepared by taking the immune pharmaceutical composition as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The invention also provides a combined medicament for immunotherapy of hepatocellular carcinoma, which comprises PNU112455A inhibitor and PD-1 antibody which are simultaneously or respectively administrated in the same or different specifications, and a pharmaceutically acceptable carrier.
Further, the weight ratio of the PNU112455A inhibitor to the PD-1 antibody is (10-20): 1.
the invention has the following positive and beneficial effects:
the PNU112455A inhibitor and the PD-1 antibody are used in combination, so that the PNU112455A inhibitor and the PD-1 antibody have good synergistic effect on the treatment of hepatocellular carcinoma immunity, and the effect of PD-1 antibody treatment is obviously improved and the survival period of mice is prolonged by the combination of the PNU112455A inhibitor and the PD-1 antibody in mice. PD-1 antibody-treated mice had only 37.5% survival 60 days post tumor inoculation, while PNU112455a inhibitor-treated mice had 87.5% survival 60 days post PD-1 antibody.
Drawings
FIG. 1 is a graph showing the effect of PNU112455A inhibitor on the protein expression level of PD-L1 in tumor cells;
FIG. 2 is a schematic diagram of the experimental process of the mouse animal;
FIG. 3 shows the effect of PNU112455A inhibitor alone or in combination with PD-1 on various factors in mice;
figure 4 shows the immunotherapeutic effect of PNU112455a inhibitors in combination with PD-1 antibodies on hepatocellular carcinoma in mice.
Detailed Description
The following detailed description of the present invention is provided for the understanding of the technical solution of the present invention, but is not intended to limit the scope of the present invention.
The raw materials and equipment used in the embodiment of the invention are all known products, and can be obtained through purchase. Wherein the PD-1 antibody is specifically InVivoMAb anti-mouse PD-1 (CD 279), and the PNU112455A is Shanghai Tao Shu organism (Topscience) PNU112455Ahydrochloride.
Example 1
This example shows that PNU112455a is able to significantly up-regulate the protein expression level of PD-L1:
(1) The cell culture medium of human liver cell liver cancer BEL-7402 is added with 5 mu M PNU112455A for treatment, and the PD-L1 expression level in the cell is detected by Western blot after 24 hours. The results are shown in FIG. 1A, and as can be seen from FIG. 1A, PNU112455A significantly promoted PD-L1 protein expression in hepatoma cells.
(2) Construction of CDK5 knockdown BEL-7402 cells by CRISPR technique sgCDK5-1 and sgCDK5-2 control cells were sgCon, 5. Mu.M PNU112455A was added to the cell culture medium for treatment, and after 24 hours the PD-L1 expression level in the cells was detected by Western blot. As shown in fig. 1B, PNU112455A significantly promoted PD-L1 protein expression in the liver cancer cells of the control group, but PNU112455A did not affect PD-L1 protein expression in the cells after CDK5 knockdown, as can be seen from fig. 1B. The result shows that PNU112455A regulates PD-L1 protein expression of liver cancer cells through CDK 5.
(3) The PD-L1 expression level in the cells was detected by Western blot after 0, 6, 12, 24 hours, respectively, by adding 10. Mu.M PNU112455A to 293T cell culture medium. As a result, as shown in FIG. 1C, it can be seen from FIG. 1C that the protein expression level of PD-L1 in 293T cells gradually increased with the increase of the drug treatment time, indicating that the promotion of the PD-L1 protein expression in 293T cells by PNU112455A was a time-dependent effect. .
(4) In 293T cell culture medium, PNU112455A was added at 0. Mu.M, 5. Mu.M, 10. Mu.M, and 20. Mu.M, respectively, and the PD-L1 expression levels in the cells were detected by Western blot after 24 hours. As a result, as shown in FIG. 1D, it can be seen from FIG. 1D that the protein expression level of PD-L1 in 293T cells gradually increased with the increase in the dose of the drug treatment, indicating that the promotion of the expression of PD-L1 protein in 293T cells by PNU112455A was a dose-dependent effect.
Example 2
PNU112455A in mice can obviously up-regulate the protein expression level of PD-L1 in hepatocellular carcinoma cells, and PNU112455A combined with PD-1 antibody can obviously increase the number of tumor infiltrating lymphocytes and raise the expression of granzyme B:
(1) Model construction and drug evaluation:
will be 1X 10 6 Hepa1-6 mice hepatocellular carcinoma cells (purchased from cell bank of China academy of sciences) were injected subcutaneously into the right side of C56BL/6 female mice, and solid tumors developed after about 9 days, at this time, the mice were randomly grouped according to a statistical method into four groups of 8 mice each, and the specific grouping and administration methods were as follows:
control group: from day 9 to day 18 after tumor cell inoculation, the mice are subjected to intraperitoneal injection of a drug solvent every 2 days, the solvent is prepared by PBS/DMSO/Solutol according to a volume ratio of 8:1:1, and each injection volume is 200 mu L;
PD-1 mab treatment group: from day 9 to day 18 after tumor cell inoculation, PD-1 antibodies were intraperitoneally injected into mice every 2 days, diluted with PBS, at a dose of 10mg/kg, at a volume of 200. Mu.L each;
PNU112455a treatment group: from day 9 to day 18 after tumor cell inoculation, PNU112455A medicine is injected into the abdominal cavity of the mice every 2 days, the injection dose is 150mg/kg, the solvent is PBS/DMSO/Solutol according to the volume ratio of 8:1:1, and each injection volume is 200 mu L;
PD-1 mab and PNU112455a inhibitor combination treatment group: PD-1 antibody and PNU112455a drug were injected intraperitoneally into mice every 2 days from day 9 to day 18 after tumor cell inoculation at doses of 10mg/kg and 150mg/kg, respectively, with the solvent PBS/DMSO/Solutol at a volume ratio of 18:1:1, each injection having a total volume of 200 μl, as shown in fig. 2;
(2) Immunohistochemical staining and scoring:
mouse hepatocellular carcinoma tumor tissue was stored in 4% paraformaldehyde, and fixed, sectioned and stained according to immunohistochemical standard protocols. CD3 positive, CD8 positive T cell numbers, granzyme B and PD-L1 protein expression were observed under a 200-fold microscope. Wherein the calculation formula of the number of the CD3 positive and CD8 positive T cells in each square millimeter of tumor area is calculated by dividing the number of the positive cells calculated under a 200-time microscope by the unit area. The percent granzyme B positive area was statistically determined by analyzing the captured images under a 200-fold microscope using ImageJ software.
The PD-L1 protein expression level is scored by a scoring formula, and positive rates and staining intensities in the immunohistochemical sections are respectively scored and multiplied to obtain comprehensive scores, wherein the specific scoring criteria are as follows: the positive rate is less than or equal to 5 percent and is 0 percent, the positive rate is 6 to 19 percent and is 1 percent, the positive rate is 20 to 49 percent and is 2 percent, the positive rate is 50 to 74 percent and is 3 percent, and the positive rate is more than or equal to 75 percent and is 4 percent. The staining intensity was negative for 0 score, weak positive for 1 score, moderate positive for 2 score, and strong positive for 3 score. According to the product of the scores of the two items, the total score is less than or equal to 3 and is PD-L1 low expression, and the total score is more than 3 and is PD-L1 high expression.
The immunohistochemical staining and scoring results are shown in fig. 3, and as can be seen from fig. 3, the number of CD8 positive T cells per square millimeter of tumor area exhibited the highest value in the PD-1 mab and PNU112455a combination treatment group, which was significantly higher than the control group (P < 0.001) and the PD-1 mab treatment group (P < 0.001); the number of CD3 positive T cells per square millimeter of tumor area exhibited the highest value in the combination treatment group, significantly higher than the control group (P < 0.001) and the PD-1 mab-treated group (P < 0.001); the percent positive area of granzyme B exhibited the highest value in the combination treatment group, significantly higher than the control group (P < 0.001) and PD-1 mab-treated group (P < 0.001); the immunohistochemical score of PD-L1 showed the highest value in PNU112455a monotherapy group, significantly higher than control group (P < 0.001).
(3) Effect of immunotherapy
Detection of tumor volume: measuring the length and width of subcutaneous tumors of mice in the control group, PNU112455A treatment group, PD-1 monoclonal antibody and PNU112455A combined treatment group by using a vernier caliper every two days, and calculating the volume, wherein the volume calculation formula is pi/6 multiplied by the length multiplied by the width 2 。
The results of the growth curves for the mice of each group are shown in fig. 4A, and tumor volumes of all mice in the control group and PNU112455a treatment group were sacrificed by reaching 1500 cubic millimeters during the observation period; as can be seen from fig. 4A, the PD-1 mab-treated group had 3/8 of the mice tumor volume reduced and survived; the tumor volume of 7/8 of the mice in the PD-1 mab and PNU112455A combination treatment group was reduced and survived, and the number of surviving mice in the combination treatment group was significantly higher than that in the other groups. The Kaplan-Meier survival curves of the mice in each treatment group were analyzed, and as shown in fig. 4B, the mice in the PD-1 mab and PNU112455a combination treatment group had significantly higher survival than the PD-1 mab treatment group (P < 0.01) and the control group (P < 0.001). Experimental results show that PNU112455A and PD-1 monoclonal antibody combination in mice can remarkably promote the effect of hepatocellular carcinoma immunotherapy.
(4) Non-experimental endpoint animals were happy standard:
if the tumor reached 1500 cubic millimeters before the end of the experiment, the mice were sacrificed.
Claims (8)
- Use of pnu112455a inhibitor and PD-1 antibody in combination for the preparation of a hepatocellular carcinoma immune medicament.
- 2. The use according to claim 1, wherein the mass ratio of the PNU112455a inhibitor to the PD-1 antibody is (10-20): 1.
- 3. An immune pharmaceutical composition for treating hepatocellular carcinoma, which is characterized in that the pharmaceutical composition consists of a PNU112455A inhibitor and a PD-1 antibody.
- 4. The pharmaceutical composition of claim 3, wherein the weight ratio of PNU112455a inhibitor to PD-1 antibody is (10-20): 1.
- 5. a method of preparing an immune pharmaceutical composition according to claim 3 or 4, comprising: mixing PNU112455A inhibitor with PD-1 antibody according to weight ratio.
- 6. An immune pharmaceutical preparation for treating hepatocellular carcinoma, which is characterized in that the immune pharmaceutical preparation is prepared by taking the pharmaceutical composition as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients into the pharmaceutical composition as claimed in claim 3 or 4.
- 7. A combination for immunotherapy of hepatocellular carcinoma, comprising a PNU112455a inhibitor and a PD-1 antibody administered simultaneously or separately, of the same or different specifications, and a pharmaceutically acceptable carrier.
- 8. The combination of claim 7, wherein the PNU112455a inhibitor and PD-1 antibody are present in a weight ratio of (10-20): 1.
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| CN202310886953.1A CN116870150A (en) | 2023-07-19 | 2023-07-19 | Application of PNU112455A inhibitor and PD-1 antibody in preparation of hepatocellular carcinoma immunotherapy medicament |
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| CN202310886953.1A CN116870150A (en) | 2023-07-19 | 2023-07-19 | Application of PNU112455A inhibitor and PD-1 antibody in preparation of hepatocellular carcinoma immunotherapy medicament |
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