CN114652838A - Medicine composition combining plant lignans or enterolactone and PD-1/PD-L1 inhibitor and application thereof - Google Patents

Medicine composition combining plant lignans or enterolactone and PD-1/PD-L1 inhibitor and application thereof Download PDF

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CN114652838A
CN114652838A CN202210494595.5A CN202210494595A CN114652838A CN 114652838 A CN114652838 A CN 114652838A CN 202210494595 A CN202210494595 A CN 202210494595A CN 114652838 A CN114652838 A CN 114652838A
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吴昊
刘树林
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Harbin Medical University
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The invention relates to a plant lignan or enterolactone and PD-1/PD-L1 inhibitor combined pharmaceutical composition and application thereof, belonging to the technical field of biological medicines. In order to solve the problem that malignant tumor patients are not sensitive to immunotherapy, the invention provides a combined pharmaceutical composition of plant lignans or enterolactone and a PD-1/PD-L1 inhibitor, which comprises an effective amount of plant lignans preparation or enterolactone preparation and also comprises an effective amount of PD-1/PD-L1 inhibitor. The combined medicine composition can increase the ratio of immune cells with anticancer function and inhibit the immune escape of the cancer cells. The combined medicine can up-regulate the proportion of CD4 and CD8 positive cells, and the effect of inhibiting the growth of the breast cancer of a mouse is better than that of the single medicine of the plant lignan, the enterolactone or the PD-L1/PD-1 inhibitor. The invention provides an unprecedented effective auxiliary or synergistic treatment strategy for immunotherapy of malignant tumors.

Description

Medicine composition combining plant lignans or enterolactone and PD-1/PD-L1 inhibitor and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a plant lignan or enterolactone and PD-1/PD-L1 inhibitor combined pharmaceutical composition and application thereof.
Background
Malignant tumor has high morbidity, strong heterogeneity and invasiveness, hidden initial onset, easy metastasis and easy relapse after treatment. Its prevention and cure has become a major public health problem all over the world. The malignant tumor patients under the traditional operation, radiotherapy and chemotherapy or targeted therapy mode have poor treatment effect, and most patients have drug resistance, relapse and metastasis in the treatment process, thus the social and economic burden is increased. Immunotherapy is an emerging means for resisting malignant tumors at present, and is known as research progress with the most breakthrough.
Immune checkpoints PD-1(Programmed death receptor) and PD-L1(Programmed death 1ligand) are the research hotspots for the immunotherapy of tumors. PD-L1 expressed on the surface of tumor cells interacts with PD-1 on the surface of T cells to inhibit the activation of effector T cells and induce the expression of FASL and immunosuppressive cytokine IL-10. The PD-L1 protein is abnormally high expressed in various malignant tumors. The inhibition of PD-L1 can remarkably promote T cell mediated tumor cell apoptosis. PD-L1 was also able to exert immunosuppressive effects in concert with FOXP3+ regulatory T cells. Heterogeneity also exists in the expression levels of PD-L1 among different malignant tumor subtypes. In breast cancer, for example, abnormally high expression of PD-L1 is associated with tumor staging, local cytotoxic immune responses, and patient prognosis.
Most malignant tumors have weak immunogenicity, strong heterogeneity and are not sensitive to immunotherapy. There is a great need to develop more effective therapeutic means to inhibit the immune escape of malignant tumors and enhance the sensitivity of tumor cells to immunotherapy.
Disclosure of Invention
In order to solve the problem that malignant tumor patients are not sensitive to immunotherapy, the invention provides a combined pharmaceutical composition of plant lignans or enterolactone and a PD-1/PD-L1 inhibitor and application thereof.
The technical scheme of the invention is as follows:
a pharmaceutical composition of plant lignan or enterolactone and PD-1/PD-L1 inhibitor comprises effective amount of plant lignan preparation or enterolactone preparation, and also comprises effective amount of PD-1/PD-L1 inhibitor.
Further, the plant lignan preparation comprises a plant resource containing a lignan precursor, wherein the lignan precursor can be converted into the enterolactone in the body, and the plant resource comprises one or more of defatted linseed, defatted sesame seed, defatted rapeseed, defatted rye bran, black wheat bran, black sesame, rapeseed, wheat bran, barley bran, corn bran, oat bran, burdock meal and seaweed.
Further, the plant lignan preparation comprises an aqueous extract of a plant resource comprising a lignan precursor, wherein the lignan precursor is converted into enterolactone in vivo, and the plant resource comprises one or more of defatted linseed, defatted sesame seed, defatted rapeseed, rye bran, black sesame, rapeseed, wheat bran, barley bran, corn bran, oat bran, burdock meal and seaweed.
Further, the lignan precursor is secoisolariciresinol, syringaresinol, arctigenin, lariciresinol, pinoresinol or sesamin.
Furthermore, the combined medicine composition is divided into two separate preparations of a plant lignan preparation and a PD-1/PD-L1 inhibitor, or two separate preparations of an enterolactone preparation and a PD-1/PD-L1 inhibitor.
Further, the plant lignan preparation or the enterolactone preparation is administered daily, and the PD-1/PD-L1 inhibitor is administered once every three days.
Further, the mass ratio of the daily dose of the plant lignan preparation to the daily dose of the PD-1/PD-L1 inhibitor is 1:10-3The mass ratio of the daily dose of the enterolactone preparation to the dose of the PD-1/PD-L1 inhibitor per three days is 1: 2.
Further, the plant lignan preparation, the enterolactone preparation or the PD-1/PD-L1 inhibitor further comprises a pharmaceutically acceptable carrier or excipient.
An application of a medicinal composition of plant lignan or enterolactone and PD-1/PD-L1 inhibitor in preparing antitumor drugs is provided.
Further, the tumor includes breast cancer, lymphoma, melanoma, lung cancer, ovarian cancer, cervical cancer, prostate cancer, kidney cancer, bladder cancer, brain glioma, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer and colorectal cancer.
The invention has the beneficial effects that:
experiments prove that the ratio of immune cells with anticancer function can be increased by combining the phytolignan or the enterolactone with a PD-1/PD-L1 inhibitor so as to inhibit the immune escape of breast cancer cells. The secoisolariciresinol diglucoside combined with a PD-L1/PD-1inhibitor can up-regulate the proportion of CD4 positive cells and CD8 positive cells, so that the secoisolariciresinol diglucoside combined with the PD-L1/PD-1inhibitor can inhibit the growth of breast cancer of mice, and has better cancer inhibition effect than that of singly taking the secoisolariciresinol diglucoside or the PD-L1/PD-1 inhibitor. The enterolactone combined with the PD-L1/PD-1inhibitor can up-regulate the proportion of CD4 positive cells and CD8 positive cells, so that the effect of inhibiting the growth of the breast cancer of a mouse is better than that of the enterolactone or the PD-L1/PD-1inhibitor which is singly used.
The combined pharmaceutical composition of the plant lignans or enterolactones and the PD-1/PD-L1 inhibitor and the application thereof provide an unprecedented effective auxiliary or synergistic treatment strategy for immunotherapy of malignant tumors, and can accelerate the conversion of the plant lignans or enterolactones from basic research to clinical practical application.
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FIG. 1 is a graph showing the comparison of the change in body weight of mice in each group in example 1;
FIG. 2 is a graph comparing the change in tumor volume in the mice of each group in example 1;
FIG. 3 is a photograph showing the comparison of the appearance of tumor tissues in the mice of example 1;
FIG. 4 is a graph comparing tumor mass in the mice of each group in example 1;
FIG. 5 is a graph comparing the staining results of tumors in the mice of each group in example 1;
FIG. 6 is a graph comparing the expression levels of ALKBH5 protein in tumors of various groups of mice in example 1;
FIG. 7 is a graph comparing the expression levels of EIF5B protein in tumors of groups of mice in example 1;
FIG. 8 is a graph comparing the expression levels of PD-L1 protein in tumors of various groups of mice in example 1;
FIG. 9 is a graph comparing the expression levels of CD38 protein in tumors of various groups of mice in example 1;
FIG. 10 is a graph comparing the expression levels of CD4 protein in tumors of various groups of mice in example 1;
FIG. 11 is a graph comparing the protein expression levels of CD8 in tumors of groups of mice in example 1;
FIG. 12 is a graph showing a comparison of the change in body weight of mice in each group in example 2;
FIG. 13 is a graph comparing the change in tumor volume in the groups of mice in example 2;
FIG. 14 is a photograph showing the tumor tissue appearance of each group of mice in example 2;
FIG. 15 is a graph comparing tumor mass in the mice of each group in example 2;
FIG. 16 is a comparison of the results of tumor staining in the mice of example 2;
FIG. 17 is a graph comparing the expression levels of ALKBH5 protein in tumors from groups of mice in example 2;
FIG. 18 is a graph comparing the expression levels of EIF5B protein in tumors of groups of mice in example 2;
FIG. 19 is a graph comparing the expression levels of PD-L1 protein in tumors of various groups of mice in example 2;
FIG. 20 is a graph comparing the expression levels of CD38 protein in tumors of various groups of mice in example 2;
FIG. 21 is a graph comparing the expression levels of CD4 protein in tumors of various groups of mice in example 2;
FIG. 22 is a graph comparing the protein expression levels of CD8 in tumors of groups of mice in example 2;
FIG. 23 is a bar graph of the relative abundance of bacteria at phyla levels in feces from groups of mice from example 3;
FIG. 24 is a bar graph of genus level relative abundance of bacteria in feces from groups of mice in example 3;
FIG. 25 is a top 50 heat map of the mean abundance of the genus-level taxa in the various mouse feces of example 3;
FIG. 26 is a thermogram of the expression of each of the immunocyte surface molecules in each of the groups of samples of example 4;
FIG. 27 is a TSNE dimension reduction analysis chart of each set of samples obtained from mass cytometry result analysis in example 4;
FIG. 28 is a TSNE map of individual clusters of samples from the mass cytometry analysis of example 4.
Detailed Description
The technical solutions of the present invention are further described below with reference to the following examples, but the present invention is not limited thereto, and any modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention. The process equipment or apparatus not specifically mentioned in the following examples are conventional in the art, and if not specifically mentioned, the raw materials and the like used in the examples of the present invention are commercially available; unless otherwise specified, the technical means used in the examples of the present invention are conventional means well known to those skilled in the art.
Example 1
In this example, the antitumor effect of a combination of an Enterolactone (ENL) preparation and a PD-1/PD-L1 inhibitor was examined by a mouse experiment.
The experimental method comprises the following steps:
24 BALB/c female mice were selected and 4T1 cells were inoculated subcutaneously into the mice. Mice were randomly divided into four groups: a Control group (Control), a PD-L1/PD-1inhibitor group (PD-L1/PD-1inhibitor), an ENL group and an ENL combined PD-L1/PD-1inhibitor group (ENL + PD-L1/PD-1 inhibitor). All groups were administered by intraperitoneal injection, wherein the ENL was administered daily at a dose of 1 mg/kg/mouse/day; the PD-L1/PD-1inhibitor was administered once every three days at a dose of 50 ug/mouse/3 days. The control group was given an equal amount of the formulated solvent for intraperitoneal injection.
The weight change of the mice is monitored to obtain a comparison graph of the weight change of the mice in each group shown in figure 1, and the results show that the weights of the mice in four groups have no obvious statistical difference.
Tumor volumes of the mice in each group were measured and administered at the beginning of day 6 after the subcutaneous tumor formation, and a comparison of the change in tumor volume of the mice in each group as shown in FIG. 2 was obtained, showing that the total tumor volume of the mice in the ENL combined with PD-L1/PD-1inhibitor group was smaller than that of the control group (P < 0.01) from day 12. By day 21, the ENL combined with PD-L1/PD-1inhibitor group mice had the smallest tumor volume, all with statistical differences (P < 0.05).
Killing the mice, dissecting tumor tissues and taking pictures to obtain the appearance contrast pictures of the tumor tissues of the mice in each group shown in figure 3; measuring the tumor mass to obtain a comparison graph of the tumor mass of each group of mice shown in figure 4; the results showed that the overall tumor mass was less than that of the control group (P < 0.001) for all groups of mice, and that the tumor volume was minimal for the ENL in combination with the PD-L1/PD-1inhibitor group of mice, with statistical differences (P < 0.05) compared to the other groups.
The resulting mouse tumors were subjected to ALKBH5, EIF5B, PD-L1, CD38, CD4, and CD8 immunohistochemical staining, methods of staining routine in the art. A comparison of the tumor staining results of the groups of mice shown in FIG. 5 and a comparison of the protein expression levels of ALKBH5, EIF5B, PD-L1, CD38, CD4 and CD8 shown in FIGS. 6-11 were obtained. The results show that: compared with a control group, the tumors ALKBH5, EIF5B, PD-L1 and CD38 of the mice in the group of ENL and the combination of ENL and PD-L1/PD-1inhibitor are all down-regulated; the expression of CD4 and CD8 in the combination treatment group is higher than that in the control group and the ENL group (P < 0.05).
The experimental result of the embodiment shows that the ENL combined with the PD-L1/PD-1inhibitor can up-regulate the proportion of CD4 positive cells and CD8 positive cells, and the effect of inhibiting the growth of the breast cancer of a mouse is better than that of the ENL or the PD-L1/PD-1inhibitor which is singly used.
Example 2
In this example, the antitumor effect of a combination of a flax lignan preparation and a PD-1/PD-L1 inhibitor was examined by a mouse experiment.
The experimental method comprises the following steps:
24 BALB/c female mice were selected and the 4T1 cell line was inoculated subcutaneously into the mice. Mice were randomized into four groups: a Control group (Control), a PD-L1/PD-1inhibitor group (PD-L1/PD-1inhibitor), a flax lignan group (Flaxseed lignan) and a flax lignan combined PD-L1/PD-1inhibitor group (Flaxseed lignan + PD-L1/PD-1 inhibitor).
The preparation method of the flaxseed lignan preparation used in this example is that 10g of defatted flaxseed is placed in 100mL of pure water, boiled for 5min and then liquid is collected to obtain the flaxseed lignan preparation, the flaxseed lignan preparation is administered by intragastric administration every day, and the intragastric volume is 500 uL/mouse/day; the PD-L1/PD-1inhibitor was administered once every three days at a dose of 50 ug/mouse/3 days. The control group was given the same amount of saline for intragastric administration and the solvent was prepared for intraperitoneal injection.
The change in body weight of the mice was monitored to obtain a comparative graph of the change in body weight of the mice in each group as shown in FIG. 12, which shows that no significant statistical difference (P > 0.05) was observed in the body weights of the mice in the four groups.
Tumor volumes of the mice in each group were measured and administration was started at day 6 after subcutaneous tumor formation, and a comparison of tumor volume changes in the mice in each group as shown in FIG. 13 was obtained, which revealed that the total tumor volume of the mice in the combination treatment group was smaller than that in the control group (P < 0.001) from day 15. The tumor volume of the mice in the 18 th combined treatment group is smaller than that of the PD-L1/PD-1inhibitor group and the flax lignan single drug group (P is less than 0.05). The tumor volume was minimal in the combination treatment group by day 21 and was statistically different from each of the other groups (P < 0.05).
Mouse feces were retained for 16S rDNA sequencing prior to sacrifice.
The mice are sacrificed, and tumor tissues are dissected and photographed to obtain comparative photos of the appearance of the tumor tissues of each group of mice shown in figure 14; measuring the tumor mass to obtain a comparison graph of the tumor mass of each group of mice shown in figure 15; the results showed that the tumor mass was minimal in the mice of the combination treatment group and was statistically different (P < 0.001) compared to the other groups.
The resulting mouse tumors were subjected to ALKBH5, EIF5B, PD-L1, CD38, CD4, and CD8 immunohistochemical staining, methods of staining routine in the art. A comparison of the tumor staining results of the groups of mice shown in FIG. 16 and a comparison of the protein expression levels of ALKBH5, EIF5B, PD-L1, CD38, CD4 and CD8 shown in FIGS. 17-22 were obtained. The results show that: mice tumors ALKBH5, EIF5B, PD-L1 and CD38 in the linoleum group and the linoleum combined PD-L1/PD-1inhibitor group are all down-regulated compared with a control group; the expression of CD4 in the combination treatment group is higher than that in the control group and the flax lignan group (P is less than 0.05); the expression of CD8 in the combination treatment group is higher than that in the control group, the flax lignan group and the PD-L1/PD-1inhibitor group.
The experimental result of the embodiment shows that the secoisolariciresinol diglucoside combined with the PD-L1/PD-1inhibitor can up-regulate the proportion of CD4 and CD8 positive cells, inhibit the growth of the breast cancer of mice and have better cancer inhibition effect than that of the secoisolariciresinol diglucoside or the PD-L1/PD-1inhibitor which is singly used.
Example 3
This example further performed 16S rDNA sequencing analysis of the mouse feces collected from groups of mice prior to sacrifice in example 2.
First, a histogram comparison of the relative abundance of the phylum of bacteria was performed, and the results are shown in fig. 23, which shows that the abundance of Verrucomicrobia (phylum of Verrucomicrobia) was increased after the treatment with secoisolariciresinol diglucoside.
Next, a histogram comparison of the relative abundance of bacterial levels was performed. As shown in FIG. 24, Blautia (Blauettia), Bacteroides (Bacteroides), and Akkermansia (Akkermansia) were more abundant in the secoisolariciresinol group and the PD-L1/PD-1inhibitor group than the control group, and were highest in the secoisolariciresinol combined with PD-L1/PD-1inhibitor group. The abundance of Clostridium (Clostridium) in the flax lignan combined PD-L1/PD-1inhibitor group was significantly increased. Lactobacillus (Lactobacillus) was reduced in the linoleum group and further in the linoleum combined with PD-L1/PD-1inhibitor group relative to the control group.
Next, species composition differences between samples were compared, taxon composition at genus level was analyzed, default heatmaps were drawn using data from the top 50 bits of mean abundance, and results are shown in fig. 25, showing: treatment with flaxseed lignans in combination with PD-L1/PD-1 inhibitors can significantly increase the abundance of chelacoccus (chelidaceae), Clostridium (Clostridium), gemmigeria (geminium), Bifidobacterium (Bifidobacterium), cupriavirtus (cupriasis), anaerobacterium (anaerobacterium), Blautia (Blautia), and Parabacteroides (paradise). Akkermansia (Ackermansia) which can obviously enhance the treatment effect of the anti-PD-1 medicament is high in the flax lignan group and the flax lignan combined PD-L1/PD-1inhibitor treatment group. Eubacterium (Eubacterium) and Clostridium (Clostridium) capable of promoting the conversion of SDG to ENL in vivo are also found in elevated abundance in the flax lignans group and flax lignans in combination with PD-L1/PD-1inhibitor treatment group.
Example 4
In this example, the effect of the combination of flax lignan and enterolactone and a PD-1/PD-L1 inhibitor on the suppression of the immune escape of breast cancer cells was examined by further observing the status of the immune cells infiltrating in the tumors of mice treated with lignan or enterolactone.
Tumor tissues of 6 groups of mice, namely a control group, a secoisolariciresinol diglucoside group, a PD-L1/PD-1inhibitor group, an ENL combined PD-L1/PD-1inhibitor group and a secoisolariciresinol diglucoside combined PD-L1/PD-1inhibitor group are taken for CyTOF (mass spectrometry flow cytometry) detection. First, it was determined that the detected panel, which contained 42 immune cell-associated markers, markers and corresponding metal channels, is shown in Table 1.
TABLE 1
Figure BDA0003632361360000071
Figure BDA0003632361360000081
The expression level of each marker in each group of samples was analyzed and heat-mapped, and the results are shown in FIG. 26.
Different markers are combined according to cell phenotypes, and the combined phenotype is 36 cell phenotypes which are respectively named as C01-C36, and the annotations of immune cell subsets are shown in Table 2.
TABLE 2
Figure BDA0003632361360000082
Figure BDA0003632361360000091
All groups were then subjected to dimensionality reduction and analyzed for TSNE dimensionality reduction, and the results are shown in FIG. 27, where it can be seen that cells of different lineages can be clearly distinguished.
Further, each group was individually clustered, and clustered TSNE plots were separately prepared to evaluate the difference in subpopulations of the 6 groups of tumor-infiltrating immune cells, with the results shown in fig. 28. The analysis result shows that: linum usitatissimum lignanThe combination of PD-L1/PD-1inhibitor can lead the efficiency Memory CD4+T (C06, C08), Effect CD4+T (C09), Memory CD8+The proportion of T (C12, C13), Granulocytes (C19) and B cells (C32, C33 and C34) is increased, and M2 type macrophages (C29) can be reduced; ENL combined with PD-L1/PD-1inhibitor can make Memory CD8+The proportion of T (C12, C13), Granulocytes (C20, C21, C22, C23) and B cells (C33) increased, and M2 type macrophages also decreased (C29). The application of the plant lignans or enterolactone in combination with a PD-L1/PD-1inhibitor can increase the ratio of anticancer immune cells and inhibit the immune escape of breast cancer cells.

Claims (10)

1. A medicine composition of plant lignans or enterolactone and a PD-1/PD-L1 inhibitor is characterized by comprising an effective amount of plant lignans preparation or enterolactone preparation and further comprising an effective amount of a PD-1/PD-L1 inhibitor.
2. The combination pharmaceutical composition of a plant lignan or enterolactone and a PD-1/PD-L1 inhibitor according to claim 1, wherein the plant lignan preparation comprises a plant source comprising a lignan precursor, wherein the lignan precursor is capable of being converted into enterolactone in vivo, and wherein the plant source comprises one or more of defatted flax seed, defatted sesame seed, defatted canola, rye bran, black sesame, rapeseed, wheat bran, barley bran, corn bran, oat bran, burdock meal, and seaweed.
3. The combination pharmaceutical composition of a plant lignan or enterolactone and a PD-1/PD-L1 inhibitor according to claim 1, wherein the plant lignan preparation comprises an aqueous extract of a plant resource comprising a lignan precursor, wherein the lignan precursor is converted into enterolactone in vivo, and wherein the plant resource comprises one or more of defatted flaxseed, defatted sesame seed, defatted rapeseed, rye bran, black sesame, rapeseed, wheat bran, barley bran, corn bran, oat bran, burdock meal, and seaweed.
4. The pharmaceutical composition of claim 2 or 3, wherein the lignan precursor is secoisolariciresinol, syringaresinol, arctigenin, lariciresinol, pinoresinol or sesamin in combination with a PD-1/PD-L1 inhibitor.
5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition comprises a phytolignan or enterolactone in combination with a PD-1/PD-L1 inhibitor, and is divided into two separate preparations, namely a phytolignan preparation and a PD-1/PD-L1 inhibitor, or a phytolignan preparation and a PD-1/PD-L1 inhibitor.
6. The pharmaceutical composition of claim 5 wherein said phytolignan or enterolactone is administered daily and said PD-1/PD-L1 inhibitor is administered once a day for three days.
7. The pharmaceutical composition of claim 6, wherein the ratio of daily dosage of the phytolignan preparation to daily dosage of the PD-1/PD-L1 inhibitor per three days is 1:10-3The mass ratio of the daily dose of the enterolactone preparation to the dose of the PD-1/PD-L1 inhibitor per three days is 1: 2.
8. The pharmaceutical composition of claim 7, wherein the plant lignan or enterolactone is combined with a PD-1/PD-L1 inhibitor, wherein the plant lignan preparation, the enterolactone preparation or the PD-1/PD-L1 inhibitor further comprises a pharmaceutically acceptable carrier or excipient.
9. Use of a combination of a plant lignan or enterolactone of any one of claims 1 to 8 and a PD-1/PD-L1 inhibitor for the preparation of an anti-tumor medicament.
10. Use of the plant lignan or enterolactone of claim 9 in combination with a PD-1/PD-L1 inhibitor for the preparation of a medicament for the treatment of tumors, including breast, lymphoma, melanoma, lung, ovarian, cervical, prostate, renal, bladder, brain glioma, esophageal, gastric, liver, pancreatic and colorectal cancers.
CN202210494595.5A 2022-05-07 2022-05-07 Medicine composition combining plant lignans or enterolactone and PD-1/PD-L1 inhibitor and application thereof Pending CN114652838A (en)

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