CN108392633A - Application of the PCSK9 inhibitor in malignant tumour immunization therapy - Google Patents
Application of the PCSK9 inhibitor in malignant tumour immunization therapy Download PDFInfo
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Abstract
The present invention relates to application of the PCSK9 inhibitor in malignant tumour immunization therapy.Present invention is disclosed PCSK9 inhibitor can effectively inhibit tumour.The PCSK9 inhibitor enhances the activity of immunocyte, to inhibit tumour by the expression of raising activated immune cell related gene.Present invention further teaches the remarkable effect of use in conjunction PCSK9 inhibitor and 1 inhibitor of PD in terms of further increasing immunologic cellular activity and inhibiting tumour.
Description
Technical field
The present invention relates to chemical medicine fields, more particularly it relates to which PCSK9 inhibitor is in anti-tumor immunotherapy
In application.
Background technology
The immunization therapy of tumour is the most promising new treatment of rising in recent years, which can enhance the anti-of immune system
Should be able to power, excite specific immune response, to reach delay tumour progression and inhibit tumor recurrence transfer, or even completely cure
The purpose of tumour.
The immunization therapy of tumour at present can be divided into following a few classes：(1) Nonspecific immunotherapy for bronchus refers to using some immune tune
Section agent activates the anti-tumor immune response of body, to reach treatment tumour by non-specifically enhancing the immune function of body
Purpose.That is applied in oncotherapy at present has cell factor (1L-2, IFN, TNF etc.), microorganism and its product, vitamin
K, heat shock protein (HSP) etc..(2) immunologic test point blocking treatment, research is found can be by immunologic test point in tumour cell
Molecule carries out negative regulation to the immunocyte in tumor microenvironment, inhibits its antitumor activity, and blocking immunity checkpoint
Effect can then restore the killing ability of immunocyte, inhibit the progress of tumour.FDA approvals as has already been are used for malignant tumour
Anti- PD1 drugs and anti-CTLA-4 drugs for the treatment of etc..(3) adoptive immunotherapy is directed toward malignant tumor patient input with anti-
The immunocyte of tumor activity, direct killing tumour or excitating organism Antitumor immunity effect, to reach the mesh for the treatment of malignant tumour
's.
Although those skilled in the art are dedicated to antitumor research, the means of kinds of tumors immunization therapy are also developed,
It is still to have more technological difficulties, such as there is also some problems in immunologic test point drug：Since PD-1/PD-L1 believes
Number access acts only on the effective stage of T cell, and the performance of anti-PD-1/PD-L1 effect of drugs needs the submission of tumour antigen, faces
For about 70% tumour of low immunogenicity, often treatment is invalid on bed, needs to be used in conjunction with drugs such as chemotherapy, radiotherapies；Separately
Outside, cancer cell realizes immunologic escape by different approaches or number of ways sometimes, simple to block PD-1/PD-L1 approach pair one
The immunologic escape of a little cancer cells may have no effect.There is the antibody of targeting CD47 activating macrophage, enhancing T cell antigen to pass
In etc. functions, it is functionally complementary with anti-PD-1/PD-L1, however the expression of CD47 is not proper tumour-specific,
Often cause the adverse reactions such as anaemia using CD47 antibody in vivo.
Therefore, there is still a need for further finding significant effect and immunotherapy of tumors method easy to implement and treatment
Drug.
Invention content
The purpose of the present invention is to provide application of the PCSK9 inhibitor in malignant tumour immunization therapy.
In the first aspect of the present invention, PCSK9 inhibitor is provided and is preparing inhibition tumour or is enhancing immunologic cellular activity
Application in drug.
In another aspect of this invention, PCSK9 inhibitor and PD-1 inhibitor are provided and preparing inhibition tumour or enhancing
Application in the drug of immunologic cellular activity.
In another preferred example, the tumour is the tumour that can be identified by immunocyte；Preferably, the tumour packet
Include (but not limited to)：Leukaemia, lymthoma, melanoma, lung cancer, liver cancer, prostate cancer, colorectal cancer, gastric cancer, the cancer of the esophagus,
Cholangiocarcinoma, gallbladder cancer etc..
In another preferred example, the PCSK9 inhibitor or the PCSK9 inhibitor and PD-1 inhibitor pass through
The expression for increasing activated immune cell related gene, enhances the activity of the inhibition tumour of immunocyte, to inhibit tumour；Preferably
Ground, the activated immune cell related gene include：GZMB, IFN γ, TNF α, NOS2, NCR1, PRF, IL15, CCL3,
CXCL10, CD8, NK1.1, FOXP3.
In another preferred example, the immunocyte includes：NK cells, T cell.
In another preferred example, the PCSK9 inhibitor includes：Anti- PCSK9 antibody；Interfere PCSK9 gene expressions
Disturbing molecule；The gene editing or gene silencing agent of specific downregulation PCSK9；Or PCSK9 micromolecular inhibitors, such as SBC-
110736, SBC-115076, R-IMPP are purchased from MCE companies；Or the PD-1 inhibitor includes：Anti- PD-1 antibody, interference
The disturbing molecule of PD-1 gene expressions, the gene editing or gene silencing agent of specific downregulation PD-1.
In another aspect of this invention, a kind of pharmaceutical composition for inhibiting tumour, described pharmaceutical composition packet are provided
It includes：PCSK9 inhibitor and PD-1 inhibitor.
In another aspect of this invention, a kind of medicine box for inhibiting tumour is provided, is pressed down containing PCSK9 in the medicine box
Preparation and PD-1 inhibitor；Or contain the pharmaceutical composition in the medicine box.
In another preferred example, further include selected from the group below one or more in the medicine box：Tumor chemotherapeutic drug；It is swollen
Tumor radiotherapeutic drug；Operation instructions.
In another preferred example, in the pharmaceutical composition or the medicine box, the PCSK9 inhibitor includes：
Anti- PCSK9 antibody interferes the disturbing molecule of PCSK9 gene expressions, gene editing or the gene silencing examination of specific downregulation PCSK9
Agent；Or PCSK9 micromolecular inhibitors are purchased from MCE companies such as SBC-110736, SBC-115076, R-IMPP；Or the PD-
1 inhibitor includes：Anti- PD-1 antibody, interfere PD-1 gene expressions disturbing molecule, the gene editing of specific downregulation PD-1 or
Gene silencing agent.
In another aspect of this invention, a kind of active method of enhancing immunocyte is provided, the method includes：It is anti-
PCSK9 inhibitor handles immunocyte；Or with PCSK9 inhibitor and PD-1 inhibitor Combined Treatment immunocytes.
In a preference, the method is nondiagnostic and non-therapeutic method.For example, the method is
A kind of in vitro method.
The other aspects of the present invention are apparent to those skilled in the art due to this disclosure
's.
Description of the drawings
Fig. 1, control group, the tumor growth curve of PCSK9 antibody group B16 mouse melanoma cell line F10 lotus knurls.
Fig. 2, control group, the representative picture of the subcutaneous lotus knurls of PCSK9 antibody group B16 mouse melanoma cell line F10.
Fig. 3, control group, PCSK9 antibody group murine hepatocarcinoma cells Hepa1-6, lung carcinoma cell LLC, prostate gland cancer cell RM-
The representative picture of 1 subcutaneous lotus knurl.
Fig. 4, control group (PBS), PCSK9 micromolecular inhibitors group (SBC-110738) organize B16 mouse melanoma cell line
The representative picture of subcutaneous lotus knurl.
Fig. 5, control group, PCSK9 antibody group mouse blood cholesterol indexs of correlation.
Fig. 6, control group, PCSK9 antibody group mouse tumor tissues, each immunocyte marker expression amount detection figure.
Fig. 7, control group, the tumor-infiltrated NK cells of PCSK9 antibody groups and CD8+The cholesterol level detection figure of T cell.
Fig. 8, control group, the tumor-infiltrated NK cells of PCSK9 antibody groups and CD8+The detection knot of T cell activation related gene
Fruit, wherein Fig. 8 A are NK cell activation related genes, and Fig. 8 B are CD8+T cell activation related gene.
Fig. 9, control group, PD-1 antibody groups, the mouse-borne tumor growth curve of PCSK9 antibody+PD-1 antibody combination groups, wherein
Fig. 9 A are the growth curves of melanin tumour b16, and Fig. 9 B are the swollen of lung carcinoma cell LLC (i.e. Lewis lung carcinoma cells are purchased from the Chinese Academy of Sciences)
Tumor growth curve.
Figure 10, control group, PD-1 antibody groups, the mouse subcutaneous tumor representative diagram of PCSK9 antibody+PD-1 antibody combination groups
Piece.Wherein Figure 10 A are melanoma representativeness pictures, and Figure 10 B are lung carcinoma cell LLC representativeness pictures.
Figure 11, control group, PD-1 antibody groups, in PCSK9 antibody+PD-1 antibody combination group subcutaneous tumors, with streaming method
Detect NK cells and CD8+The Infiltrating of T cell.
Figure 12, control group, PD-1 antibody groups, in PCSK9 antibody+PD-1 antibody combination groups, tumor-infiltrated NK cells and
CD8+The testing result of T cell activation related gene.Wherein Figure 12 A are NK cell activation related gene testing results, and Figure 12 B are
CD8+T cell activation related gene testing result.
Specific implementation mode
After extensive and in-depth study, disclosing PCSK9 inhibitor (such as antibody) for the first time can effectively press down the present inventor
Tumour processed.The PCSK9 inhibitor enhances the work of immunocyte by the expression of raising activated immune cell related gene
Property, to inhibit tumour.Present invention further teaches use in conjunction PCSK9 inhibitor and PD-1 inhibitor (such as antibody) further
Remarkable effect in terms of improving immunologic cellular activity and inhibiting tumour.
As used herein, " tumour " is to be identified by immunocyte " tumour "." tumour " this term wraps
Solid tumor has been included, and has included non-physical knurl；E.g., including but be not limited to：Melanoma, lung cancer, leukaemia, liver cancer, gastric cancer,
The cancer of the esophagus, cholangiocarcinoma, gallbladder cancer, colorectal cancer, prostate cancer, breast cancer.
As used herein, " immunocyte " includes：T cell, NK cells, NKT cells, regulatory T cells
(Regulatory cell, abbreviation Treg).
PCSK9 inhibitor
PCSK9 is a kind of liver source property secretory protein synthesized by liver cell, synthesizes PCSK9 proenzymes in endoplasmic reticulum first,
Self catalysis reaction occurs in it in endoplasmic reticulum or golgiosome, and cracking releases propetide, forms ripe protease, exist side by side
It is secreted into blood, it is combined with the extracellular region of the low-density lipoprotein receptor (LDLR) of cell surface, mediates the internalization and drop of LDLR
Solution, to inhibit the intake of liver cell and peripheral cells to low density lipoprotein cholesterol (LDL-C), the LDL- in elevating blood
C and total cholesterol level.Studies have shown that PCSK9 levels and cholesterol, ox-LDL, triglycerides etc. are significantly correlated.It can not only
The level for influencing plasma cholesterol, adjusts the apoptosis of nerve cell, also there is certain correlation with inflammatory reaction.Currently, about
The norcholesterol effect of anti-PCSK9 antibody drugs has had experiment and clinical research, and adjusts immune cell function about it
And antitumor action has not been reported.
As used herein, " the PCSK9 inhibitor " include nucleic acid inhibitor, antagonist, lower adjustment, retarding agent,
Blocking agent etc., as long as they can descend the expression of PCSK9, inhibit the activity or function of PCSK9.They can be chemical combination
Object, chemical small molecule, biomolecule.The biomolecule can be nucleic acid level (including DNA, RNA), can also be egg
White level.
The PCSK9 inhibitor refers to any activity for reducing PCSK9, the stability for reducing PCSK9, lowers
The expression of PCSK9, the substance for reducing PCSK9 effective acting times, these substances are used equally for the present invention, as lowering
Substance useful PCSK9, so as to be used to inhibit tumour.For example, the lower adjustment is：Nucleic acid inhibitor, protein inhibitor,
Antibody, ligand, compound, nuclease, nucleic acid binding molecule etc., if its can lower the expression of PCSK9, inhibit its activity or
Function.The nucleic acid inhibitor includes but not limited to：It is inhibition or the interference of silence target with PCSK9 genes or its transcript
Molecule such as shRNA, antisense nucleic acid, siRNA, Microrna, or can express or be formed the shRNA are antisense nucleic acid, small dry
Disturb the construction of RNA, Microrna.
The PCSK9 inhibitor, which can also be, inhibits some active small-molecule substances of PCSK9, such as small molecule chemical combination
Object.Some of this field inhibit the active small molecules of PCSK9 that can be applied in the present invention, for inhibiting tumour or enhancing to exempt from
Epidemic disease cell activity.As the preferred embodiment of the present invention, described described PCSK9 inhibitor such as SBC-110736, the SBC-
115076, R-IMPP (being purchased from MCE companies).
In addition, there are also some gene editing means, can directionally be inhibited by the gene editing of orientation or under
It adjusts the expression of gene, this means and reagent that can also be applied in the present invention, prepares PCSK9 inhibitor.
As the preferred embodiment of the present invention, the PCSK9 inhibitor is anti-PCSK9 antibody.
It can be monoclonal antibody or polyclonal antibody that the specificity, which inhibits the antibody of PCSK9,.PCSK9 albumen can be used
Immune animal, such as rabbit mouse, the polyclonal antibody of the productions such as rat；A variety of adjuvants can be used for enhancing immune response, including but
It is not limited to Freund's adjuvant etc..Similar, it expresses PCSK9 or its cell with antigenic segment can be used to immune animal
To produce antibody.The antibody can also be monoclonal antibody, and such monoclonal antibody can be made using hybridoma technology
It is standby.
PD-1 inhibitor
As used herein, " the PD-1 inhibitor " includes nucleic acid inhibitor, antagonist, lower adjustment, retarding agent, resistance
Disconnected agent etc., as long as they can descend the expression of PD-1, inhibit the activity or function of PD-1.They can be compounds, change
Learn small molecule, biomolecule.The biomolecule can be nucleic acid level (including DNA, RNA), can also be albumen water
Flat.
The PD-1 inhibitor refers to any activity for reducing PD-1, the stability for reducing PD-1, lowers PD-1
Expression, the substance for reducing PD-1 effective acting times, these substances are used equally for the present invention, as useful for lowering PD-1
Substance, so as to be used to inhibit tumour.For example, the lower adjustment is：Nucleic acid inhibitor, protein inhibitor, antibody, ligand,
Compound, nuclease, nucleic acid binding molecule etc., as long as it can lower the expression of PD-1, inhibit its activity or function.Described
Nucleic acid inhibitor includes but not limited to：With PD-1 genes or its transcript be inhibit or silence target disturbing molecule such as shRNA,
Antisense nucleic acid, siRNA, Microrna, or the shRNA can be expressed or be formed, antisense nucleic acid, siRNA, Microrna
Construction.
In addition, there are also some gene editing means, can directionally be inhibited by the gene editing of orientation or under
It adjusts the expression of gene, this means and reagent that can also be applied in the present invention, prepares PD-1 inhibitor.
As the preferred embodiment of the present invention, the PD-1 inhibitor is anti-PD-1 antibody.
It can be monoclonal antibody or polyclonal antibody that the specificity, which inhibits the antibody of PD-1,.It can be exempted from PD-1 albumen
Epidemic disease animal, such as rabbit mouse, the polyclonal antibody of the productions such as rat；A variety of adjuvants can be used for enhancing immune response, including but not
It is limited to Freund's adjuvant etc..Similar, it expresses PD-1 or its cell with antigenic segment can be used to immune animal and come
Produce antibody.The antibody can also be monoclonal antibody, and such monoclonal antibody can be prepared using hybridoma technology.
Using
In the preferred embodiment, the present inventor using PCSK9 antibody as separate constituent in mouse tumor lotus
It is tested in tumor model.By the way that the K-1735 and lung cancer cell line in mouse source is subcutaneously injected, establish small
Mouse lotus knurl model observes the Survival of the growing state and mouse of mouse subcutaneous tumor, finds control group Subcutaneous Tumor Growth
Rapidly, PCSK9 Antybody therapy mice tumors grews are given obviously to slow down.The total courage of mouse blood is found by being detected to mouse blood
Sterol levels reduce, and low-density lipoprotein cholesterol level also decreases, and are found by carrying out PCR detections to tumor tissues
CD8+T cell and NK cellular infiltrations increase, and sorting immunocyte by magnetic bead sorting method finds that its cholesterol level increases, and resists
Tumor promotion obviously increases.And by the way that PCSK9 antibody and PD1 antibody to be combined, treatment tumor-bearing mice is found, combined treatment is to swollen
Tumor growth inhibiting effect better than merely apply PD1 antibody, flow cytometer detection find combination therapy can further improve NK cells and
CD8+The infiltration of T cell, PCR detections find NK cells and CD8+The secretion of the antitumor type cytokines of T cell also obviously increases.
Above-mentioned new discovery based on the present inventor, the present invention provides the purposes of PCSK9 inhibitor, and it is swollen to be used to prepare inhibition
Tumor or the drug for enhancing immunologic cellular activity.The PCSK9 inhibitor or the PCSK9 inhibitor and PD-1 inhibitor
By increasing the expression of activated immune cell related gene, enhance the activity of the inhibition tumour of immunocyte, to inhibit tumour；
Preferably, the activated immune cell related gene includes：GZMB, IFN γ, TNF α, NOS2, NCR1, PRF, IL15,
CCL3, CXCL10, CD8, NK1.1, FOXP3.
Further, the present invention also provides PCSK9 inhibitor and PD-1 inhibitor as pharmaceutical composition, presses down preparing
Application in the drug of tumour processed or enhancing immunologic cellular activity.
Pharmaceutical composition and medicine box
The present invention also provides a kind of pharmaceutical compositions, it contains effective quantity (such as 0.000001-50wt%；Preferably
0.00001-20wt%；More preferably, 0.0001-10wt%) the PCSK9 inhibitor and pharmaceutically acceptable load
Body.
PCSK9 inhibitor of the present invention can be used as separate constituent and prepare antitumor drug, be alternatively arranged as separate constituent
Combine the complex treatment for tumour with PD1 inhibitor.It is thus preferable to further include effective quantity in the pharmaceutical composition
(such as 0.000001-50wt%；Preferable 0.00001-20wt%；More preferably, 0.0001-10wt%) described in PD-1 inhibit
Agent.The pharmaceutical composition can be used for inhibiting tumour.
As used herein, described " effective quantity " refer to people and/or animal can be generated function or it is active and can by people and/
Or the amount that animal is received.
As used herein, described " pharmaceutically acceptable carrier " refers to the carrier for Therapeutic Administration, including various taxes
Shape agent and diluent.The term refers to some such medicament carriers：It themselves is not necessary active constituent, and is not had after applying
There is excessive toxicity.
Suitable carrier is well known to those of ordinary skill in the art.The acceptable load in pharmaceutical composition Chinese pharmacology
Body can contain liquid, such as water, brine, buffer solution.In addition, there is likely to be complementary substance in these carriers, as filler,
Lubricant, glidant, wetting agent or emulsifier, pH buffer substance etc..Lipofectamine can also be contained in the carrier.
After the purposes for knowing the PCSK9 inhibitor, a variety of methods well known in the art may be used will be described
PCSK9 inhibitor or its pharmaceutical composition deliver medicine to mammal；Preferably, go back while giving the PD-1 inhibitor.
The mode of administration includes but not limited to：Hypodermic injection, intramuscular injection, for percutaneous administration of, administer locally to, be implanted into, be sustained and give；It is excellent
Choosing, the administering mode is that non-bowel is given.
PCSK9 inhibitor and/or PD-1 inhibitor of the present invention, or the pharmaceutical composition containing the inhibitor ingredient
The effective quantity of object can change with the pattern of administration and the severity of disease to be treated etc..Preferred a effective amount of selection can
To be determined (such as passing through clinical test) depending on various factors by those of ordinary skill in the art.The factor includes but not
It is limited to：The pharmacokinetic parameter such as bioavailability of the PCSK9 inhibitor and/or PD-1 inhibitor, partly declines at metabolism
Phase etc.；Patient the severity of disease to be treated, the weight of patient, the immune state of patient, administration approach etc..
The present invention also provides containing the pharmaceutical composition or directly contain the PCSK9 inhibitor and/or PD-
The medicine box of 1 inhibitor.In addition, may also include in the medicine box selected from the group below one or more：Tumor chemotherapeutic drug, tumour
Radiotherapeutic drug, and illustrate the specification of the application method of drug in medicine box.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part such as J. Pehanorm Brookers etc. is write, Molecular Cloning:A Laboratory guide, the third edition, Science Press, the condition described in 2002, or
According to the normal condition proposed by manufacturer.
The primed probe such as table 1 of genetic test is carried out for qPCR.
Table 1
Embodiment 1：The foundation of mouse tumor lotus knurl model
First, in PCSK9 antibody (being purchased from BPS Bioscience companies) group mouse-borne tumor experiment, 6~8 week old of selection,
Male C 57 BL/6 J mouse 20, using every inoculation 2 × 10 of injected s.c.6A melanin tumour b16 F10 cells, liver cancer
Cell Hepa1-6, lung carcinoma cell LLC, prostate gland cancer cell RM-1 (being purchased from the Chinese Academy of Sciences), observe tumor formation situation after 8 days.It chooses swollen
Mouse 16 similar in tumor size divide them into control group (8), PCSK9 antibody groups (8) immediately.
Secondly, in the experiment of PCSK9 antibody group mouse-borne tumors, 6~8 week old, male C 57 BL/6 J mouse 30 is chosen, is used
Every inoculation 2 × 10 of injected s.c.6A melanin tumour b16 F10 cells or lung carcinoma cell LLC observe tumor formation feelings after 8 days
Condition.Choose tumor size similar in mouse 24, divide them into immediately control group (8), PD-1 antibody groups (8) and
PCSK9 antibody+PD-1 antibody (being purchased from Bio X Cell companies) combination group (8).
Embodiment 2：Influence of the PCSK9 inhibitor for mice tumors grew
1, influence of the PCSK9 antibody for mice tumors grew
After mice group, control group mice gives Isotype control IgG, experimental mice gives PCSK9 antibody and (is dissolved in physiology
Brine), 10mg/Kg is primary every 3 days, intraperitoneal injection, or gives PD-1 antibody, each every 200 μ g (about 10mg/Kg), often
It is primary every 3 days, intraperitoneal injection or the two combination.Each group mouse subcutaneous tumor size is measured after administration weekly, calculates tumour body
Product (gross tumor volume=tumour major diameter × tumour minor axis2/2).Maximum mouse tumor volume reaches 2cm3When left and right, it is small to put to death each group
Mouse takes out subcutaneous tumor and draws tumor growth curve.
Such as Fig. 1, shown in 2,3, control group mice Subcutaneous Tumor Growth is rapider, and volume significantly increases.Give PCSK9 antibody
Experimental group, mouse Subcutaneous Tumor Growth speed obviously slows down, and volume is obviously reduced.It is above-mentioned it is experimentally confirmed that injection PCSK9 antibody
The growth of kinds of tumor cells in Mice Body can obviously be inhibited.
Such as Fig. 9, shown in 10, after transplanting melanoma (Fig. 9 A, 10A) or lung carcinoma cell (Fig. 9 B, 10B), control group is small
Mouse Subcutaneous Tumor Growth is rapider, and volume significantly increases.After giving PD-1 antibody, mouse Subcutaneous Tumor Growth speed slows down, body
Product reduces；After PD-1 antibody and PCSK9 antibody is given in combination, mouse Subcutaneous Tumor Growth speed further slows down, and volume is into one
Step reduces.
It is above-mentioned it is experimentally confirmed that PCSK9 antibody can be cooperateed with PD-1 antibody is used for antineoplaston.
2, influence of the PCSK9 micromolecular inhibitors for mice tumors grew
After mice group, control group mice gives PBS, experimental mice gives PCSK9 micromolecular inhibitors SBC-
110736 (being dissolved in PBS), 8mg/Kg, once a day, intraperitoneal injection.Mouse subcutaneous tumor size is observed after administration weekly, it is maximum
Mouse tumor volume reaches 2cm3When left and right, each group mouse is put to death, takes out subcutaneous tumor.
The results are shown in Figure 4, and control group mice subcutaneous tumor volumes are significantly greater than and give PCSK9 micromolecular inhibitor groups.
The above results confirm, give the growth that the processing of PCSK9 micromolecular inhibitors can obviously inhibit interior tumor cell.
Embodiment 3：Mouse blood cholesterol index of correlation detects
Each group mouse with anticoagulant tube collects blood before putting to death, and supernatant is taken to carry out blood total cholesterol content, low close after centrifugation
Spend lipoprotein cholesterol content detection.
As shown in figure 5, giving PCSK9 antibody injection mouse, blood total cholesterol content and low-density lipoprotein courage
Sterol content is substantially reduced, and triglycerides and high-density lipoprotein cholesterol be without significant change, the medicinal effect with PCSK9 antibody
Fruit is consistent.
Embodiment 4：Mouse-borne tumor tissue coherent detection
Each group mouse collects lotus knurl tissue after putting to death, carrying out reverse transcription after extracting RNA obtains cDNA, is examined by the method for qPCR
Survey the expression of each immunocyte marker (CD4, CD8, NK1.1, CD19, CD209, CD68, FOXP3) in lotus knurl tissue.
As shown in fig. 6, giving PCSK9 antibody injection mouse, the expression of CD8 and NK1.1 is apparent in lotus knurl tissue
It increases, shows CD8 in tumor tissues+The infiltration of T cell and NK cells increased.
Embodiment 5：Mouse tumor infiltrates NK and CD8+T cell coherent detections
After mouse is put to death, for tumor tissues by the isolated single cell suspension of collagenase digestion procedure, a part of suspension is logical
Overflow-type colouring method detect tissue in immunocyte ratio, remaining cell by magnetic bead sorting method obtain NK cells and
CD8+T cell.The cholesterol levels in two kinds of immunocytes, and extracting RNA reverse transcription are detected by cholesterin detection reagent box
CDNA, by qPCR methods detect activation related gene (GZMB, IFN γ, TNF α, NOS2, NCR1, NRG2D, PRF, IL15,
CCL3, CXCL10) expression.
As shown in fig. 7, after giving the injection of mouse PCSK9 antibody, tumor-infiltrated NK and CD8+T cell cholesterol levels have
Conspicuousness increases, and illustrates that PCSK9 antibody drugs have positive effect for increasing immunocyte cholesterol levels.
As shown in figure 8, wherein Fig. 8 A are NK cell activation related genes, Fig. 8 B are CD8+T cell activation related gene.It can
See, tumor-infiltrated NK and CD8+The expression of T cell activation related gene is significantly increased in PCSK9 groups, illustrates the anti-of immunocyte
Tumor promotion is also increased.
NK cells and CD8 are detected with streaming method+The Infiltrating of T cell compares control group, PD- as shown in figure 11
1 antibody group, the tumor-infiltrated NK and CD8 of PCSK9 antibody+PD-1 antibody combination groups+The ratio of T cell is significantly raised, combination group
NK cell proportion ratio PD-1 antibody groups have further up, and CD8+T cell ratio and no significant difference.
In activation related gene context of detection, such as Figure 12 A-B, PD-1 antibody groups, PCSK9 antibody+PD-1 antibody combination groups
Tumor-infiltrated NK and CD8+T cell activity comparison control group is increased significantly.And combination group IFN γ, Perforin (i.e.
PRF), GZMB expression, which increases, becomes apparent, and illustrates that PCSK9 antibody can realize further synergistic effect with the combination of PD-1 antibody,
Further increase NK cells and CD8+The activity of T cell.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Sequence table
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Claims (10)
1.PCSK9 inhibitor is preparing the application in inhibiting tumour or enhancing the drug of immunologic cellular activity.
2.PCSK9 inhibitor and PD-1 inhibitor answering in preparing the drug for inhibiting tumour or enhancing immunologic cellular activity
With.
3. purposes as claimed in claim 1 or 2, which is characterized in that the tumour is the tumour that can be identified by immunocyte；
Preferably, the tumour includes：Leukaemia, lymthoma, melanoma, lung cancer, liver cancer, prostate cancer, colorectal cancer, stomach
Cancer, the cancer of the esophagus, cholangiocarcinoma, gallbladder cancer etc..
4. purposes as claimed in claim 1 or 2, which is characterized in that the PCSK9 inhibitor or the PCSK9 inhibit
Agent and PD-1 inhibitor enhance the work of the inhibition tumour of immunocyte by the expression of raising activated immune cell related gene
Property, to inhibit tumour；Preferably, the activated immune cell related gene includes：GZMB, IFN γ, TNF α, NOS2,
NCR1, PRF, IL15, CCL3, CXCL10, CD8, NK1.1, FOXP3.
5. purposes as claimed in claim 3, which is characterized in that the immunocyte includes：NK cells, T cell.
6. purposes as claimed in claim 1 or 2, which is characterized in that the PCSK9 inhibitor includes：Anti- PCSK9 antibody；
Interfere the disturbing molecule of PCSK9 gene expressions；The gene editing or gene silencing agent of specific downregulation PCSK9；Or PCSK9 is small
Molecule inhibitor is purchased from MCE companies such as SBC-110736, SBC-115076, R-IMPP；Or
The PD-1 inhibitor includes：Anti- PD-1 antibody interferes the disturbing molecule of PD-1 gene expressions, specific downregulation PD-1
Gene editing or gene silencing agent.
7. a kind of for inhibiting the pharmaceutical composition of tumour, which is characterized in that described pharmaceutical composition includes：PCSK9 inhibitor
And PD-1 inhibitor.
8. a kind of medicine box for inhibiting tumour, which is characterized in that press down containing PCSK9 inhibitor and PD-1 in the medicine box
Preparation；Or
Contain the pharmaceutical composition described in claim 7 in the medicine box.
9. pharmaceutical composition as claimed in claim 7 or medicine box according to any one of claims 8, which is characterized in that the PCSK9
Inhibitor includes：Anti- PCSK9 antibody interferes the disturbing molecule of PCSK9 gene expressions, the gene editing of specific downregulation PCSK9
Or gene silencing agent；Or PCSK9 micromolecular inhibitors, it is public purchased from MCE such as SBC-110736, SBC-115076, R-IMPP
Department；Or
The PD-1 inhibitor includes：Anti- PD-1 antibody interferes the disturbing molecule of PD-1 gene expressions, specific downregulation PD-1
Gene editing or gene silencing agent.
10. a kind of active method of enhancing immunocyte, which is characterized in that the method includes：Anti- PCSK9 inhibitor processing
Immunocyte；Or with PCSK9 inhibitor and PD-1 inhibitor Combined Treatment immunocytes.
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| CN109776680A (en) * | 2019-01-25 | 2019-05-21 | 浙江蓝盾药业有限公司 | Anti-human PCSK9 monoclonal antibody and application thereof |
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| ES2794149A1 (en) * | 2019-05-16 | 2020-11-17 | Fundacion Para La Investig E Innovacion Biosanitaria Principado De Asturias | PCSK9 INHIBITORS FOR THE PREVENTION AND/OR TREATMENT OF CANCER (Machine-translation by Google Translate, not legally binding) |
| CN112638372A (en) * | 2018-06-25 | 2021-04-09 | 杜克大学 | Compositions and methods for treating cancers characterized by PCSK9 expression |
| CN112831469A (en) * | 2019-11-25 | 2021-05-25 | 上海交通大学医学院 | Modulating the amount of CS in the microenvironment of T cells and uses thereof |
| CN113663075A (en) * | 2021-09-14 | 2021-11-19 | 清华大学深圳国际研究生院 | Application of PCSK9 inhibitor in preparation of medicine for treating or assisting in treating tumors |
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| EP3705497A4 (en) * | 2019-01-25 | 2021-02-24 | Zhejiang Blue Shield Pharmaceutical Co., Ltd. | Anti-human pcsk9 monoclonal antibody and use thereof |
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