CN116747311A - Application of PPAR delta antagonist combined with SIRP alpha antibody medicament in preparation of tumor immunotherapy medicament - Google Patents
Application of PPAR delta antagonist combined with SIRP alpha antibody medicament in preparation of tumor immunotherapy medicament Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides an application of PPAR delta antagonist combined SIRP alpha antibody medicine in preparing tumor immunotherapy medicine, belonging to the technical field of biological medicine and tumor immunotherapy; according to the invention, a large number of experiments prove that the PPAR delta antagonist can obviously reduce the level of CD47 protein and inhibit the gene expression of CD47, so that the tumor immunotherapy effect of SIRP alpha antibody can be increased when SIRP alpha antibody medicines are jointly applied, and the tumor growth is better inhibited; compared with single SIRP alpha antibody treatment, the PPAR delta antagonist combined SIRP alpha antibody disclosed by the invention can obviously inhibit the growth level of tumors in mice, and is obviously higher than that of a single conventional antibody drug, so that the PPAR delta antagonist combined SIRP alpha antibody drug has obvious effect on the aspect of tumor immunotherapy effect and has good practical value.
Description
Technical Field
The invention belongs to the technical field of biological medicine and tumor immunotherapy, and in particular relates to application of a PPAR delta antagonist combined with a SIRP alpha antibody medicament in preparation of a tumor immunotherapy medicament.
Background
Cancer has become the main death disease at present, and radiotherapy, chemotherapy and surgical excision are mainly adopted in the cancer treatment at present, but the treatment methods have the limitations of drug resistance of patients, easy recurrence and the like. Numerous research has shown that cancer genesis is associated with reduced function of the body's autoimmune system, and cancer immunotherapy has become increasingly significant in recent years and is the fourth mainstay of current cancer therapies. Although immunotherapy has a higher efficacy than traditional therapies, it still has certain drawbacks, such as antibody drugs (e.g., PD-1) approved by the united states Food and Drug Administration (FDA) and acting at immune checkpoints (immune checkpoint) are effective in treating more than 25 types of cancer, but less than 40% of cancer patients do not respond to the antibody drugs.
The host immune system is able to kill tumor cells and resist tumor formation by innate or adaptive immunity. The surface of tumor cells expresses CD47 protein, which is the binding of macrophage sirpa receptor, thereby inhibiting phagocytosis of tumor cells by macrophages. CD47 is therefore a key signaling protein in the innate immune system that is "don't eat me". A number of clinical studies have shown that overexpression of CD47 inhibits immunotherapy or enhances tumor immune escape.
As one of the nuclear receptor protein members, peroxisome proliferator-activated receptor δ (pparδ) plays an important role in regulating metabolism, tumorigenesis, inflammation, and the like. In most tissues, pparδ protein is widely expressed. Although studies have demonstrated that pparδ antagonists can inhibit pparδ -mediated tumor growth, it is currently unclear what role pparδ antagonists have in sirpa antibody-mediated tumor immunotherapy. Thus, there is a need to obtain a new tumor immunotherapeutic agent by studying the relevant mechanisms of the combined use of pparδ antagonists and sirpa antibodies.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides an application of a PPAR delta antagonist combined with SIRP alpha antibody medicament in preparing tumor immunotherapy medicaments; according to the invention, a large number of experiments prove that the PPAR delta antagonist can obviously reduce the level of CD47 protein and inhibit the gene expression of CD47, so that the tumor immunotherapy effect of SIRP alpha antibody can be increased when SIRP alpha antibody medicines are jointly applied, and the tumor growth is better inhibited; compared with single SIRP alpha antibody treatment, the PPAR delta antagonist combined SIRP alpha antibody disclosed by the invention can obviously inhibit the growth level of tumors in mice, and is obviously higher than that of a single conventional antibody drug, so that the PPAR delta antagonist combined SIRP alpha antibody drug has obvious effect on the aspect of tumor immunotherapy effect and has good practical value.
In order to achieve the technical purpose, the invention adopts the following technical means:
the invention firstly provides application of PPAR delta antagonist combined SIRP alpha antibody medicine in preparing tumor immunotherapy medicine.
Preferably, in said use, the pparδ antagonist modulates the level of CD47 protein.
Preferably, the modulation is inhibition of expression of CD47 protein.
Preferably, the pparδ antagonist comprises GSK0660.
Preferably, the sirpa antibody drug comprises an anti-human sirpa monoclonal antibody.
Preferably, the tumor comprises colon cancer.
The invention also provides a pharmaceutical composition for treating tumors, wherein the active ingredients of the pharmaceutical composition comprise a PPAR delta antagonist and a SIRP alpha antibody drug.
Preferably, the pparδ antagonist comprises GSK0660.
Preferably, the sirpa antibody drug comprises an anti-human sirpa monoclonal antibody.
The invention also provides the use of a pparδ antagonist in the manufacture of a medicament for modulating the level of a gene encoding a CD47 protein and/or CD47 protein.
Preferably, the modulation is inhibition of expression of a gene encoding a CD47 protein and/or a CD47 protein.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a new application of PPAR delta antagonist combined SIRP alpha antibody medicine in tumor immunotherapy medicine. A large number of experiments prove that the PPAR delta antagonist can obviously reduce the level of CD47 protein and inhibit the gene expression of CD47, so that the tumor immunotherapy effect of SIRP alpha antibody can be improved and the tumor growth can be better inhibited when SIRP alpha antibody medicaments are jointly applied. Compared with single SIRPalpha antibody treatment, the PPARdelta antagonist combined SIRPalpha antibody disclosed by the invention can obviously inhibit the growth of tumors in mice, and is obviously higher than that of the single SIRPalpha antibody treatment. Has remarkable effect on the tumor immunotherapy effect.
Drawings
FIG. 1 shows the result of Western blot analysis of CD47 protein by PPARdelta antagonists; in the figure, (A) is HCT-116 cells and (B) is CT-26 cells.
FIG. 2 shows the results of flow cytometry analysis of CD47 protein by PPARdelta antagonists.
FIG. 3 is a graph showing the results of qPCR analysis of gene expression levels of CD47 by PPARdelta antagonists.
FIG. 4 is the effect of PPARdelta antagonists in combination with SIRPalpha antibodies on tumor growth; in the figure, a is a tumor volume map; b is the result of Western blot analysis of the expression level of CD47 protein in tumor tissues, wherein Tubulin is an internal reference protein.
Detailed Description
The invention will be further described with reference to the drawings and the specific embodiments, but the scope of the invention is not limited thereto. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
It is further intended that the invention be limited to the specific form disclosed as the best mode contemplated for carrying out this invention, but that the invention will include the generic and specific form herein defined by the terms and phrases used herein. The term "antagonist" refers to a substance that inhibits pparδ transcriptional activity.
The present invention generally and/or specifically describes the materials used in the test as well as the test methods. Although many materials and methods of operation are known in the art for accomplishing the objectives of the present invention, the present invention will be described in as much detail herein. It will be clear to those skilled in the art that hereinafter, unless otherwise indicated, the materials and methods of operation used in the present invention are well known in the art.
Experimental reagent:
HCT-116, CT-26 colon cancer cell lines were purchased from the Shanghai cell Bank of the national academy of sciences and PPAR delta antagonist GSK0660 was purchased from CSNpharm (China); 0.25% pancreatin was purchased from Gibco company (containing EDTA). The Actin, CD47, pparδ antibodies were purchased from wuhan eagle corporation. Fetal bovine serum Fetal Bovine Serum (FBS) and DMEM complete media are all drugs commonly used by those skilled in the art, and methods of formulation and use are well known in the art. Total RNA extraction kits were purchased from Shanghai, and qPCR reaction kits were purchased from TaKaRa.
The sequences of the CD47 and beta-actin primers used in the invention are as follows:
the upstream primer sequence of the CD47 is shown as SEQ ID NO. 1, namely: GTTGGAGCCATTCTTTTCGTCCC, the sequence of the downstream primer is shown as SEQ ID NO. 2, namely: ATACACGCCGCAATACAGAGACT; the upstream primer sequence of the beta-actin is shown as SEQ ID NO. 3, namely: GGTGGGCATGGGTCAGAAGGAT, the sequence of the downstream primer is shown as SEQ ID NO. 4, namely: GCCACACGCAGCTCATTGTAGAAG.
Example 1: pparδ antagonists reduce CD47 protein levels
The effect of pparδ antagonist GSK0660 on CD47 protein levels was demonstrated in this example, with the following procedure:
HCT-116, CT26 cells were routinely cultured in DMEM complete medium containing 10% Fetal Bovine Serum (FBS), and when microscopic examination reached 80% confluence, they were digested with 0.25% pancreatin, inoculated in 6-well plates, and placed at 37 ℃ in 5% co 2 When the density of the cells in the incubator is 70% -90% of that of the cells, the cells are treated for 12 hours respectively by taking dimethyl sulfoxide (DMSO) as a control group and GSK0660 as an experimental group. Performing cell lysis and Western blot analysis on the treated cellsCD47 protein expression and analysis results are shown in figure 1.
FIG. 1 is a Western blot analysis of PPARdelta antagonists versus CD47 protein; in the figure, (A) is HCT-116 cells and (B) is CT-26 cells. Wherein pparδ is an endogenous pparδ protein; tubulin is an internal reference protein. As can be seen from FIG. 1, PPARdelta antagonist GSK0660 has an inhibitory effect on the expression of CD47 protein in HCT-116 cells and CT-26 cells.
In this example, the cells after 12 hours of treatment were collected and centrifuged at 2X10 5 Cells were incubated with fluorescence-labeled CD47 antibody for 30 minutes at room temperature, washed several times with PBS, and analyzed by flow cytometry for the effect of pparδ antagonist GSK0660 on the expression level of CD47 membrane protein, the analysis results are shown in fig. 2.
FIG. 2 is a flow cytometry analysis of the CD47 protein by PPARdelta antagonists; results are expressed as mean ± SEM (n=3), P <0.05. As shown in fig. 2, the fluorescence intensity of pparδ antagonist GSK0660 (5 μm) was significantly reduced compared to control DMSO, indicating that pparδ antagonists significantly reduced CD47 protein levels in HCT-116 and CT-26 cells.
Example 2: inhibition of CD47 gene expression by ppardelta antagonists
The effect of pparδ antagonist GSK0660 on CD47 gene expression was verified in this example, and the specific procedure is as follows:
HCT-116, ct-26 cells were routinely cultured in DMEM complete medium containing 10% Fetal Bovine Serum (FBS), and when microscopic examination reached 80% confluence, digested with 0.25% pancreatin, the cells were seeded in 6-well plates and placed at 37 ℃ in 5% co 2 Cell treatments were performed in the incubator overnight and at a density of 70% -90% of the wells, with DMSO as control and GSK0660 (5 μm) as experimental group. After 12h of cell treatment, the cells were lysed and CD47 gene expression was analyzed by qPCR using CD47 and beta-actin primers shown in SEQ ID NO. 1-SEQ ID NO. 4.
FIG. 3 is a graph of PPARdelta antagonists versus CD47 gene expression analysis; results are expressed as mean ± SEM (n=3), P <0.05. As shown in FIG. 3, PPARdelta antagonist GSK0660 (5. Mu.M) significantly reduced CD47 gene levels in HCT-116 and CT-26 cells compared to control DMSO.
Example 3: significant inhibition of tumor growth by pparδ antagonists in combination with sirpa antibodies
The effect of pparδ antagonist GSK0660 in combination with sirpa antibodies on tumor growth was demonstrated in this example, and the specific procedure is as follows:
CT-26 cells (2X 10) 5 ) Inoculated subcutaneously into BALB/c mice (experimental animal center of Jiangsu university), and the inoculated mice were randomly divided into four groups: igG group (control group), sirpa antibody group, GSK0660 group, and sirpa antibody+gsk 0660 group.
Wherein, igG group (control group): after the mice are inoculated with tumor cells subcutaneously for one week, igG is injected subcutaneously every day with an injection amount of 100 μg/mouse;
sirpa antibody group: after the mice are inoculated with tumor cells subcutaneously for one week, SIRPalpha is injected subcutaneously every day with the injection amount of 100 mug/mouse;
GSK0660 group: after the mice are inoculated with tumor cells subcutaneously for one week, the mice are irrigated with GSK0660 daily with the dosage of 2mg/kg/day;
sirpa antibody+gsk 0660 group: after the mice are inoculated with tumor cells subcutaneously for one week, SIRPalpha is injected subcutaneously every day with the injection amount of 100 mug/mouse; and, the administration amount of GSK0660 is 2mg/kg/day by lavage every day.
Tumor volumes were measured weekly for 4 weeks and mice were sacrificed by cervical scission. Tumor volume calculation formula = 1/2 (length x width 2 ). And analyzing the expression level of CD47 protein in tumor tissue lysates by using Western blot, wherein Tubulin is an internal reference protein, and the investigation result is shown in FIG. 4.
FIG. 4 is a graph showing the effect of PPARdelta antagonists in combination with SIRPalpha antibodies on tumor growth; in the figure, a is a tumor volume map; b is a Western blot analysis tumor tissue CD47 protein expression level diagram, wherein Tubulin is an internal reference protein. As can be seen from fig. 4, the pparδ antagonist GSK0660 in combination with the antibody drug sirpa can significantly inhibit tumor growth, which is associated with reduced CD47 protein expression in tumor tissue.
In conclusion, a large number of experiments prove that the PPAR delta antagonist can obviously reduce the level of CD47 protein and inhibit the gene expression of CD47, so that the effect of tumor immunotherapy of SIRP alpha antibody can be improved and the tumor growth can be better inhibited when SIRP alpha antibody medicines are jointly applied; compared with single SIRP alpha antibody treatment, the PPAR delta antagonist combined SIRP alpha antibody disclosed by the invention can obviously inhibit the growth level of tumors in mice, and is obviously higher than that of a single conventional antibody drug, so that the PPAR delta antagonist combined SIRP alpha antibody drug has obvious effect on the aspect of tumor immunotherapy effect and has good practical value.
The examples are preferred embodiments of the present invention, but the present invention is not limited to the above-described embodiments, and any obvious modifications, substitutions or variations that can be made by one skilled in the art without departing from the spirit of the present invention are within the scope of the present invention.
Claims (10)
- Application of PPAR delta antagonist combined with SIRP alpha antibody medicine in preparing tumor immunotherapy medicine.
- 2. The use according to claim 1, wherein in said use, the pparδ antagonist modulates the level of CD47 protein.
- 3. The use according to claim 2, wherein the modulation is inhibition of expression of the encoded CD47 protein.
- 4. The use according to claim 1, wherein the pparδ antagonist comprises GSK0660.
- 5. The use of claim 1, wherein the sirpa antibody drug comprises an anti-human sirpa monoclonal antibody.
- 6. A pharmaceutical composition for treating tumors, wherein the active ingredients in the pharmaceutical composition comprise a pparδ antagonist and a sirpa antibody drug.
- 7. The pharmaceutical composition for treating tumors of claim 6, wherein said pparδ antagonist comprises GSK0660.
- 8. The pharmaceutical composition for treating tumors of claim 6, wherein the sirpa antibody drug comprises an anti-human sirpa monoclonal antibody.
- Use of a pparδ antagonist in the manufacture of a medicament for modulating the level of a gene encoding a CD47 protein and/or CD47 protein.
- 10. The use according to claim 9, wherein the modulation is inhibition of expression of a gene encoding a CD47 protein and/or a CD47 protein.
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