LU506370B1 - Small molecular pharmaceutical composition for enhancing tumor immunogenicity and application thereof - Google Patents
Small molecular pharmaceutical composition for enhancing tumor immunogenicity and application thereof Download PDFInfo
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- LU506370B1 LU506370B1 LU506370A LU506370A LU506370B1 LU 506370 B1 LU506370 B1 LU 506370B1 LU 506370 A LU506370 A LU 506370A LU 506370 A LU506370 A LU 506370A LU 506370 B1 LU506370 B1 LU 506370B1
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Classifications
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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
- A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2013—IL-2
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
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- C07—ORGANIC CHEMISTRY
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Abstract
The invention discloses a small molecular pharmaceutical composition for enhancing tumor immunogenicity and application thereof, belonging to the technical field of biomedicine. The small molecular pharmaceutical composition comprises an active ingredient A, an active ingredient B; the active ingredient A is an adjuvant, the active ingredient B is an immune checkpoint inhibitor; the immune checkpoint inhibitor comprises a PD-1 inhibitor and a PD-L1 inhibitor; the PD-1 inhibitor is pabolizumab,, the PD-L1 inhibitor is atilizumab; the adjuvant is IL-2. In the invention, a low dose of IL-2 is applied to activate T cell activity, and then a PD-1 inhibitor, a PD-L1 inhibitor are used in combination, so that the tumor immunogenicity is obviously enhanced, the tumor inhibition effect is improved, and the survival time of tumor patients is effectively prolonged. It can be seen that the invention provides a new pharmaceutical composition and treatment route for the treatment of tumor diseases.
Description
DESCRIPTION LU506370
SMALL MOLECULAR PHARMACEUTICAL COMPOSITION FOR ENHANCING
TUMOR IMMUNOGENICITY AND APPLICATION THEREOF
The invention relates to the technical field of biomedicine, in particular to a small molecular pharmaceutical composition for enhancing tumor immunogenicity and application thereof.
Immune checkpoint inhibitors are a kind of drugs that can activate the immune system and are used to treat some cancers and autoimmune diseases. They enhance the immune response of patients by inhibiting the function of immune checkpoint proteins, thus achieving the therapeutic purpose. Immunocheckpoint inhibitors mainly act on receptors on the surface of immune cells, such as PD-1, PD-L1 and CTLA-4.
Under normal circumstances, these receptors can inhibit the immune response to prevent excessive immune response. However, in some cases, tumor cells or infectious pathogens will overexpress these immune checkpoint receptors, thus inhibiting the activity of immune cells and making the immune system unable to effectively attack pathogens or tumor cells.
The mechanism of immune checkpoint inhibitors is to restore the function of immune cells by blocking the combination of immune checkpoint receptors and their ligands. Specifically, PD-1 inhibitors can block the combination of PD-1 and PD-L1, so that immune cells can be reactivated and attack tumor cells. CTLA-4 inhibitor can block the binding of CTLA-4 with B7, enhance the activity of T cells, and thus enhance the immune response.
Although immune checkpoint inhibitors have great potential in the treatment of various cancers, they have limited effect in some so-called "cold" tumors, and many cancer patients have not responded to this innovative treatment. The response rate of LU506370 immune checkpoint inhibitors ranges from 10% to 35% when treated with single drug.
For example, the effective rate of classical Hodgkin's lymphoma and melanoma can reach more than 80%, and the average response rate is less than 30%, and another 70% people cannot benefit. Therefore, at present, the combination of immune checkpoint inhibitors with different targets or the combination of immune checkpoint inhibitors with other treatment methods are being discussed clinically. Therefore, the invention provides a small molecular medicine composition which can effectively improve the tumor treatment effect.
The purpose of the present invention is to provide a small molecular pharmaceutical composition for enhancing tumor immunogenicity and application thereof, so as to solve the problems existing in the prior art. The small molecular pharmaceutical composition provided by the present invention significantly enhances tumor immunogenicity, improves tumor inhibition effect, effectively prolongs the survival period of tumor patients, and provides a new pharmaceutical composition and treatment approach for the treatment of tumor diseases.
In order to achieve the above objectives, the present invention provides the following scheme:
The invention provides a small molecular pharmaceutical composition for enhancing tumor immunogenicity, which comprises an active ingredient A and an active ingredient B; the active ingredient A is an adjuvant, and the active ingredient B is an immune checkpoint inhibitor; the immune checkpoint inhibitor comprises a PD-1 inhibitor and a PD-L1 inhibitor; the PD-1 inhibitor is pabolizumab, and the PD-L1 inhibitor is atilizumab; the adjuvant is IL-2.
Further, in each single dose, the content of pabolizumab is 3-10 ng/time, the content of pabolizumab is 300-1000 ng/time, and the content of atilizumab is 400-1000 ng/time.
Further, the active ingredient A and the active ingredient B exist separately; apply LU506370 active ingredient A first, and then apply active ingredient B.
Further, the tumor is a solid tumor; the solid tumor comprises lung cancer, gastric cancer, liver cancer, pancreatic cancer, esophageal cancer, colorectal cancer, renal cancer, urothelial cancer, ovarian cancer, breast cancer, malignant melanoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, glioma or lymphoma.
The invention also provides an application of the small molecular pharmaceutical composition in preparing medicines for enhancing tumor immunogenicity.
The invention also provides the application of the small molecular pharmaceutical composition in preparing medicines for inhibiting tumor growth.
Further, the tumor is a solid tumor; the solid tumor comprises lung cancer, gastric cancer, liver cancer, pancreatic cancer, esophageal cancer, colorectal cancer, renal cancer, urothelial cancer, ovarian cancer, breast cancer, malignant melanoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, glioma or lymphoma.
Further, the medicine also comprises a pharmaceutically acceptable carrier.
Further, the dosage form of the medicine comprises an injection or an oral preparation.
Further, the medicine is taken orally or parenterally.
The invention discloses the following technical effects.
The small molecular pharmaceutical composition provided by the invention adopts a combination of a PD-1 inhibitor, a PD-L1 inhibitor and IL-2, and low-dose
IL-2 is applied to activate T cell activity, and then the PD-1 inhibitor and the PD-L1 inhibitor are used in combination, so that the tumor immunogenicity is obviously enhanced, the tumor inhibition effect is improved, and the survival period of tumor patients is effectively prolonged. It can be seen that the invention provides a new pharmaceutical composition and treatment route for the treatment of tumor diseases.
DESCRIPTION OF THE INVENTION LU506370
A number of exemplary embodiments of the present invention will now be described in detail, and this detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention.
It should be understood that the terminology described in the present invention is only for describing specific embodiments and is not used to limit the present invention.
In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper limit and the lower limit of the range is also specifically disclosed. Intermediate values within any stated value or stated range, as well as each smaller range between any other stated value or intermediate values within the stated range are also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded from the range.
Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention relates. Although the present invention only describes the preferred methods and materials, any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention.
All documents mentioned in this specification are incorporated by reference to disclose and describe methods and/or materials related to the documents. In case of conflict with any incorporated document, the contents of this specification shall prevail.
It is obvious to those skilled in the art that many improvements and changes can be made to the specific embodiments of the present invention without departing from the scope or spirit of the present invention. Other embodiments will be apparent to the skilled person from the description of the invention. The description and example of that present invention are exemplary only.
The terms "including", "comprising", "having" and "containing" used in this LU506370 description are all open terms, which means including but not limited to.
Unless otherwise specified, the materials, instruments and reagents used in the present invention can be obtained by commercial means. Unless otherwise specified, the experimental methods used are all conventional experimental methods in this field.
The drugs used in the following examples include IL-2 (recombinant human interleukin-2 (125Ala) (Hingir)), pabolizumab (Coreda/Keytruda) and atilizumab (Taishengqi).
Embodiment 1
A small molecular pharmaceutical composition for enhancing tumor immunogenicity comprises an immune checkpoint inhibitor and an adjuvant; the immune checkpoint inhibitor comprises a PD-1 inhibitor and a PD-L1 inhibitor; the
PD-1 inhibitor is pabolizumab; the PD-L1 inhibitor is atilizumab; the adjuvant is IL-2.
Among them, the mass ratio of pabolizumab, atilizumab and IL-2 is 100: 100: 1.
Embodiment 2
A small molecular pharmaceutical composition for enhancing tumor immunogenicity comprises an immune checkpoint inhibitor and an adjuvant; the immune checkpoint inhibitor comprises a PD-1 inhibitor and a PD-L1 inhibitor; the
PD-1 inhibitor is pabolizumab; the PD-L1 inhibitor is atilizumab; the adjuvant is IL-2.
Among them, the mass ratio of pabolizumab, atilizumab and IL-2 is 300: 300: 1.
Embodiment 3
A small molecular pharmaceutical composition for enhancing tumor immunogenicity comprises an immune checkpoint inhibitor and an adjuvant; the immune checkpoint inhibitor comprises a PD-1 inhibitor and a PD-L1 inhibitor; the
PD-1 inhibitor is pabolizumab; the PD-L1 inhibitor is atilizumab; the adjuvant is IL-2.
Among them, the mass ratio of pabolizumab, atilizumab and IL-2 is 500: 300: 1.
Comparative embodiment 1 LU506370
A small molecular pharmaceutical composition for enhancing tumor immunogenicity comprises a PD-1 inhibitor and a PD-L1 inhibitor; the PD-1 inhibitor is pabolizumab; the PD-L1 inhibitor is atilizumab. Among them, the mass ratio of pabolizumab to atilizumab is 1: 1.
Comparative embodiment 2
A small molecular pharmaceutical composition for enhancing tumor immunogenicity comprises an immune checkpoint inhibitor and an adjuvant; the immune checkpoint inhibitor is a PD-1 inhibitor: pabolizumab; the adjuvant is IL-2. The mass ratio of pabolizumab to IL-2 is 100: 1.
Comparative embodiment 3
A small molecular pharmaceutical composition for enhancing tumor immunogenicity comprises an immune checkpoint inhibitor and an adjuvant; the immune checkpoint inhibitor is a PD-L1 inhibitor: atilizumab; the adjuvant is IL-2.
Among them, the mass ratio of atilizumab to IL-2 is 100: 1.
Effect verification 1. Construct a tumor mouse model 1.1 Cell culture
Human lung cancer cell line PC-9 is purchased from American Type Culture
Collection (ATCC), and cultured in RPMI-1640 medium containing 10% (volume fraction) fetal bovine serum, 10 mg/L streptomycin sulfate and 100 U penicillin, and under the conditions of 90% humidity and 5% (volume fraction) CO». Collecting cell count, adjusting concentration, and mixing with matrix glue; Cell suspension and matrix glue are mixed evenly on ice according to the volume ratio of 1: 1, and then placed on ice for later use. 1.2 Tumor cell inoculation and grouping
The experimental mice are randomly divided into 8 groups according to their body weight, with 10 mice in each group. The breast of each mouse is inoculated with 1x10°/0.05ML of mixed solution of cell suspension and matrix glue. 80 mice are inoculated with 0.1mL/mouse of mixed solution, which is administered about 4 hours after inoculation.
1.3 Animal Administration LU506370
Administration mode: each group is given drugs twice a week, intraperitoneal injection, a total of 9 times; after 12 hours of IL-2 administration, pabolizumab and atilzumab are injected in turn, and the purpose of early administration of IL-2 is to stimulate T cell activity in advance and achieve better therapeutic effect. The mode of administration is as follows:
Table 1 nf
Drugs (ng/mL) (mL)
Comogopees | on 1.4 Observation indicators 1.4.1 Survival period
Monitor the survival of mice and record the survival time of mice (taking the day of modeling as the starting point of survival, and euthanasia as the end point of survival). 1.4.2 Tumor inhibition rate
The mice are euthanized after 4 weeks of medication or at the humane end of the mice. The weight of lung tumor is dissected and weighed, and the tumor inhibition rate is calculated.
1.4.3 Number of MDSCs in lung cancer tissues LU506370
Placing lung tumor in PBS buffer solution, grinding and filtering the tissue with a tissue grinding rod and a 200-mesh filter screen, taking the filtered cell fluid and blowing it several times with a 1 mL pipette gun to prepare a cell suspension, centrifuging, discarding the supernatant, adding red blood cell lysate with the volume of 3 times of cell precipitation, cracking red blood cells in the dark at room temperature for 5 min, washing with PBS once and suspending again, adjusting the cell concentration to 1-2 x 107 cells/mL, and subpackaging each tube with 300 uL. Flow antibody staining (1.5 uL/tube) is performed in a dark environment. After 40min incubation at room temperature, PBS is washed twice, and the cell percentage is analyzed by CytExpert. 2 Experimental results 2.1 Comparison of average survival time of mice in each group
Table 2
Note: Compared with the control group, *p<0.05, **p<0.01, * * P < 0.001. 2.2 Comparison of tumor inhibition rates in each group
Table 3 LU506370 gp es OO [2 ass 2.3 Comparison of the number of MDSCs in lung cancer tissues of mice in each group
Table 4
Combined with the experimental results in Table 2- Table 4, it can be seen that LU506370 the combined use of IL-2, pabolizumab and atilizumab can significantly enhance tumor immunogenicity and play a more efficient role in tumor inhibition compared with single drug or combination of two drugs. During the experimental administration, with the growth of tumor, the average body weight of mice in each group decreased from the 20th day after administration, but the body weight of mice in the administration group is still significantly larger than that of mice in the control group, which proved that the combination of IL-2, pabolizumab and atilizumab had no obvious toxic and side effects on animals and had good safety.
The above experiment takes lung cancer tumor as an example, and the small molecule pharmaceutical composition can be used to treat various solid tumors, including but not limited to lung cancer, gastric cancer, liver cancer, pancreatic cancer, esophageal cancer, colorectal cancer, renal cancer, urothelial cancer, ovarian cancer, breast cancer, malignant melanoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, glioma or lymphoma.
The above-mentioned embodiments only describe the preferred mode of the invention, and do not limit the scope of the invention. Under the premise of not departing from the design spirit of the invention, various modifications and improvements made by ordinary technicians in the field to the technical scheme of the invention shall fall within the protection scope determined by the claims of the invention.
Claims (10)
1. A small molecular pharmaceutical composition for enhancing tumor immunogenicity, characterized in that the small molecular pharmaceutical composition comprises an active ingredient À and an active ingredient B; the active ingredient À is an adjuvant, and the active ingredient B is an immune checkpoint inhibitor; the immune checkpoint inhibitor comprises a PD-1 inhibitor and a PD-L1 inhibitor; the PD-1 inhibitor is pabolizumab, and the PD-L1 inhibitor is atilizumab; the adjuvant is IL-2.
2. The small molecule pharmaceutical composition according to claim 1, characterized in that the content of pabolizumab is 3-10 ng/time, the content of pabolizumab is 300-1000 ng/time, and the content of atilizumab is 400-1000 ng/time.
3. The small molecule pharmaceutical composition according to claim 1, characterized in that the active ingredient A and the active ingredient B exist separately; apply active ingredient A first, and then apply active ingredient B.
4. The small molecule pharmaceutical composition according to clam 1, characterized in that the tumor is a solid tumor; the solid tumor comprises lung cancer, gastric cancer, liver cancer, pancreatic cancer, esophageal cancer, colorectal cancer, renal cancer, urothelial cancer, ovarian cancer, breast cancer, malignant melanoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, glioma or lymphoma.
5. An application of the small molecule pharmaceutical composition according to any one of claims 1 to 4 in preparation of medicines for enhancing tumor immunogenicity.
6. An application of the small molecule pharmaceutical composition according to any one of claims 1 to 4 in the preparation of medicines for inhibiting tumor growth.
7. The application according to claim 6, characterized in that the tumor is a solid LU506370 tumor; the solid tumor comprises lung cancer, gastric cancer, liver cancer, pancreatic cancer, esophageal cancer, colorectal cancer, renal cancer, urothelial cancer, ovarian cancer, breast cancer, malignant melanoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, glioma or lymphoma.
8. The application according to claim 6, characterized in that the medicine further comprises a pharmaceutically acceptable carrier.
9. The application according to claim 6, characterized in that the dosage form of the medicine comprises an injection or an oral preparation.
10. The application according to claim 6, characterized in that the medicine is taken orally or parenterally.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU506370A LU506370B1 (en) | 2024-02-08 | 2024-02-08 | Small molecular pharmaceutical composition for enhancing tumor immunogenicity and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU506370A LU506370B1 (en) | 2024-02-08 | 2024-02-08 | Small molecular pharmaceutical composition for enhancing tumor immunogenicity and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LU506370B1 true LU506370B1 (en) | 2024-08-09 |
Family
ID=92424873
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LU506370A LU506370B1 (en) | 2024-02-08 | 2024-02-08 | Small molecular pharmaceutical composition for enhancing tumor immunogenicity and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| LU (1) | LU506370B1 (en) |
-
2024
- 2024-02-08 LU LU506370A patent/LU506370B1/en active IP Right Grant
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG | Patent granted |
Effective date: 20240809 |