CN115414343B - Application of alpha-ketoglutaric acid and derivatives thereof and medicine for preventing and treating skin tumor - Google Patents
Application of alpha-ketoglutaric acid and derivatives thereof and medicine for preventing and treating skin tumor Download PDFInfo
- Publication number
- CN115414343B CN115414343B CN202211197711.3A CN202211197711A CN115414343B CN 115414343 B CN115414343 B CN 115414343B CN 202211197711 A CN202211197711 A CN 202211197711A CN 115414343 B CN115414343 B CN 115414343B
- Authority
- CN
- China
- Prior art keywords
- alpha
- ketoglutaric acid
- derivatives
- preventing
- melanoma
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 title claims abstract description 142
- 239000003814 drug Substances 0.000 title claims abstract description 74
- HWXBTNAVRSUOJR-UHFFFAOYSA-N alpha-hydroxyglutaric acid Natural products OC(=O)C(O)CCC(O)=O HWXBTNAVRSUOJR-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 229940009533 alpha-ketoglutaric acid Drugs 0.000 title claims abstract description 53
- 206010029098 Neoplasm skin Diseases 0.000 title abstract description 59
- 208000000453 Skin Neoplasms Diseases 0.000 title abstract description 49
- 201000001441 melanoma Diseases 0.000 claims abstract description 51
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 20
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 230000002708 enhancing effect Effects 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 230000003915 cell function Effects 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 description 35
- 238000004519 manufacturing process Methods 0.000 description 21
- 241000699670 Mus sp. Species 0.000 description 16
- 239000007928 intraperitoneal injection Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 9
- 239000002953 phosphate buffered saline Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 230000001276 controlling effect Effects 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 101150063370 Gzmb gene Proteins 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 108091007744 Programmed cell death receptors Proteins 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000005746 immune checkpoint blockade Effects 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 3
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- JXYWFNAQESKDNC-BTJKTKAUSA-N (z)-4-hydroxy-4-oxobut-2-enoate;2-[(4-methoxyphenyl)methyl-pyridin-2-ylamino]ethyl-dimethylazanium Chemical group OC(=O)\C=C/C(O)=O.C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 JXYWFNAQESKDNC-BTJKTKAUSA-N 0.000 description 2
- 102100030385 Granzyme B Human genes 0.000 description 2
- 101001009603 Homo sapiens Granzyme B Proteins 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
- 208000030381 cutaneous melanoma Diseases 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000005740 tumor formation Effects 0.000 description 2
- FECNVDHIIJYRIA-UHFFFAOYSA-N 2-oxopentanedioic acid Chemical compound OC(=O)CCC(=O)C(O)=O.OC(=O)CCC(=O)C(O)=O FECNVDHIIJYRIA-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 206010027145 Melanocytic naevus Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000007256 Nevus Diseases 0.000 description 1
- 206010029488 Nodular melanoma Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000011502 immune monitoring Methods 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000003731 mucosal melanoma Diseases 0.000 description 1
- 210000004985 myeloid-derived suppressor cell Anatomy 0.000 description 1
- 201000000032 nodular malignant melanoma Diseases 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to an application of alpha-ketoglutaric acid and derivatives thereof, and a medicine for preventing and treating skin tumors. Wherein, the alpha-ketoglutarate and the derivatives thereof have the effect of preventing and treating skin tumors, and can effectively inhibit the volume increase of B16F10 melanoma. The application provides a new application for alpha-ketoglutarate and derivatives thereof, and simultaneously provides a new medicine for preventing and treating skin tumors.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to an application of alpha-ketoglutaric acid and derivatives thereof and a medicine for preventing and treating skin tumors.
Background
Skin melanoma derived from melanocytes is an invasive malignancy, and currently clinical histological typing of skin malignant melanoma employs Clark typing, which includes four types: malignant nevus, superficial diffuse, acrofreckle-like/mucosal and nodular melanoma. Clinical symptoms of cutaneous malignant melanoma include bleeding, itching, tenderness, ulcers, and the like.
Immune Checkpoint Blocking (ICB) therapy, a method that can treat tumors, is based on the principle: based on the activation mechanism of immune cell T cells, programmed death receptor is expressed on the surface of T cells, and ligand is expressed on the surfaces of tumor cells and myeloid-derived suppressor cells; the binding of the programmed death receptor and the ligand thereof can lead the T cells to be depleted and not to normally kill the tumor cells, and the tumor cells can escape from the immune monitoring of the host; the apoptosis receptor and its ligand are referred to as "immune checkpoints"; immune checkpoint blocking therapies based on programmed death receptors and their ligands increase the aggressiveness of the host immune system to tumor cells by inhibiting the binding of both. However, the response rate of traditional immune checkpoint blockade therapies is less than 30% and some patients exhibit complete resistance, ineffective for immune checkpoint blockade therapy treatment.
Therefore, it is necessary to provide a novel skin tumor drug which can prevent and treat malignant melanoma of skin.
Disclosure of Invention
Based on the above, the invention provides an application of alpha-ketoglutaric acid and derivatives thereof in preparing medicines for preventing and treating skin tumor, and the medicines.
The technical scheme for solving the technical problems is as follows.
The invention provides an application of alpha-ketoglutaric acid and derivatives thereof in preparing medicines for preventing and treating skin tumor.
In some embodiments, the use of alpha-ketoglutaric acid and derivatives thereof in the manufacture of a medicament for the treatment of skin tumours, at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid is combined with anti-PD-1 for the manufacture of a medicament for the treatment of skin tumours.
In some of these embodiments, the use of alpha-ketoglutaric acid and derivatives thereof in the manufacture of a medicament for the prevention and treatment of skin tumors, including melanoma.
In some of these embodiments, the use of alpha-ketoglutarate and derivatives thereof in the manufacture of a medicament for the prevention and treatment of skin tumors, including B16F10 melanoma.
In some embodiments, the application of the alpha-ketoglutaric acid and the derivatives thereof in preparing the medicines for preventing and treating skin tumors is that the medicines for preventing and treating skin tumors prepared by combining at least one of the alpha-ketoglutaric acid and the derivatives of the alpha-ketoglutaric acid with the anti-PD-1 are medicines for enhancing T cell functions.
In some embodiments, the alpha-ketoglutaric acid and derivatives thereof are used for preparing medicines for preventing and treating skin tumors, wherein the medicines for preventing and treating skin tumors are medicines for inhibiting volume increase of melanoma.
The invention also provides a medicine for preventing and treating skin tumor, which comprises at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid and pharmaceutically acceptable auxiliary materials.
In some of these embodiments, the composition of the medicament for controlling skin tumors further comprises anti-PD-1.
In some embodiments, the mass ratio of at least one of the alpha-ketoglutaric acid and the derivative of alpha-ketoglutaric acid to the anti-PD-1 in the medicament for preventing and treating skin tumor is (5-10): 1.
In some embodiments, the pharmaceutically acceptable adjuvant is selected from at least one of a slow release agent, an excipient, a filler, an adhesive, a wetting agent, a disintegrating agent, an absorption enhancer, an adsorption carrier, a surfactant, and a lubricant.
In some embodiments, the medicament for preventing and treating skin tumor is an injection preparation.
The technical personnel of the invention find that the alpha-ketoglutaric acid and the derivatives thereof have the effect of preventing and treating skin tumors, and can effectively inhibit the increase of the volume of B16F10 melanoma. The application provides a new application for alpha-ketoglutarate and derivatives thereof, and simultaneously provides a new medicine for preventing and treating skin tumors.
The research shows that the alpha-ketoglutaric acid and the derivatives thereof have obvious drug effect for preventing and treating skin tumor, have wide application prospect and have great popularization and application value.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph comparing alpha-ketoglutarate levels in plasma of melanoma patients and healthy humans;
FIG. 2 is a graph showing comparison of tumor volume curves of groups (1) to (4) in example 2;
FIG. 3 is a diagram showing comparison of tumor masses in groups (1) to (4) in example 2;
FIG. 4 is a graph showing the percentage comparison of CD45+CD3+ cells in the tumor mass of groups (1) to (4) in example 2;
FIG. 5 is a graph showing comparison of the ratios of CD8+/CD4+T cells in the tumor bodies of groups (1) to (4) in example 2;
FIG. 6 is a graph showing the percentage comparison of CD8+IFN+T cells in tumor cells of groups (1) to (4) in example 2;
FIG. 7 is a graph showing the percentage comparison of CD8+GZMB+T cells in the tumor bodies of groups (1) to (4) in example 2;
FIG. 8 is a graph showing the percentage comparison of CD4+GZMB+T cells in the tumor bodies of groups (1) to (4) in example 2;
FIG. 9 is a graph showing comparison of tumor volume curves of groups (1) to (4) in example 3;
FIG. 10 is a diagram showing comparison of tumor masses in groups (1) to (4) in example 3.
Detailed Description
Reference now will be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be used on another embodiment to yield still a further embodiment.
Accordingly, it is intended that the present invention cover such modifications and variations as fall within the scope of the appended claims and their equivalents. Other objects, features and aspects of the present invention will be disclosed in or be apparent from the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not intended as limiting the broader aspects of the present invention.
Unless defined otherwise, 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 belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one … …" does not exclude the presence of other like elements in a process, method, article, or apparatus that comprises the element. The indefinite articles "a" and "an" preceding an element or component of the invention are not limited to the requirement (i.e. the number of occurrences) of the element or component. Thus, the use of "a" or "an" should be interpreted as including one or at least one, and the singular reference of an element or component includes the plural reference unless the amount clearly dictates otherwise. The meaning of "a plurality of" means at least two, e.g., two, three, etc., unless explicitly defined otherwise.
The weights of the relevant components mentioned in the description of the embodiments of the present invention may refer not only to the specific contents of the components, but also to the proportional relationship between the weights of the components, so long as the contents of the relevant components in the description of the embodiments of the present invention are scaled up or down within the scope of the disclosure of the embodiments of the present invention. Specifically, the weight described in the specification of the embodiment of the present invention may be mass units known in the chemical industry field such as μ g, mg, g, kg.
Except where shown or otherwise indicated in the operating examples, all numbers expressing quantities of ingredients, physical and chemical properties, and so forth, used in the specification and claims are to be understood as being modified in all instances by the term "about". For example, therefore, unless indicated to the contrary, the numerical parameters set forth in the foregoing specification and attached claims are approximations that can be varied appropriately by those skilled in the art utilizing the teachings disclosed herein seeking to obtain the desired properties. The use of numerical ranges by endpoints includes all numbers subsumed within that range and any range within that range, e.g., 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4, 5, and the like.
The skilled person in the present invention found that the content of alpha-ketoglutarate in the plasma of melanoma patients was lower than in healthy people not suffering from melanoma during the course of the study.
In order to prove the role of alpha-ketoglutarate in melanoma immunity, the technical personnel constructs a C57-B16F10 tumor-bearing mouse model, and the alpha-ketoglutarate is used for treating melanoma, so that the result shows that the alpha-ketoglutarate can effectively inhibit the increase of B16F10 melanoma volume and has a therapeutic effect on melanoma; at least one of alpha-ketoglutarate and derivatives of alpha-ketoglutarate is combined with anti-PD-1, which can effectively increase the number of T cells of a melanoma patient, thereby enhancing the function of the T cells of the melanoma patient; the application provides a new application for alpha-ketoglutarate and a new medicine for preventing and treating skin tumor; the method comprises the following steps:
the embodiment of the invention provides an application of alpha-ketoglutaric acid and derivatives thereof in preparing medicines for preventing and treating skin tumors.
Derivative (derivative) refers to a more complex product derived from a simple compound in which a hydrogen atom or group is replaced by another atom or group; it is understood that derivatives of alpha-ketoglutarate include, but are not limited to, esters, salts, amides, acid halides of alpha-ketoglutarate.
Alpha-ketoglutaric acid (Alpha-Ketoglutaric acid), abbreviated as Alpha-KG, white fine crystalline powder with CAS number 328-50-7, molecular formula C 5 H 6 O 5 The molecular weight is 146.10, and the structural formula is as follows:
alpha-ketoglutarate participates in the tricarboxylic acid cycle in organisms to produce amino acids, which are routinely taken by fitness personnel on the market as dietary supplements.
The alpha-ketoglutaric acid has obvious drug effect for preventing and treating skin tumor, has wide application prospect and has larger popularization and application value. And the alpha-ketoglutarate is a kind of existing nutrition, the pharmacological action is relatively clear, and the research and development cost is reduced.
In some examples, the use of alpha-ketoglutaric acid and derivatives thereof in the manufacture of a medicament for the prevention and treatment of skin tumours, including melanoma.
In some examples, the use of alpha-ketoglutarate and derivatives thereof in the manufacture of a medicament for the prevention and treatment of skin tumors, including B16F10 melanoma.
In some examples, the alpha-ketoglutaric acid and derivatives thereof are used for preparing medicines for preventing and treating skin tumors, wherein the medicines for preventing and treating skin tumors are medicines for inhibiting volume increase of melanoma. It will be appreciated that an embodiment of the present invention provides the use of alpha-ketoglutarate and derivatives thereof in the manufacture of a medicament for inhibiting the volume increase of melanoma.
In some examples, the alpha-ketoglutaric acid and derivatives thereof are used for preparing medicines for preventing and treating skin tumor, and the medicines for preventing and treating skin tumor are injection preparations.
In some examples, the use of alpha-ketoglutaric acid and derivatives thereof in the manufacture of a medicament for the treatment of skin tumours, at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid is combined with anti-PD-1 for the manufacture of a medicament for the treatment of skin tumours.
It will be appreciated that another embodiment of the present invention provides the use of at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid in combination with anti-PD-1 for the manufacture of a medicament for the prevention and treatment of skin tumours.
PD-1 (programmed death receptor 1), also known as CD279 (cluster 279), is an important immunosuppressive molecule. Autoimmune diseases can be prevented by down regulating the immune system's response to human cells, and by inhibiting T cell inflammatory activity to regulate the immune system and promote self tolerance. However, PD-1 can also bind to its ligand (PD-L1) to deplete T cells and prevent them from killing cancer cells normally, thus preventing the immune system from killing cancer cells. anti-PD-1 (anti-PD-1 antibody) can be combined with PD-1, so that the combination of PD-1 and PD-L1 is inhibited, and the aggressiveness of a host immune system to tumor cells is improved.
anti-PD-1/PD-L1 antibodies can reduce tumor burden and improve overall survival in patients with advanced melanoma. However, in sensitive tumor types including melanoma, the response rate of immune checkpoint blockade therapy is less than 30%, and some patients exhibit complete resistance, ineffective for immune checkpoint blockade therapy treatment.
According to the invention, at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid is combined with anti-PD-1, so that the immunotherapy effect of melanoma is remarkably enhanced, the number of T cells of a patient suffering from melanoma is remarkably increased, the function of the T cells of the patient suffering from melanoma is remarkably enhanced, and the increase of the volume of B16F10 melanoma is remarkably inhibited.
In some examples, at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid is used in combination with anti-PD-1 in the manufacture of a medicament for the treatment of skin tumours, including melanoma.
In some examples, at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid is used in combination with anti-PD-1 in the manufacture of a medicament for the treatment of skin tumors, including B16F10 melanoma.
In some examples, the at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid is used in combination with anti-PD-1 in the manufacture of a medicament for the treatment of skin tumors, which is a medicament for enhancing T cell function. It will be appreciated that an embodiment of the present invention provides the use of at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid in combination with anti-PD-1 for the manufacture of a medicament for enhancing T cell function.
In some examples, the use of at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid in combination with anti-PD-1 in the manufacture of a medicament for controlling skin tumors, the enhancement of T cell function comprises enhancing the killing function of T cells on tumor cells.
In some examples, the at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid is used in combination with anti-PD-1 in the manufacture of a medicament for the treatment of skin tumors, which is a medicament for increasing the number of T cells. It will be appreciated that an embodiment of the present invention provides for the use of at least one of alpha-ketoglutarate and derivatives of alpha-ketoglutarate in combination with anti-PD-1 in the manufacture of a medicament for enhancing T cell numbers.
In some examples, the at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid is used in combination with anti-PD-1 in the manufacture of a medicament for the treatment of skin tumors, which is a medicament for inhibiting the volume increase of melanoma. It will be appreciated that an embodiment of the present invention provides the use of at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid in combination with anti-PD-1 for the manufacture of a medicament for inhibiting the volume increase of melanoma.
In some examples, the at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid is used in combination with anti-PD-1 in the manufacture of a medicament for the treatment of skin tumours, the medicament for the treatment of skin tumours being an injectable formulation.
An embodiment of the invention provides a medicine for preventing and treating skin tumor, which comprises at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid and pharmaceutically acceptable auxiliary materials.
The invention further provides a medicine for preventing and treating skin tumors, which comprises at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid, anti-PD-1 and pharmaceutically acceptable auxiliary materials.
In some examples, the mass ratio of at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid to anti-PD-1 in the medicament for preventing and treating skin tumor is (5-10): 1.
It is understood that the mass ratio of at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid to anti-PD-1 includes, but is not limited to, 5:1, 5.2:1, 5.5:1, 6:1, 7:1, 8:1, 9:1, 10:1. It is further understood that the mass ratio of at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid to anti-PD-1 is not limited to the above exemplified concentrations.
In some examples, the mass ratio of at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid to anti-PD-1 in the medicament for controlling skin tumours is 10:1.
In some embodiments, the pharmaceutically acceptable adjuvant is selected from at least one of a sustained release agent, an excipient, a filler, an adhesive, a wetting agent, a disintegrant, an absorption enhancer, an adsorption carrier, a surfactant, and a lubricant.
It will be appreciated that the pharmaceutically acceptable excipients may be selected from one of a slow release agent, an excipient, a filler, an adhesive, a wetting agent, a disintegrant, an absorption enhancer, an adsorption carrier, a surfactant and a lubricant, or may be selected from two or more of a slow release agent, an excipient, a filler, an adhesive, a wetting agent, a disintegrant, an absorption enhancer, an adsorption carrier, a surfactant and a lubricant; and is not limited to the above list.
In some embodiments, the pharmaceutical formulation of the pharmaceutical for preventing and treating skin tumor is a tablet, a granule, a capsule, an injection, an ointment, a cream or a suspension.
In some examples, the skin tumor preventing and treating medicine is injection and the supplementary material includes water.
In some examples, the skin tumor preventing and treating medicine is injection and the supplementary material includes phosphate buffer salt solution.
Phosphate Buffered Saline (PBS) containing Na as main ingredient 2 HPO 4 、KH 2 PO 4 NaCl and KCl.
In some examples, the drug for preventing and treating skin tumor is administered in form of application, oral administration or injection.
An embodiment of the invention provides a preparation method of a medicine for preventing and treating skin tumors, which comprises the step of mixing at least one of alpha-ketoglutaric acid and derivatives of alpha-ketoglutaric acid with auxiliary materials.
In some examples, in the method for producing a drug for preventing and treating skin tumor, an aqueous solution of α -ketoglutaric acid is produced by mixing at least one of α -ketoglutaric acid and a derivative of α -ketoglutaric acid with water, and then adjusting the pH to neutral with a base. It can be understood that the prepared ketoglutaric acid aqueous solution can be used as a medicament for preventing and treating skin tumor.
In some specific examples, the pH is adjusted to 7 with sodium hydroxide in the preparation of a medicament for controlling skin tumors.
In other examples, in a method of preparing a medicament for controlling skin tumors, at least one of α -ketoglutaric acid and derivatives of α -ketoglutaric acid, anti-PD-1, and an adjuvant are mixed.
In some examples, the method of preparing a medicament for controlling skin tumors comprises the steps of:
mixing anti-PD-1 with PBS solution to prepare PBS solution of anti-PD-1;
at least one of alpha-ketoglutaric acid and a derivative of alpha-ketoglutaric acid is mixed with water, and then the pH is adjusted to neutral with a base to prepare an aqueous solution of alpha-ketoglutaric acid.
It will be appreciated that anti-PD-1 in PBS and alpha-ketoglutaric acid in aqueous solution are administered separately.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following examples of the application of the α -ketoglutaric acid according to the invention in the preparation of a medicament for controlling skin tumors, the medicament is not limited to the following examples.
Example 1
The nuclear magnetic resonance spectroscopy was used to detect alpha-ketoglutarate levels in plasma of 20 melanoma patients and 20 healthy persons, and the results are shown in fig. 1; wherein, the ordinate Concentration of α -Ketoglutarate is the Concentration of α -Ketoglutarate, the abscissa Melanoma (n=20) represents 20 Melanoma patients, and the Normal (n=20) represents 20 healthy people.
As can be seen from fig. 1, α -ketoglutarate is lower in the plasma of melanoma patients than in healthy people.
Example 2
Animal test
The test process comprises the following steps: preparing 28C 57BL/6 mice, carrying out subcutaneous tumor formation by using mouse melanoma cells B16F10 after back shaving, and randomly dividing the mice into 4 groups once tumors are accessible, wherein 7 mice in each group are respectively (1) Vehicle+LgG2a group, (2) PD-1mAb group, (3) alpha-KG+IgG 2a group and (4) alpha-KG+PD-1 mAb group; wherein, the LgG2a and the PD-1mAb are prepared by taking phosphate buffer salt solution as solvent to respectively obtain PBS solution of the LgG2a and PBS solution of the PD-1 mAb; after dissolving the alpha-KG by taking water as a solvent, regulating the PH value to 7 by using NaOH to obtain an alpha-KG aqueous solution; the vehicle+lgg2a group was given treatment by intraperitoneal injection at a dose of 10mg lggg2a per 1kg mice, once every 3 days; the PD-1mAb group was given treatment by intraperitoneal injection at a dose of 10mg PD-1mAb per 1kg mouse, once every 3 days; the α -kg+igg2a group was given treatment by intraperitoneal injection at a dose of 100mg α -ketoglutarate per 1KG of mice, once daily, while 10mg lgg2a was given treatment by intraperitoneal injection per 1KG of mice, once every 3 days; the PD-1mAb+α -KG group was given by intraperitoneal injection at a dose of 10mg of PD-1mAb per 1KG of mice, once every 3 days, while 100mg of α -ketoglutarate was given by intraperitoneal injection per 1KG of mice, once a day; tumor volume was measured on alternate Days, and the Tumor volume graph is shown in fig. 2, in which the abscissa day is the number of Days of treatment and the ordinate Tumor volume is the Tumor volume, and the repeated experimental data is expressed as average (n=7) ±sd; * P is less than 0.05.
As can be seen from fig. 2, α -ketoglutarate can inhibit the increase of B16F10 melanoma volume, and has therapeutic effect on melanoma; compared with the PD-1mAb group and the alpha-KG+IgG 2a group, the combination of the alpha-KG and the PD-1mAb (anti-PD-1) has more obvious effect of inhibiting the volume increase of B16F10 melanoma, namely, the combination of the alpha-ketoglutarate and the anti-PD-1 can further obviously enhance the immunotherapy effect of the melanoma.
Taking out tumor bodies, wherein an actual comparison graph of each group of tumor bodies is shown in fig. 3; flow cytometry analysis was performed on each group of tumor bodies, as shown in fig. 4 to 8, in which fig. 4 shows the percentage of cd4+cd3+ cells in each group of tumor bodies, fig. 5 shows the ratio of cd8+/cd4+tcells in each group of tumor bodies, fig. 6 shows the percentage of cd8+ifn+tcells in each group of tumor bodies, fig. 7 shows the percentage of cd8+gzmb+tcells in each group of tumor bodies, and fig. 8 shows the percentage of cd4+gzmb+tcells in each group of tumor bodies.
As can be seen from fig. 4, the T cell percentage of the PD-1mab+α -KG group was significantly increased over the other groups; as can be seen from fig. 5, the ratio of cd8+/cd4+ T cells in the PD-1mab+α -KG group was significantly increased over the other groups; as can be seen from fig. 6, the cd8+ifn+t cells percentage of the PD-1mab+α -KG group was significantly increased over the other groups; as can be seen from fig. 7, the cd8+gzmb+t cells percentage of the PD-1mab+α -KG group was significantly increased over the other groups; as can be seen from fig. 8, the cd4+gzmb+t cells percentage of the PD-1mab+α -KG group was significantly increased over the other groups; that is, the use of α -KG in combination with anti-PD-1 can significantly increase the number of T cells as well as the function of T cells.
Comparative example
The test process comprises the following steps: preparing 20C 57BL/6 mice, carrying out subcutaneous tumor formation by using mouse melanoma cells B16F10 after back shaving, and randomly dividing the mice into 4 groups once tumors are accessible, wherein 5 mice in each group are respectively (1) Vehicle+LgG2a group, (2) PD-1mAb group, (3) Histindine+IgG2a (histidine) group, (4) PD-1 mAb+Histindine group; wherein, the injection uses phosphate buffer salt solution as solvent; the vehicle+lgg2a group was given treatment by intraperitoneal injection at a dose of 10mg lggg2a per 1kg mice, once every 3 days, with daily PBS treatment; the PD-1mAb group was given treatment by intraperitoneal injection at a dose of 10mg PD-1mAb per 1kg mouse, once every 3 days, with PBS treatment given daily; the Histidine group was given treatment by intraperitoneal injection at a dose of 1000mg of Histidine per 1kg of mice, once daily, while the treatment was given by intraperitoneal injection at a dose of 10mg of lgg2a per 1kg of mice, once every 3 days; the PD-1 mAb+Histine group was given by intraperitoneal injection at a dose of 10mg PD-1mAb per 1kg of mice, once every 3 days, while 1000mg Histine was given by intraperitoneal injection per 1kg of mice, once a day; tumor volume was measured on alternate Days, and the Tumor volume graph is shown in fig. 9, in which the abscissa day is the number of Days of treatment and the ordinate Tumor volume is the Tumor volume, and the repeated experimental data is expressed as the mean (n=7) ±sd; * P is less than 0.05; the tumor bodies were removed, and an actual comparison of the tumor bodies of each group is shown in fig. 10.
As can be seen from figures 9-10, histidine, and histidine in combination with anti-PD-1, have limited inhibition of B16F10 melanoma volume increase and are not as effective as PD-1mAb in immunotherapy of melanoma.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted as illustrative of the contents of the claims.
Claims (6)
1. The application of the combination of the alpha-ketoglutaric acid and the anti-PD-1 in preparing the medicine for preventing and treating the melanoma is characterized in that the mass ratio of the alpha-ketoglutaric acid to the anti-PD-1 is 10:1.
2. The use of claim 1, wherein the melanoma comprises B16F10 melanoma.
3. The use according to any one of claims 1 to 2, wherein the medicament for preventing and treating melanoma is a medicament for inhibiting volume increase of melanoma.
4. The use according to any one of claims 1 to 2, wherein the medicament for preventing and treating melanoma is a medicament for enhancing T cell function.
5. The medicine for preventing and treating melanoma is characterized by comprising alpha-ketoglutaric acid, anti-PD-1 and pharmaceutically acceptable auxiliary materials; the mass ratio of the alpha-ketoglutaric acid to the anti-PD-1 is 10:1.
6. The drug for preventing and treating melanoma according to claim 5, wherein the drug is an injection preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211197711.3A CN115414343B (en) | 2022-09-29 | 2022-09-29 | Application of alpha-ketoglutaric acid and derivatives thereof and medicine for preventing and treating skin tumor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211197711.3A CN115414343B (en) | 2022-09-29 | 2022-09-29 | Application of alpha-ketoglutaric acid and derivatives thereof and medicine for preventing and treating skin tumor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115414343A CN115414343A (en) | 2022-12-02 |
| CN115414343B true CN115414343B (en) | 2023-11-21 |
Family
ID=84206067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211197711.3A Active CN115414343B (en) | 2022-09-29 | 2022-09-29 | Application of alpha-ketoglutaric acid and derivatives thereof and medicine for preventing and treating skin tumor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115414343B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101884631A (en) * | 2009-05-12 | 2010-11-17 | 复旦大学 | Anti-tumor medicament based on alpha ketoglutaric acid and derivatives thereof |
| CN108601840A (en) * | 2015-12-07 | 2018-09-28 | 国立大学法人京都大学 | PD-1 signal inhibitor and use therapy |
| CN110734493A (en) * | 2018-07-20 | 2020-01-31 | 厦门大学 | anti-PD-1 antibodies and uses thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3735590A1 (en) * | 2018-01-04 | 2020-11-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma resistant |
-
2022
- 2022-09-29 CN CN202211197711.3A patent/CN115414343B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101884631A (en) * | 2009-05-12 | 2010-11-17 | 复旦大学 | Anti-tumor medicament based on alpha ketoglutaric acid and derivatives thereof |
| CN108601840A (en) * | 2015-12-07 | 2018-09-28 | 国立大学法人京都大学 | PD-1 signal inhibitor and use therapy |
| CN110734493A (en) * | 2018-07-20 | 2020-01-31 | 厦门大学 | anti-PD-1 antibodies and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115414343A (en) | 2022-12-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2888259B2 (en) | Preparation for activating natural killer cells (NK cells) containing interferon-α and histamine, serotonin or a substance having a corresponding receptor activity | |
| JPH07233064A (en) | Anticancer agent wherein tachysol is active ingredient | |
| CA2362288A1 (en) | Use of lipoic acid combination with ascorbic acid in the treatment of cancer | |
| CA2859940C (en) | Method for administration of an anti tumor agent | |
| DE69023442T2 (en) | Use of a cyanine color in an anti-tumor agent. | |
| Kubicek et al. | Phase I trial using the proteasome inhibitor bortezomib and concurrent chemoradiotherapy for head-and-neck malignancies | |
| CN108498802A (en) | pharmaceutical composition for treating non-small cell lung cancer and its preparation | |
| CA3116731A1 (en) | Combinations for immune-modulation in cancer treatment | |
| KR20180014834A (en) | Compositions and uses containing carboplatin | |
| JP2001520656A (en) | Phorbol esters as antitumor agents | |
| Li et al. | Review on combination strategy of immune checkpoint blockade, photodynamic therapy and nanomedicine against solid tumor | |
| CN111514306A (en) | Fullerene nano-particles for enhancing anti-tumor immunotherapy | |
| JPH0296523A (en) | Platinum chemical remedy product | |
| CN106232588A (en) | Cyclohexenyl group compound, the compositions comprising it and application thereof | |
| JP2022500485A (en) | Grapiplant unit dosage form | |
| EP1549329B1 (en) | Extract with anti-tumor and anti-poisonous activity | |
| CN115414343B (en) | Application of alpha-ketoglutaric acid and derivatives thereof and medicine for preventing and treating skin tumor | |
| AU711536B2 (en) | Composition for treating cancer containing a ribose compound, beta-alanine, ascorbic acid and nicotinic acid | |
| CN115463127A (en) | Application of brucea javanica picrol combined with 17-AAG as PD-L1 inhibitor | |
| TW201919645A (en) | PHOSPHAPLATIN compounds as immuno-modulatory agents and therapeutic uses thereof | |
| WO2021023291A1 (en) | Use of proflavine in treatment of lung cancers | |
| CN113577266A (en) | Compound immunopotentiator and preparation method and application thereof | |
| CN111514290B (en) | Cucurbitacin composition and application thereof | |
| DE4127469A1 (en) | Compsn. contg. chemotherapeutic agent and lithium salt - for treatment of bacterial or viral infection e.g. HSV and HIV, malaria, leishmaniasis, trypanosoma infection and Candida albicans | |
| CN111569078A (en) | Use of SIRT1 inhibitors for side effects caused by combination of VEGFR inhibitors and immune checkpoint inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |