CN116687933A - 甲氨蝶呤及其药物组合物在肿瘤免疫治疗中的用途 - Google Patents
甲氨蝶呤及其药物组合物在肿瘤免疫治疗中的用途 Download PDFInfo
- Publication number
- CN116687933A CN116687933A CN202210186636.4A CN202210186636A CN116687933A CN 116687933 A CN116687933 A CN 116687933A CN 202210186636 A CN202210186636 A CN 202210186636A CN 116687933 A CN116687933 A CN 116687933A
- Authority
- CN
- China
- Prior art keywords
- tumor
- mtx
- methotrexate
- cells
- enpp1
- 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.)
- Pending
Links
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 title claims abstract description 95
- 229960000485 methotrexate Drugs 0.000 title claims abstract description 93
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 60
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 238000009169 immunotherapy Methods 0.000 title abstract description 3
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 claims abstract description 37
- 229960004432 raltitrexed Drugs 0.000 claims abstract description 37
- 239000003112 inhibitor Substances 0.000 claims abstract description 10
- 238000001959 radiotherapy Methods 0.000 claims abstract description 10
- 101000812677 Homo sapiens Nucleotide pyrophosphatase Proteins 0.000 claims abstract 3
- 102100039306 Nucleotide pyrophosphatase Human genes 0.000 claims abstract 3
- 238000011282 treatment Methods 0.000 claims description 12
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 30
- 241000699670 Mus sp. Species 0.000 abstract description 29
- 210000002865 immune cell Anatomy 0.000 abstract description 10
- 230000008595 infiltration Effects 0.000 abstract description 10
- 238000001764 infiltration Methods 0.000 abstract description 10
- 210000001239 CD8-positive, alpha-beta cytotoxic T lymphocyte Anatomy 0.000 abstract description 7
- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 7
- 230000000779 depleting effect Effects 0.000 abstract description 5
- 230000002708 enhancing effect Effects 0.000 abstract description 4
- 108010067341 ectonucleotide pyrophosphatase phosphodiesterase 1 Proteins 0.000 description 33
- 229960005079 pemetrexed Drugs 0.000 description 27
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 27
- 206010003402 Arthropod sting Diseases 0.000 description 24
- 208000003014 Bites and Stings Diseases 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 24
- 101710196623 Stimulator of interferon genes protein Proteins 0.000 description 21
- RFCBNSCSPXMEBK-INFSMZHSSA-N c-GMP-AMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]3[C@@H](O)[C@H](N4C5=NC=NC(N)=C5N=C4)O[C@@H]3COP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 RFCBNSCSPXMEBK-INFSMZHSSA-N 0.000 description 20
- 238000002474 experimental method Methods 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 16
- 230000004083 survival effect Effects 0.000 description 12
- 210000004881 tumor cell Anatomy 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 101000665442 Homo sapiens Serine/threonine-protein kinase TBK1 Proteins 0.000 description 8
- 241001529936 Murinae Species 0.000 description 8
- 102100038192 Serine/threonine-protein kinase TBK1 Human genes 0.000 description 8
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 102100031256 Cyclic GMP-AMP synthase Human genes 0.000 description 7
- 108030002637 Cyclic GMP-AMP synthases Proteins 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 7
- 230000019491 signal transduction Effects 0.000 description 7
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 6
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 6
- 101150007193 IFNB1 gene Proteins 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 238000013518 transcription Methods 0.000 description 6
- 230000035897 transcription Effects 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- 102000053602 DNA Human genes 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102100026720 Interferon beta Human genes 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 4
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 4
- 101001054334 Homo sapiens Interferon beta Proteins 0.000 description 4
- 102000004889 Interleukin-6 Human genes 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229960005305 adenosine Drugs 0.000 description 4
- 229960003896 aminopterin Drugs 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 238000000111 isothermal titration calorimetry Methods 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 102000002227 Interferon Type I Human genes 0.000 description 3
- 108010014726 Interferon Type I Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000005206 flow analysis Methods 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 101150063370 Gzmb gene Proteins 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000005975 antitumor immune response Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 235000011180 diphosphates Nutrition 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- KUBWJGWIWGGEPZ-UHFFFAOYSA-N 1-[amino(ethoxy)phosphoryl]oxy-4-nitrobenzene Chemical compound CCOP(N)(=O)OC1=CC=C([N+]([O-])=O)C=C1 KUBWJGWIWGGEPZ-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- AHLXCGRWNKUNTQ-UHFFFAOYSA-N 3c-e Chemical compound CCOC1=C(OC)C=C(CC(C)N)C=C1OC AHLXCGRWNKUNTQ-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- 102100022464 5'-nucleotidase Human genes 0.000 description 1
- 102000006267 AMP Deaminase Human genes 0.000 description 1
- 108700016228 AMP deaminases Proteins 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 102000055025 Adenosine deaminases Human genes 0.000 description 1
- 102000009346 Adenosine receptors Human genes 0.000 description 1
- 108050000203 Adenosine receptors Proteins 0.000 description 1
- 206010050559 Aortic valve calcification Diseases 0.000 description 1
- 101100225890 Aplysia californica ENPP gene Proteins 0.000 description 1
- 101150077124 CXCL10 gene Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 1
- 101000643024 Homo sapiens Stimulator of interferon genes protein Proteins 0.000 description 1
- 102100022297 Integrin alpha-X Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 229940044665 STING agonist Drugs 0.000 description 1
- 102100035533 Stimulator of interferon genes protein Human genes 0.000 description 1
- 230000033540 T cell apoptotic process Effects 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 101710086987 X protein Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000013473 artificial intelligence Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 108700009082 methotrexate polyglutamate Proteins 0.000 description 1
- 239000001048 orange dye Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- -1 p-TBK1 Proteins 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000005909 tumor killing Effects 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明提供甲氨蝶呤及其药物组合物在肿瘤免疫治疗中的用途。本发明验证了甲氨蝶呤(MTX)及其类似物雷替曲塞作为ENPP1抑制剂的药物活性,还验证了甲氨蝶呤在增强辐射疗法疗效中的作用,进一步验证了甲氨蝶呤可抑制肿瘤对PD‑1单抗的抵抗,MTX与PD‑1单抗联用增强小鼠肿瘤组织免疫细胞的浸润,增加了活性杀伤性T细胞数量,减少了耗竭性T细胞数量。
Description
技术领域
本发明属于医药技术领域,具体地,本发明涉及
背景技术
甲氨蝶呤(MTX)及其类似物氨基喋呤(AP)、雷替曲塞(RTD)、培美曲塞(PTD)通过拮抗叶酸代谢,干扰DNA和RNA的合成,阻碍肿瘤生长,在临床上被广泛用于多种恶性肿瘤,包括急性白血病[1]、恶性淋巴瘤[2],乳腺癌[3]以及头颈部肿瘤[4]。
甲氨蝶呤在临床上另一个重要的应用就是作为免疫抑制剂来治疗类风湿性关节炎[5]。其作用机制有多种学说,现在被普遍认可的是甲氨蝶呤代谢产物甲氨蝶呤多聚谷氨酸盐间接抑制了AMP脱氨酶和腺苷脱氨酶的活性,增加了细胞外腺苷的释放,腺苷与细胞表面受体结合从而抑制免疫和炎症反应[6]。也有研究报道甲氨蝶呤虽然不能直接诱导T细胞凋亡但是可以逆转T细胞对凋亡的抵抗[7],以及抑制类风湿性关节炎病人体内T细胞中持续激活的NF-κB通路[8],从而减少免疫反应。尽管有许多生物制剂被用于治疗类风湿性关节炎和其他形式的炎症性关节炎,但低剂量甲氨蝶呤治疗仍是类风湿性关节炎治疗的金标准。
干扰素基因刺激蛋白(Stimulator of interferon genes,STING)是位于内质网上的跨膜蛋白,在固有免疫信号通路中发挥着重要的功能[9]。肿瘤细胞来源的DNA可以激活环GMP-AMP合成酶(cyclic GMP-AMP synthase,cGAS)合成第二信使cGAMP,cGAMP结合并激活STING,接着STING激活激酶TBK1和IKK,最终引起Ⅰ型干扰素(typeⅠinterferons,IFNs)和促炎细胞因子的释放[10,11]。Ⅰ型干扰素能够促进肿瘤抗原呈递,活化肿瘤杀伤性CD8T细胞,从而启动对肿瘤的适应性免疫反应[12]。已经有多个STING小分子激动剂被报道可以诱导小鼠抗肿瘤免疫反应并引起肿瘤持久消退[13-15]。
ENPP1(Ectonucleotide pyrophosphatase phosphodiesterase 1)是位于细胞膜外的磷酸二酯酶,可以催化ATP或GTP水解为AMP或GMP,同时生成无机焦磷酸盐。无机焦磷酸盐抑制骨和软骨矿化,ENPP1的过表达会造成焦磷酸盐关节病、主动脉瓣钙化病等疾病[16]。
近来研究报道ENPP1还可以水解cGAMP负调控cGAS-STING信号通路[17],在肿瘤免疫中发挥重要功能。肿瘤细胞表面的ENPP1通过水解cGAMP产生AMP,AMP继续被CD73去磷酸化产生腺苷,腺苷与细胞表面腺苷受体结合发挥免疫抑制作用,共同促进肿瘤细胞的免疫逃逸[18,19]。相对于正常组织,ENPP1在乳腺癌[18],肺癌[19]以及卵巢癌[20]细胞中高表达,这为开发ENPP1抑制剂选择性激活肿瘤微环境中STING通路提供了可能,避免了STING激动剂全身给药带来的免疫过度激活。
【参考文献】:
1.Yoon,S.-A.,et al.,Influence of reduced folate carrier anddihydrofolate reductase genes on methotrexate-induced cytotoxicity.Cancerresearch and treatment,2010.42(3):p.163-171.
2.Kim,A.,et al.,A combination of methotrexate and irradiationpromotes cell death in NK/T-cell lymphoma cells via down-regulation of NF-κBsignaling.Leukemia Research,2012.36(3):p.350-357.
3.Shakeran,Z.,et al.,Biodegradable nanocarriers based on chitosan-modified mesoporous silica nanoparticles for delivery of methotrexate forapplication in breast cancer treatment.2021.118:p.111526.
4.Ham,J.C.,et al.,Methotrexate plus or minus cetuximab as first-linetreatment in arecurrent or metastatic(R/M)squamous cell carcinoma populationof the head and neck(SCCHN),unfit for cisplatin combination treatment,a phaseIb-randomized phase II study Commence.2020.42(5):p.828-838.
5.Cronstein,B.N.and T.M.Aune,Methotrexate and its mechanisms ofaction in inflammatory arthritis.Nature Reviews Rheumatology,2020.16(3):p.145-154.
6.Montesinos,M.C.,et al.,The antiinflammatory mechanism ofmethotrexate depends on extracellular conversion of adenine nucleotides toadenosine by ecto-5′-nucleotidase:findings in a study of ecto-5′-nucleotidasegene–deficient mice.Arthritis Rheum,2007.56(5):p.1440-1445.
7.Spurlock III,C.F.,et al.,Increased sensitivity to apoptosis inducedby methotrexate is mediated by JNK.Arthritis&Rheumatism,2011.63(9):p.2606-2616.
8.Spurlock III,C.F.,et al.,Methotrexate-mediated inhibition ofnuclear factorκB activation by distinct pathways in T cells and fibroblast-like synoviocytes.Rheumatology,2015.54(1):p.178-187.
9.Shang,G.,et al.,Cryo-EM structures of STING reveal its mechanism ofactivation by cyclic GMP–AMP.Nature,2019.
10.Woo,S.-R.,et al.,STING-dependent cytosolic DNA sensing mediatesinnate immune recognition of immunogenic tumors.2014.41(5):p.830-842.
11.Zhang,X.,et al.,Cyclic GMP-AMP containing mixed phosphodiesterlinkages is an endogenous high-affinity ligand for STING.Mol Cell,2013.51(2):p.226-35.
12.Diamond,M.S.,et al.,Type I interferon is selectively required bydendritic cells for immune rejection of tumors.2011.208(10):p.1989-2003.
13.Ramanjulu,J.M.,et al.,Design of amidobenzimidazole STING receptoragonists with systemic activity.Nature,2018.564(7736):p.439-443.
14.Chin,E.N.,et al.,Antitumor activity of a systemic STING-activatingnon-nucleotide cGAMP mimetic.Science,2020.369(6506):p.993.
15.Pan,B.-S.,et al.,An orally available non-nucleotide STING agonistwith antitumor activity.Science,2020.369(6506):p.eaba6098.
16.Onyedibe,K.I.,M.Wang,and H.O.Sintim,ENPP1,an Old Enzyme with NewFunctions,and Small Molecule Inhibitors—A STING in the Tale ofENPP1.Molecules,2019.24(22).
17.Carozza,J.A.,et al.,Extracellular cGAMP is a cancer-cell-producedimmunotransmitter involved in radiation-induced anticancer immunity.NatureCancer,2020.1(2):p.184-196.
18.Lau,W.M.,et al.,Enpp1:a potential facilitator of breast cancerbone metastasis.2013.8(7):p.e66752.
19.Hu,M.,et al.,Dysregulated ENPP1 increases the malignancy of humanlung cancer by inducing epithelial-mesenchymal transition phenotypes and stemcell features.2019.9(1):p.134.
20.Wang,H.,et al.,High expression of ENPP1 in high-grade serousovarian carcinoma predicts poor prognosis and as a molecular therapytarget.2021.16(2):p.e0245733.
发明内容
本发明的一个技术目的是开发一种新型的ENPP1抑制剂。
本发明的另一技术目的是提供一种用于肿瘤治疗的药物组合物。
本发明的又一技术目的是提供甲氨蝶呤在制备肿瘤辐射疗法增效剂的用途。
因此,一方面,本发明提供甲氨蝶呤及雷替曲塞在制备ENPP1抑制剂中的用途。
在具体实施方式中,所述ENPP1抑制剂可用于肿瘤的治疗。
在具体实施方式中,所述肿瘤选自乳腺癌、肺癌、卵巢癌以及结直肠癌。
另一方面,本发明提供甲氨蝶呤在制备肿瘤辐射疗法增效剂中的用途。
在具体实施方式中,所述肿瘤选自乳腺癌、肺癌、卵巢癌以及结直肠癌。
再一方面,本发明提供一种药物组合物,其包含治疗有效量的甲氨蝶呤及PD-1单抗,以及任选地药学上可接受的辅料。
在具体实施方式中,在所述药物组合物中,甲氨蝶呤与PD-1单抗的重量比为1:0.1~1,优选为1:0.5。
再一方面,本发明提供上述药物组合物在制备用于治疗或预防肿瘤的药物中的用途。
在具体实施方式中,所述肿瘤选自乳腺癌、肺癌、卵巢癌以及结直肠癌。
有益效果
本发明采用自行开发的SSGCN模型,预测出了7个对ENPP1可能有活性的化合物,然后通过生物化学(酶活实验)和生物物理(蛋白热迁移、核磁共振、,等温滴定量热法)的方法确定了甲氨蝶呤(MTX)是ENPP1的抑制剂。进一步的细胞和动物实验发现,甲氨蝶呤(MTX)及其类似物氨基喋呤、雷替曲塞,可以抑制ENPP1活性,从而抑制cGAMP水解,增强STING信号通路活性;同时,由于cGAMP和ATP水解减少,导致AMP来源减少,因此MTX及其类似物还可以减少肿瘤微环境中腺苷水平;此外,MTX及其类似物还可以造成乳腺癌、结肠癌等癌细胞中基因组损伤,释放双链DNA,从而激活癌细胞中cGAS-STING信号通路,释放cGAMP、I型干扰素和促炎细胞因子。本发明人还发现MTX及其类似物可以增强肿瘤对辐射疗法的敏感性,可以提高PD-1单抗对敏感肿瘤模型的疗效,还可以使对PD-1单抗不敏感的肿瘤产生抗肿瘤免疫应答。
综上,本发明在以下方面对现有技术做出了贡献:
1.本发明基于人工智能辅助药物设计的方法,发现了MTX及其类似物氨基喋呤、雷替曲塞为强效的ENPP1抑制剂;
2.本发明阐明了MTX在肿瘤微环境中激活肿瘤细胞中cGAS-STING信号通路,同时抑制cGAMP和ATP水解,降低腺苷水平,共同发挥抗肿瘤免疫效果;
3.本发明人发现MTX可以增强肿瘤对辐射疗法的敏感性;
4.本发明人还发现MTX与PD-1单抗联用可以使对PD-1抵抗的肿瘤恢复响应。
附图说明
图1:显示MTX及其类似物(RTD、PTD)以及阳性化合物E1直接与ENPP1结合抑制了其酶活。
A.化合物对人和鼠ENPP1酶活的抑制率;B.化合物升高蛋白热稳定性值;C.一维核磁共振实验显示MTX和RTD与人ENPP1蛋白直接结合。
图2:显示MTX及其类似物(RTD、PTD)与ENPP1结合的KD值。
图3:显示MTX及其类似物抑制胞外cGAMP的水解,增强STING信号通路。
A-B.不同化合物组合处理下细胞外(A)和细胞内(B)cGAMP浓度随时间变化;C-D.不同化合物组合处理下IFNB1和CXCL10基因表达量随时间变化;E.单独MTX、RTD、PTD及STING阳性激动剂cGAMP处理对细胞中IFNB1表达的影响;F.Western Blot检测MTX处理后STING通路激活关键蛋白pSTING,pTBK1,pIRF3表达量。
图4:显示MTX及其类似物激活肿瘤细胞中的cGAS-STING信号通路。
A-C.MTX、RTD与PTD升高了肿瘤细胞中Ifnb1、Cxcl10和Il6的转录水平;D-F.阻断cGAS、STING或者TBK1功能,MTX、RTD以及PTD都不再能促进Ifnb1的转录;G-H.MTX、RTD与PTD造成了细胞质dsDNA积累。
图5:显示MTX增强了肿瘤辐射疗效。
A-B.MTX与辐射疗法联用,使小鼠肿瘤消退(A),延长了小鼠生存期(B);C-F.MTX与辐射联用增强小鼠肿瘤组织免疫细胞的浸润,增加了杀伤性T细胞(CD8+)与树突状细胞(DCs,CD11c+)的数量,P<0.05,**P<0.01,***P<0.001,ns,没有明显差异。
图6:显示MTX增强了PD-1单抗的抗肿瘤效果。
A-B.MTX增强了PD-1单抗对MC-38肿瘤生长的抑制效果,二者联用延长了小鼠生存周期;C-E.MTX与PD-1单抗联用增加小鼠肿瘤组织免疫细胞的浸润,增加了杀伤性T细胞(CD8+)数量,减少了耗竭性T细胞数量(PD1+CD8+),P<0.05,**P<0.01,***P<0.001,ns,没有明显差异。
图7:显示MTX与PD-1单抗联用,克服了4T-1肿瘤细胞对PD-1单抗的抵抗。
A-B.MTX与PD-1单抗联用克服了4T-1肿瘤对PD-1单抗的抵抗,联用延长了小鼠生存周期;C-E.MTX与PD-1单抗联用增强小鼠肿瘤组织免疫细胞的浸润,增加了活性杀伤性T细胞(GzmB+CD8+)数量,减少了耗竭性T细胞数量(PD1+CD8+),P<0.05,**P<0.01,***P<0.001,ns,没有明显差异。
具体实施方式
术语:
甲氨蝶呤类似物:本申请中提及的甲氨蝶呤类似物可包括雷替曲塞(RTD)及培美曲塞(PTD)
以下实施例仅为了本领域的技术人员更好地了解本发明的技术内容,而不用于限制本发明的范围。
实施例1分子水平确证MTX及其类似物RTD、PTD对ENPP1的抑制活性
1.1MTX及其类似物RTD、PTD对重组人源和鼠源ENPP1酶活的影响。
实验方法:
使用重组人源和鼠源ENPP1蛋白,以p-Nph-5’-TMP为底物来进行酶活实验.酶活反应体系中含有50mM Tris-HCl(pH 8.5)、130mM NaCl、1mM CaCl2、5mM KCl、1nM人源或者鼠源ENPP1蛋白和不同浓度的化合物。最后1mM p-Nph-5-TMP启动反应。在37℃下,通过监测产物对硝基苯酚的吸光度变化来表征酶活进程。
实验结果:
如图1A所示,MTX和RTD显著地抑制人源ENPP1酶活,IC50分别是0.16μM和0.67μM;MTX对鼠源ENPP1也有强的抑制效果,IC50为0.57μM;PTD没有活性。
1.2 MTX及其类似物RTD、PTD对重组人源和鼠源ENPP1蛋白热稳定性影响。
实验方法:
采用蛋白热迁移实验评价化合物对蛋白热稳定的影响。反应体系20μL,在白色96孔板中加入1.25μM的鼠源和人源ENPP1蛋白,5xSYPRO Orange染料(Sigma S5692)以及不同浓度的待测化合物。在bio-rad CFX connect仪器上检测,设置加热温度25℃到95℃线性升高,记录温度和荧光强度。使用CFX manager分析温度-荧光数据,拟合得到ENPP1蛋白的溶解温度(Tm)值,DMSO组作为对照,分析不同化合物对ENPP1蛋白Tm值的影响
实验结果:如图1B所示,MTX和RTD都可以与鼠源和人源ENPP1蛋白直接结合,升高其Tm值;PTD基本没有作用。
1.3饱和转移差谱(STD)和T1ρ核磁共振相结合测定MTX及其类似物RTD、PTD与人源ENPP1蛋白的直接结合。
实验方法:
在装载低温冷却探头的核磁共振仪进行饱和转移差谱(STD)和T1p核磁共振实验,实验温度25℃,采集STD谱图和T1ρ谱图。
实验结果:
如图1C所示,MTX和RTD与人源ENPP1蛋白直接结合。
1.4等温滴定量热法(ITC)测定MTX及其类似物RTD、PTD与重组人源ENPP1蛋白的结合解离常数(KD)。
实验方法:
将纯化到的人源ENPP1蛋白与待测化合物都透析到ITC缓冲液中(20mM Tris,150mM NaCl),终浓度分别为20μM与200μM。在ITC200calorimeter(General Electric Co.)上进行化合物滴定蛋白,实时监测热量变化,测定焓变(△H);根据滴定平衡时的浓度计算KD值。
实验结果:
如图2所示,MTX和RTD与人源ENPP1直接结合,KD值分别为0.27μM和0.38μM;PTD没有作用。
实施例2 MTX及其类似物RTD抑制胞外cGAMP的水解,增强STING信号通路
2.1 MTX及其类似物RTD对细胞外和细胞内cGAMP浓度的影响。
实验方法:
提前2小时用10μM的化合物或者DMSO处理THP-1细胞,然后培养基中加入500nM的cGAMP,在孵育6,12,24,48小时后,收集培养基上清和细胞,用试剂盒测定细胞外和细胞内cGAMP浓度。
实验结果:
如图3A-B所示,MTX和RTD可以抑制细胞外cGAMP水解,从而胞外和胞内长时间维持高浓度cGAMP。
2.2 MTX及其类似物RTD对THP-1细胞中STING通路下游IFNB1和CXCL10转录水平的影响。
实验方法:
提前2小时用10μM的化合物或者DMSO处理THP-1细胞,然后培养基中加入500nM的cGAMP,在孵育6,12,24,48小时后,收集细胞,通过RT-qPCR分析IFNB1和CXCL10的mRNA转录水平变化。
实验结果:
如图3C-E所示,MTX和RTD可以增强STING通路下游IFNB1和CXCL10的转录。
2.3 MTX对THP-1细胞中STING蛋白水平及STING下游关键蛋白TBK1、IRF3激活的影响。
实验方法:
提前2小时用10μM的MTX或者DMSO处理THP-1细胞,然后培养基中加入500nM的cGAMP,在孵育8小时后收细胞,WB检测STING蛋白水平及STING下游关键蛋白TBK1、p-TBK1、IRF、p-IRF3的水平。
实验结果:
如图3F所示,MTX升高STING下游TBK1和IRF3的磷酸化水平。
实施例3 MTX及其类似物激活肿瘤细胞中的cGAS-STING信号通路
3.1 MTX及其类似物RTD、PTD对肿瘤细胞中IFN-β、CXCL10及IL-6表达的影响。
实验方法:
肿瘤细胞(4T-1、MC-38)给10μM的化合物,24小时后,收细胞提取RNA,RT-qPCR分析Ifnb1、Cxcl10和Il6的mRNA转录水平的变化。
实验结果:
如图4A-C所示,MTX、RTD与PTD都可以升高肿瘤细胞Ifnb1、Cxcl10和Il6的转录。
3.2阻断STING通路关键蛋白cGAS,STING,TBK1功能,检测MTX对IFN-β、CXCL10及IL-6表达的影响
实验方法:
提前2小时用cGAS,STING,TBK1抑制剂处理4T-1细胞,然后再给10μM MTX、RTD以及PTD,检测对IFN-β、CXCL10及IL-6表达的影响。
实验结果:
如图4D-F所示,阻断cGAS、STING或者TBK1功能,MTX、RTD以及PTD都不再能促进Ifnb1的转录。
3.3 MTX及其类似物RTD、PTD引起肿瘤细胞dsDNA损伤。
实验方法:
4T-1细胞给10μM的化合物(MTX、RTD、PTD),24小时后,收集细胞,分别用westernblot分析H2A.X以及λH2A.X蛋白水平,免疫荧光检测胞质dsDNA和λH2A.X。
实验结果:
如图4G-H所示:MTX、RTD与PTD都增加了λH2A.X的蛋白水平,并且在胞质中检测到了dsDNA。
实施例4甲氨蝶呤对肿瘤辐射疗效的影响
实验方法:
MTX抑制细胞外cGAMP水解,而辐射疗法可以造成DNA损伤,激活cGAS合成cGAMP,这提示MTX可以与辐射联用增强疗效。Balb/c小鼠脂肪垫接种4T-1细胞,待肿瘤体积长到50mm3时,接受12GY辐射治疗,同时开始每天腹腔注射10mg/kg的MTX或者PTD,连续7天,记录小鼠肿瘤体积变化。在给药结束之后,取肿瘤组织,用流式细胞术分析肿瘤组织免疫细胞浸润情况。重新一批Balb/c小鼠脂肪垫接种4T-1细胞,给药方式同上,记录小鼠肿瘤体积和自然死亡时间,根据IACUC动物福利规定,如果肿瘤体积大于2000mm3即认为死亡,然后小鼠安乐死。根据Kaplan-Meier方法计算生存曲线,使用logrank方法进行小鼠存活周期分析。
实验结果:
如图5A-B所示,MTX与辐射联用,使小鼠肿瘤消退,延长存活周期。流式分析结果表明(图5C-F),MTX与辐射联用增强小鼠肿瘤组织免疫细胞的浸润,增加了杀伤性T细胞(CD8+)与树突状细胞(DCs,CD11c+)的数量。
实施例5甲氨蝶呤与Anti-PD1单抗联用对肿瘤生长的影响
5.1甲氨蝶呤与Anti-PD1单抗联用对MC-38肿瘤生长影响。
实验方法:
C57/BL6N小鼠皮下接种MC-38细胞,待肿瘤体积长到50mm3时,每隔3天接受200ugPD-1单抗,持续两次,同时开始每天腹腔注射10mg/kg的MTX或者PTD,连续7天,记录小鼠肿瘤体积变化。在给药结束之后,取肿瘤组织,用流式细胞术分析免疫细胞浸润情况。重新一批C57/BL6N小鼠皮下接种MC-38细胞,给药方式同上,记录小鼠肿瘤体积和自然死亡时间,根据IACUC动物福利规定,如果肿瘤体积大于2000mm3即认为死亡,然后小鼠安乐死。根据Kaplan-Meier方法计算生存曲线,使用logrank方法进行小鼠存活周期分析。
实验结果:
如图6A-B所示,MTX可以增加PD-1单抗对MC-38肿瘤生长的抑制效果,二者联用延长了小鼠生存周期。流式分析表明(图6C-E),MTX与PD-1单抗联用增强小鼠肿瘤组织免疫细胞的浸润,增加了杀伤性T细胞(CD8+)数量,减少了耗竭性T细胞数量(PD1+CD8+)。
5.2甲氨蝶呤与Anti-PD1单抗联用对4T-1肿瘤生长影响。
实验方法:
Balb/c小鼠脂肪垫接种4T-1细胞,给药方式同上,记录小鼠肿瘤体积变化。在给药结束之后,取肿瘤组织,用流式细胞术分析免疫细胞浸润情况。重新一批Balb/c小鼠脂肪垫接种4T-1细胞,给药方式同上,记录小鼠肿瘤体积和自然死亡时间,根据IACUC动物福利规定,如果肿瘤体积大于2000mm3即认为死亡,然后小鼠安乐死。根据Kaplan-Meier方法计算生存曲线,使用logrank方法进行小鼠存活周期分析。
实验结果:
如图7A-B所示,MTX与PD-1单抗联用克服了4T-1肿瘤对PD-1单抗的抵抗,联用延长了小鼠生存周期。流式分析表明(图7C-E),MTX与PD-1单抗联用增强小鼠肿瘤组织免疫细胞的浸润,增加了活性杀伤性T细胞(GzmB+CD8+)数量,减少了耗竭性T细胞数量(PD1+CD8+)。
Claims (10)
1.甲氨蝶呤或雷替曲塞在制备ENPP1抑制剂中的用途。
2.根据权利要求1所述的用途,其中,所述ENPP1抑制剂可用于肿瘤的治疗。
3.根据权利要求2所述的用途,其中,所述肿瘤选自乳腺癌、肺癌、卵巢癌以及结直肠癌。
4.甲氨蝶呤在制备肿瘤辐射疗法增效剂中的用途。
5.根据权利要求4所述的用途,其中,所述肿瘤选自乳腺癌、肺癌、卵巢癌以及结直肠癌。
6.一种药物组合物,其包含治疗有效量的甲氨蝶呤及PD-1单抗,以及任选地药学上可接受的辅料。
7.根据权利要求6所述的药物组合物,其中,在所述药物组合物中,甲氨蝶呤与PD-1单抗的重量比为1:0.1~1。
8.根据权利要求7所述的药物组合物,其中,在所述药物组合物中,甲氨蝶呤与PD-1单抗的重量比为1:0.5。
9.如权利要求6至8任一项所述的药物组合物在制备用于治疗或预防肿瘤的药物中的用途。
10.根据权利要求9所述的用途,其中,所述肿瘤选自乳腺癌、肺癌、卵巢癌以及结直肠癌。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210186636.4A CN116687933A (zh) | 2022-02-28 | 2022-02-28 | 甲氨蝶呤及其药物组合物在肿瘤免疫治疗中的用途 |
PCT/CN2023/077542 WO2023160562A1 (zh) | 2022-02-28 | 2023-02-22 | 甲氨蝶呤及其药物组合物在肿瘤免疫治疗中的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210186636.4A CN116687933A (zh) | 2022-02-28 | 2022-02-28 | 甲氨蝶呤及其药物组合物在肿瘤免疫治疗中的用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116687933A true CN116687933A (zh) | 2023-09-05 |
Family
ID=87764778
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210186636.4A Pending CN116687933A (zh) | 2022-02-28 | 2022-02-28 | 甲氨蝶呤及其药物组合物在肿瘤免疫治疗中的用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN116687933A (zh) |
WO (1) | WO2023160562A1 (zh) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102127063A (zh) * | 2011-01-06 | 2011-07-20 | 深圳市普迈达科技有限公司 | 抗癌药物雷替曲塞的合成新工艺 |
CN102989005A (zh) * | 2012-12-05 | 2013-03-27 | 华侨大学 | 一种负载甲氨蝶呤的磁小体药物载体及其制备方法 |
WO2018050027A1 (zh) * | 2016-09-14 | 2018-03-22 | 北京韩美药品有限公司 | 一种能够特异性地结合pd-1的抗体及其功能片段 |
WO2019005635A2 (en) * | 2017-06-25 | 2019-01-03 | Systimmune, Inc. | ANTI-PD-1 ANTIBODIES AND METHODS OF PREPARATION AND USE |
-
2022
- 2022-02-28 CN CN202210186636.4A patent/CN116687933A/zh active Pending
-
2023
- 2023-02-22 WO PCT/CN2023/077542 patent/WO2023160562A1/zh unknown
Also Published As
Publication number | Publication date |
---|---|
WO2023160562A1 (zh) | 2023-08-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Otsuka et al. | Hedgehog signaling in basal cell carcinoma | |
Beider et al. | Interaction between CXCR4 and CCL20 pathways regulates tumor growth | |
US20200108066A1 (en) | Methods for modulating regulatory t cells and immune responses using cdk4/6 inhibitors | |
JP7495390B2 (ja) | Fgfr1変異陽性脳腫瘍を治療するための医薬組成物及び治療方法 | |
Fontana et al. | Gonadotropin-releasing hormone receptors in prostate cancer: molecular aspects and biological functions | |
CN100478689C (zh) | 多肽及其用途 | |
CN111148527A (zh) | 通用abt化合物及其用途 | |
CN101942017B (zh) | 一种新的肿瘤标志物 | |
Byrne et al. | G-protein-coupled receptors as therapeutic targets for glioblastoma | |
US7892767B2 (en) | Phosphospecific chemokine receptor antibodies | |
CN102348796B (zh) | 新型癌抗原eEF2 | |
Wolf et al. | The clinical relevance of OSM in inflammatory diseases: a comprehensive review | |
Zhang et al. | The potential role of anibamine, a natural product CCR5 antagonist, and its analogues as leads toward development of anti-ovarian cancer agents | |
Dell’Agnola et al. | Clinical utilization of chemokines to combat cancer: the double-edged sword | |
Shin et al. | Histone deacetylase as a valuable predictive biomarker and therapeutic target in immunotherapy for non-small cell lung cancer | |
Yuan et al. | Marsdenia tenacissima extract induces endoplasmic reticulum stress-associated immunogenic cell death in non-small cell lung cancer cells through targeting AXL | |
KR102558988B1 (ko) | 항암제 내성을 완화하고 항암제의 민감성을 강화하기 위한 약학적 조성물 및 그 용도 | |
JP2015502137A (ja) | E1酵素変異体およびその用途 | |
JP5832541B2 (ja) | Kras遺伝子変異型の結腸直腸癌患者に対する抗腫瘍剤及び治療効果予測方法 | |
CN116687933A (zh) | 甲氨蝶呤及其药物组合物在肿瘤免疫治疗中的用途 | |
CN114874308B (zh) | 一种核素标记的抑制肽及其制备方法和应用 | |
US20060093575A1 (en) | Oxaliplatin anti-resistance agent | |
JP6214397B2 (ja) | 新規ホスファチジルイノシトール3キナーゼ阻害剤及び医薬組成物 | |
WO2018162924A1 (en) | Usl-311 for use in the treatment of cancer | |
Zhang et al. | Bioinformatics analysis of breast cancer bone metastasis related gene-CXCR4 |
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 |