WO2017078049A1 - ジアミノヘテロ環カルボキサミド化合物を有効成分とするがん免疫治療用、及び/又は、免疫活性化用医薬組成物 - Google Patents
ジアミノヘテロ環カルボキサミド化合物を有効成分とするがん免疫治療用、及び/又は、免疫活性化用医薬組成物 Download PDFInfo
- Publication number
- WO2017078049A1 WO2017078049A1 PCT/JP2016/082536 JP2016082536W WO2017078049A1 WO 2017078049 A1 WO2017078049 A1 WO 2017078049A1 JP 2016082536 W JP2016082536 W JP 2016082536W WO 2017078049 A1 WO2017078049 A1 WO 2017078049A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- pharmaceutical composition
- compound
- pharmaceutically acceptable
- acceptable salt
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 67
- 239000004480 active ingredient Substances 0.000 title claims abstract description 28
- 238000002619 cancer immunotherapy Methods 0.000 title claims abstract description 23
- -1 heterocyclic carboxamide compound Chemical class 0.000 title claims description 9
- 230000003308 immunostimulating effect Effects 0.000 title abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 71
- 206010028980 Neoplasm Diseases 0.000 claims description 111
- 201000011510 cancer Diseases 0.000 claims description 70
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 41
- 102000008096 B7-H1 Antigen Human genes 0.000 claims description 41
- 230000007246 mechanism Effects 0.000 claims description 30
- 230000005934 immune activation Effects 0.000 claims description 26
- 230000017188 evasion or tolerance of host immune response Effects 0.000 claims description 23
- 229960003301 nivolumab Drugs 0.000 claims description 12
- 229960002621 pembrolizumab Drugs 0.000 claims description 9
- 229950009791 durvalumab Drugs 0.000 claims description 8
- 229950010773 pidilizumab Drugs 0.000 claims description 8
- 230000001965 increasing effect Effects 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 3
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 46
- 230000000694 effects Effects 0.000 abstract description 4
- GYQYAJJFPNQOOW-UHFFFAOYSA-N gilteritinib Chemical compound N1=C(NC2CCOCC2)C(CC)=NC(C(N)=O)=C1NC(C=C1OC)=CC=C1N(CC1)CCC1N1CCN(C)CC1 GYQYAJJFPNQOOW-UHFFFAOYSA-N 0.000 abstract description 3
- 229940126062 Compound A Drugs 0.000 description 89
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 89
- 210000004027 cell Anatomy 0.000 description 48
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 39
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 39
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 description 26
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 21
- 201000001441 melanoma Diseases 0.000 description 21
- 206010009944 Colon cancer Diseases 0.000 description 20
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 19
- 210000001744 T-lymphocyte Anatomy 0.000 description 16
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 15
- 238000011282 treatment Methods 0.000 description 15
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 15
- 206010060862 Prostate cancer Diseases 0.000 description 14
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 230000014509 gene expression Effects 0.000 description 14
- 208000006265 Renal cell carcinoma Diseases 0.000 description 13
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 13
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 13
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 12
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 12
- 208000005718 Stomach Neoplasms Diseases 0.000 description 12
- 201000004101 esophageal cancer Diseases 0.000 description 12
- 206010017758 gastric cancer Diseases 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 201000011549 stomach cancer Diseases 0.000 description 12
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 11
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 11
- 208000029742 colonic neoplasm Diseases 0.000 description 11
- 206010044412 transitional cell carcinoma Diseases 0.000 description 11
- 206010005003 Bladder cancer Diseases 0.000 description 10
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 10
- 201000010536 head and neck cancer Diseases 0.000 description 10
- 208000014829 head and neck neoplasm Diseases 0.000 description 10
- 201000005112 urinary bladder cancer Diseases 0.000 description 10
- 208000003950 B-cell lymphoma Diseases 0.000 description 9
- 208000006154 Chronic hepatitis C Diseases 0.000 description 9
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 208000005176 Hepatitis C Diseases 0.000 description 9
- 208000017604 Hodgkin disease Diseases 0.000 description 9
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 9
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 9
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 9
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 9
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 9
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 9
- 208000005017 glioblastoma Diseases 0.000 description 9
- 208000010710 hepatitis C virus infection Diseases 0.000 description 9
- 230000000306 recurrent effect Effects 0.000 description 9
- 229940124597 therapeutic agent Drugs 0.000 description 9
- 108090000695 Cytokines Proteins 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 210000000952 spleen Anatomy 0.000 description 7
- 238000007920 subcutaneous administration Methods 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 210000002865 immune cell Anatomy 0.000 description 6
- 230000036039 immunity Effects 0.000 description 6
- 230000002757 inflammatory effect Effects 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 206010033128 Ovarian cancer Diseases 0.000 description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000036737 immune function Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 201000009030 Carcinoma Diseases 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 206010038389 Renal cancer Diseases 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 239000002955 immunomodulating agent Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 201000010982 kidney cancer Diseases 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 3
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 3
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 3
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 3
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 3
- 201000009036 biliary tract cancer Diseases 0.000 description 3
- 208000020790 biliary tract neoplasm Diseases 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 3
- 210000004443 dendritic cell Anatomy 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 description 3
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 208000021039 metastatic melanoma Diseases 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010000830 Acute leukaemia Diseases 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 229940045513 CTLA4 antagonist Drugs 0.000 description 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- 201000001342 Fallopian tube cancer Diseases 0.000 description 2
- 208000013452 Fallopian tube neoplasm Diseases 0.000 description 2
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 2
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108700027336 Suppressor of Cytokine Signaling 1 Proteins 0.000 description 2
- 102100024779 Suppressor of cytokine signaling 1 Human genes 0.000 description 2
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 210000003162 effector t lymphocyte Anatomy 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000037451 immune surveillance Effects 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 201000002628 peritoneum cancer Diseases 0.000 description 2
- 230000002974 pharmacogenomic effect Effects 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000007420 reactivation Effects 0.000 description 2
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 208000032568 B-cell prolymphocytic leukaemia Diseases 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 101000852870 Homo sapiens Interferon alpha/beta receptor 1 Proteins 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- 101000606129 Homo sapiens Tyrosine-protein kinase receptor TYRO3 Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102100036714 Interferon alpha/beta receptor 1 Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- FBKMWOJEPMPVTQ-UHFFFAOYSA-N N'-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboximidamide Chemical compound NS(=O)(=O)NCCNC1=NON=C1C(=NO)NC1=CC=C(F)C(Br)=C1 FBKMWOJEPMPVTQ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 201000005746 Pituitary adenoma Diseases 0.000 description 1
- 206010061538 Pituitary tumour benign Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000035416 Prolymphocytic B-Cell Leukemia Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 101150045565 Socs1 gene Proteins 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 108700027337 Suppressor of Cytokine Signaling 3 Proteins 0.000 description 1
- 102100024283 Suppressor of cytokine signaling 3 Human genes 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102100039127 Tyrosine-protein kinase receptor TYRO3 Human genes 0.000 description 1
- 208000023915 Ureteral Neoplasms Diseases 0.000 description 1
- 206010046392 Ureteric cancer Diseases 0.000 description 1
- 206010046431 Urethral cancer Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 201000003761 Vaginal carcinoma Diseases 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 208000037919 acquired disease Diseases 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000013593 acute megakaryoblastic leukemia Diseases 0.000 description 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 1
- 229960004671 enzalutamide Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 201000001343 fallopian tube carcinoma Diseases 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000029559 malignant endocrine neoplasm Diseases 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000029115 microtubule polymerization Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 101710135378 pH 6 antigen Proteins 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 201000008129 pancreatic ductal adenocarcinoma Diseases 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- 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 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 208000037959 spinal tumor Diseases 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 201000004916 vulva carcinoma Diseases 0.000 description 1
- 208000013013 vulvar carcinoma Diseases 0.000 description 1
Images
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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Definitions
- PD-1 is expressed in T cells and is responsible for immune checkpoints (Pharmacogenomics and Personalized Medicine, 2014; 7: 357-365, Current Opinion in Immunology, 2014; 27: 89-97).
- PD-L1 or PD-L2 which are ligands of PD-1, binds, the activation of T cells is suppressed and the immune response is prevented.
- activated effector T cells recognize cancer cells and produce inflammatory cytokines such as interferon gamma.
- cancer cells increase the expression of PD-L1 in response to inflammatory cytokines, and suppress immune responses by PD-1 positive effector T cells.
- Is marketed as a treatment for malignant melanoma and some other anti-PD-1 or anti-PD-L1 antibodies are also used for malignant melanoma, non-small cell lung cancer, renal cell carcinoma, recurrent glioblastoma Tumor, head and neck cancer, gastric cancer, esophageal cancer, colorectal cancer, bladder cancer, urothelial cancer, hepatocellular carcinoma, prostate cancer, Merkel cell carcinoma, non-Hodgkin lymphoma, Hodgkin lymphoma, B cell lymphoma, acute myeloid leukemia, Or clinical development is underway as a therapeutic agent for chronic hepatitis C.
- compound A that is, 6-ethyl-3-( ⁇ 3- Methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl ⁇ amino) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazine-2-carboxamide or pharmaceutics thereof
- a pharmaceutical composition having an excellent immunostimulatory effect on a chemically acceptable salt, and comprising a compound A or a pharmaceutically acceptable salt thereof as an active ingredient The present invention has been completed by discovering that it is expected to be used as a pharmaceutical composition for immunostimulation and / or immune activation.
- a pharmaceutical composition for cancer immunotherapy comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient.
- the pharmaceutical composition for cancer immunotherapy with respect to the cancer which acquired the immune escape mechanism by the expression of AXL and / or MER containing the compound A or its pharmaceutically acceptable salt as an active ingredient.
- the pharmaceutical composition for immune activation which contains the compound A or its pharmaceutically acceptable salt as an active ingredient.
- a pharmaceutical composition for immune activation comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient.
- CD8-positive cells for cancer that have acquired an immune escape mechanism by expressing AXL and / or MER, comprising administering an effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject.
- the present invention also relates to the following inventions.
- the use of (22), wherein the monoclonal antibody that inhibits the binding between PD-1 and PD-L1 is an antibody selected from nivolumab, pembrolizumab, atelolizumab, pidilizumab, averumab, and durvalumab.
- the present invention is characterized in that the monoclonal antibody that inhibits the binding between PD-1 and PD-L1 is administered simultaneously, separately, sequentially, or at intervals, (22) or (23) Use of.
- Cancer immunotherapy refers to the reactivation of immune cells, particularly activated T cells, whose ability to suppress the growth of cancer cells or to reduce or eliminate cancer cells (hereinafter referred to as antitumor activity) is reduced. And / or means that an anti-cancer treatment is performed by increasing the number of immune cells, particularly activated T cells.
- the pharmaceutical composition of the present invention is administered in combination with a monoclonal antibody that inhibits the binding between PD-1 and PD-L1, and inhibits the binding between the PD-1 and PD-L1 It is expected that the monoclonal antibody that is effective also has a combined effect against cancer.
- a monoclonal antibody that inhibits the binding between PD-1 and PD-L1 include solid cancers.
- Tablets, powders, granules, etc. are used as solid compositions for oral administration.
- one or more active ingredients are mixed with at least one inert excipient.
- the composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
- the pharmaceutical composition of the present invention can be used in combination with various therapeutic agents.
- the combination may be administered simultaneously, separately separately, or at desired time intervals.
- simultaneous administration it may be a combination drug or separately formulated.
- Drugs that can be used in combination include platinum preparations such as cisplatin and carboplatin, antimetabolites such as gemcitabine, pemetrexed, 5-fluorouracil, capecitabine, bendamustine, microtubule polymerization inhibitors such as paclitaxel and vinorelbine, and angiogenesis such as bevacizumab Inhibitors, topoisomerase inhibitors such as irinotecan and etoposide, cytokine preparations such as interferon, kinase inhibitors such as sunitinib, pazopanib, sorafenib and axitinib, antiandrogens such as enzalutamide, temozolomide, dacarbazine, cyclophosp
- the compound A compound of hemifumarate a test compound dissolved in 0.5% methylcellulose
- a group COMPPOUND A 60 mg / kg qd in which compound A hemifumarate was orally administered at a dose of 60 mg / kg once a day for 17 days, and as a control With respect to the group to which Compound A was not administered (control), each change in tumor volume was measured twice a week.
- Example 3 Antitumor Evaluation for Mouse Syngeneic Carcinoma Model Using Combination with PD-1 / PD-L1 Antibody Compound A as Test Compound of the Invention Hemifumarate and Anti-PD-1 Antibody, or Compound A as Test Compound
- Hemifumarate and Anti-PD-1 Antibody, or Compound A as Test Compound The effect of the combined use of hemifumarate and anti-PD-L1 antibody can be confirmed by evaluating the antitumor action and life-prolonging action when administered to a mouse syngeneic tumor-bearing model.
- Examples of cells derived from mouse tumors include CT26, A20, J558, 4T1, and MC38.
- Compound A or a pharmaceutically acceptable salt thereof which is an active ingredient of the pharmaceutical composition of the present invention, has an excellent immunostimulatory action, and based on this action, compound A or a pharmaceutically acceptable salt thereof It is expected that a pharmaceutical composition containing as an active ingredient can be used as a cancer immunotherapeutic agent and / or an immune activator.
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)
- Mycology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
PD-1とPD-L1との結合を阻害する抗体としては、現在までに抗PD-1抗体であるニボルマブ(nivolumab)が悪性黒色腫、非小細胞肺癌の治療剤として、またペンブロリズマブ(pembrolizumab)が悪性黒色腫の治療薬として、それぞれ上市されており、その他いくつかの抗PD-1抗体又は抗PD-L1抗体についても、悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療薬として臨床開発が進められている。ニボルマブを悪性黒色腫に対する第1選択薬として用いた二重盲検の無作為化フェーズ3試験CheckMate-066において、ニボルマブ群の72.9%において全生存期間の延長を示すことが報告されたが、奏功しない患者の存在も認められている。
(17)PD-1とPD-L1との結合を阻害するモノクローナル抗体と組み合わせて投与されることを特徴とする、(2)又は(13)の使用。
(18)PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、(17)の使用。
(19)PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、(17)又は(18)の使用。
(20)PD-1とPD-L1との結合を阻害するモノクローナル抗体の投与を受けている対象におけるがんの治療用である(17)~(19)の使用。
(21)悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療用である(17)~(20)の使用。
(22)PD-1とPD-L1との結合を阻害するモノクローナル抗体と組み合わせて併用投与されることを特徴とする、(3)又は(14)の使用。
(23)PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、(22)の使用。
(24)PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、(22)又は(23)の使用。
(25)PD-1とPD-L1との結合を阻害するモノクローナル抗体の投与を受けている対象におけるがんの治療用である(22)~(24)の使用。
(26)悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療用である(22)~(25)の使用。
(27)PD-1とPD-L1との結合を阻害するモノクローナル抗体と組み合わせて併用投与されることを特徴とする、(4)又は(15)の化合物又はその塩。
(28)PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、(27)の化合物又はその塩。
(29)PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、(27)又は(28)の化合物又はその塩。
(30)PD-1とPD-L1との結合を阻害するモノクローナル抗体の投与を受けている対象におけるがんの治療用である(27)~(29)の化合物又はその塩。
(31)悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療用である(27)~(30)の化合物又はその塩。
(32)PD-1とPD-L1との結合を阻害するモノクローナル抗体の併用治療に用いる場合の治療有効用量、並びに化合物A又はその製薬学的に許容される塩を併用治療に用いる場合の治療有効用量とを組み合わせて、対象に投与することを特徴とするがん免疫治療方法。
(33)化合物A又はその製薬学的に許容される塩が化合物A ヘミフマル酸塩である(32)のがん免疫治療方法。
(34)PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、(32)又は(33)の治療方法。
(35)PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、(32)~(34)の治療方法。
(36)PD-1とPD-L1との結合を阻害するモノクローナル抗体の投与を受けている対象におけるがんの治療用である(32)~(35)の治療方法。
(37)悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療用である(32)~(36)の治療方法。
(38)化合物A又はその製薬学的に許容される塩を含有する免疫活性化によるがん治療剤。
(39)(38)の治療剤であって、PD-1とPD-L1との結合を阻害するモノクローナル抗体と併用されることを特徴とする剤。
(40)PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、(39)の剤。
(41)PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、(39)又は(40)の剤。
(42)PD-1とPD-L1との結合を阻害するモノクローナル抗体の投与を受けている対象におけるがんの治療用である(39)~(41)の剤。
(43)悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療用である(39)~(42)の剤。
上述の通り、化合物Aの化学名は6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミドであり、その化学構造は以下に示すとおりである。
なお、「化合物A又はその製薬学的に許容される塩」のある態様としては、化合物Aが挙げられ、またある態様としては、化合物Aのフマル酸との酸付加塩が挙げられる。またある態様としては、化合物A ヘミフマル酸塩が挙げられる。
投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、関節内、静脈内、筋肉内等の注射剤、坐剤、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。
大腸癌細胞株MC38細胞(National Cancer Institute)を10% Fetal Bovine Serum(FBS)を添加したダルベッコ・フォークト変法イーグル最小必須培地(DMEM)にて培養した。その後、C57BL/6Jマウス(雌、日本チャ-ルスリバー)の背部にMC38細胞を皮下移植することでMC38皮下担癌マウスを作製した。腫瘍の生着を確認した後、0.5% メチルセルロースにて溶解した被験化合物である化合物A ヘミフマル酸塩をフリー体換算で30 mg/kgの用量で1日2回、17日間経口投与した群(COMPOUND A 30 mg/kg bid)、及び化合物A ヘミフマル酸塩をフリー体換算で60 mg/kgの用量で1日1回、17日間経口投与した群(COMPOUND A 60 mg/kg qd)、及び対照として化合物Aを投与していない群(control)について、それぞれの、腫瘍体積の変化を週2回の頻度で測定した。
C57BL/6Jマウス(雌、日本チャ-ルスリバー)の背部にMC38細胞を皮下移植することでMC38皮下担癌マウスを作製した。腫瘍の生着を確認した後、被験化合物である化合物A ヘミフマル酸塩をフリー体換算で100 mg/kgの用量で1日1回、7日間、7例のマウスそれぞれへ経口投与した。また対照として0.5% メチルセルロースも100 mg/kg投与と同様の用法で1日1回、7日間、7例のマウスそれぞれへ経口投与した。投与後4日目、7日目の腫瘍体積の変化を測定した後、対照群から抽出した3例(control-1、control-2及びcontrol-3)および化合物A投与群から抽出した3例(COMPOUND A 100mg/kg qd-1、同qd-2、及び同qd-3)の計6例のマウスから脾臓及び腫瘍を回収し、抗CD3抗体(eBioscience)、抗CD4抗体(Biolegend)、抗CD8抗体(eBioscience)、抗CD45抗体(Biolegend)にて染色を実施し、フローサイトメーター(BD FACSVerse)を用いて各抗原の陽性細胞の数を測定した。
本発明の被験化合物である化合物A ヘミフマル酸塩と抗PD-1抗体、又は被験化合物である化合物A ヘミフマル酸塩と抗PD-L1抗体との併用による効果は、マウス同系担癌モデルに投与した際の抗腫瘍作用と延命作用を評価することにより確認することができる。マウスの腫瘍由来の細胞としては、例えばCT26、A20、 J558、4T1、MC38が挙げられる。
Claims (10)
- 6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩を有効成分として含有するがん免疫治療用医薬組成物。
- がん免疫治療用医薬組成物が、AXL及び/又はMERの発現により免疫逃避機構を獲得したがんに対するがん免疫治療用医薬組成物である、請求項1に記載の医薬組成物。
- 6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩を有効成分として含有する、免疫活性化用医薬組成物。
- 免疫活性化用医薬組成物が、AXL及び/又はMERの発現により免疫逃避機構を獲得したがんに対する免疫活性化用医薬組成物である、請求項3に記載の医薬組成物。
- 免疫活性化が、CD8陽性細胞数の増加作用を介した免疫活性化である、請求項4に記載の医薬組成物。
- PD-1とPD-L1との結合を阻害するモノクローナル抗体と組み合わせて投与されることを特徴とする、請求項1乃至5に記載の医薬組成物。
- PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、請求項6に記載の医薬組成物。
- PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、請求項7に記載の医薬組成物。
- 6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩、及び製薬学的に許容される賦形剤を含有する、請求項1乃至8に記載の医薬組成物。
- 6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩が、6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミド ヘミフマル酸塩である、請求項1乃至9に記載の医薬組成物。
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017548795A JP6859954B2 (ja) | 2015-11-04 | 2016-11-02 | ジアミノヘテロ環カルボキサミド化合物を有効成分とするがん免疫治療用、及び/又は、免疫活性化用医薬組成物 |
ES16862109T ES2894691T3 (es) | 2015-11-04 | 2016-11-02 | Composición farmacéutica para propósitos de inmunoterapia y/o inmunoestimulación que contiene compuesto heterocíclico de diamino-carboxamida como principio activo |
EP16862109.2A EP3372231B1 (en) | 2015-11-04 | 2016-11-02 | Pharmaceutical composition for cancer immunotherapy purposes and/or immunostimulation purposes which contains diamino heterocyclic carboxamide compound as active ingredient |
US15/773,225 US10744134B2 (en) | 2015-11-04 | 2016-11-02 | Pharmaceutical composition for cancer immunotherapy and/or immunological activation containing diamino heterocyclic carboxamide compound as active ingredient |
US16/860,322 US20200289505A1 (en) | 2015-11-04 | 2020-04-28 | Pharmaceutical composition for cancer immunotherapy and/or immunological activation containing diamino heterocyclic carboxamide compound as active ingredient |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015-217152 | 2015-11-04 | ||
JP2015217152 | 2015-11-04 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/773,225 A-371-Of-International US10744134B2 (en) | 2015-11-04 | 2016-11-02 | Pharmaceutical composition for cancer immunotherapy and/or immunological activation containing diamino heterocyclic carboxamide compound as active ingredient |
US16/860,322 Continuation US20200289505A1 (en) | 2015-11-04 | 2020-04-28 | Pharmaceutical composition for cancer immunotherapy and/or immunological activation containing diamino heterocyclic carboxamide compound as active ingredient |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2017078049A1 true WO2017078049A1 (ja) | 2017-05-11 |
Family
ID=58661957
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2016/082536 WO2017078049A1 (ja) | 2015-11-04 | 2016-11-02 | ジアミノヘテロ環カルボキサミド化合物を有効成分とするがん免疫治療用、及び/又は、免疫活性化用医薬組成物 |
Country Status (5)
Country | Link |
---|---|
US (2) | US10744134B2 (ja) |
EP (1) | EP3372231B1 (ja) |
JP (1) | JP6859954B2 (ja) |
ES (1) | ES2894691T3 (ja) |
WO (1) | WO2017078049A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017078049A1 (ja) * | 2015-11-04 | 2017-05-11 | アステラス製薬株式会社 | ジアミノヘテロ環カルボキサミド化合物を有効成分とするがん免疫治療用、及び/又は、免疫活性化用医薬組成物 |
US11945785B2 (en) | 2021-12-30 | 2024-04-02 | Biomea Fusion, Inc. | Pyrazine compounds as inhibitors of FLT3 |
WO2024032410A1 (zh) * | 2022-08-09 | 2024-02-15 | 成都百裕制药股份有限公司 | 哌嗪类化合物和pd-1抑制剂或pd-l1抑制剂的组合物以及其治疗肿瘤的用途 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010128659A1 (ja) * | 2009-05-08 | 2010-11-11 | アステラス製薬株式会社 | ジアミノへテロ環カルボキサミド化合物 |
WO2015016718A1 (en) * | 2013-08-02 | 2015-02-05 | Bionovion Holding B.V. | Combining cd27 agonists and immune checkpoint inhibition for immune stimulation |
WO2015054642A2 (en) * | 2013-10-11 | 2015-04-16 | Genentech, Inc. | Use of cbp/ep300 bromodomain inhibitors for cancer immunotherapy |
WO2015061752A1 (en) * | 2013-10-25 | 2015-04-30 | Pharmacyclics, Inc. | Treatment using bruton's tyrosine kinase inhibitors and immunotherapy |
WO2015119122A1 (ja) * | 2014-02-04 | 2015-08-13 | アステラス製薬株式会社 | ジアミノヘテロ環カルボキサミド化合物を有効成分とする医薬組成物 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8415361B2 (en) * | 2007-11-09 | 2013-04-09 | The Salk Institute For Biological Studies | Use of TAM receptor inhibitors as antimicrobials |
TWI649308B (zh) | 2013-07-24 | 2019-02-01 | 小野藥品工業股份有限公司 | 喹啉衍生物 |
WO2017078049A1 (ja) * | 2015-11-04 | 2017-05-11 | アステラス製薬株式会社 | ジアミノヘテロ環カルボキサミド化合物を有効成分とするがん免疫治療用、及び/又は、免疫活性化用医薬組成物 |
-
2016
- 2016-11-02 WO PCT/JP2016/082536 patent/WO2017078049A1/ja active Application Filing
- 2016-11-02 EP EP16862109.2A patent/EP3372231B1/en active Active
- 2016-11-02 ES ES16862109T patent/ES2894691T3/es active Active
- 2016-11-02 JP JP2017548795A patent/JP6859954B2/ja active Active
- 2016-11-02 US US15/773,225 patent/US10744134B2/en not_active Expired - Fee Related
-
2020
- 2020-04-28 US US16/860,322 patent/US20200289505A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010128659A1 (ja) * | 2009-05-08 | 2010-11-11 | アステラス製薬株式会社 | ジアミノへテロ環カルボキサミド化合物 |
WO2015016718A1 (en) * | 2013-08-02 | 2015-02-05 | Bionovion Holding B.V. | Combining cd27 agonists and immune checkpoint inhibition for immune stimulation |
WO2015054642A2 (en) * | 2013-10-11 | 2015-04-16 | Genentech, Inc. | Use of cbp/ep300 bromodomain inhibitors for cancer immunotherapy |
WO2015061752A1 (en) * | 2013-10-25 | 2015-04-30 | Pharmacyclics, Inc. | Treatment using bruton's tyrosine kinase inhibitors and immunotherapy |
WO2015119122A1 (ja) * | 2014-02-04 | 2015-08-13 | アステラス製薬株式会社 | ジアミノヘテロ環カルボキサミド化合物を有効成分とする医薬組成物 |
Non-Patent Citations (2)
Title |
---|
M. JANE EHRKE: "Immunomodulation in cancer therapeutics", INTERNATIONAL IMMUNOPHARMACOLOGY, vol. 3, 2003, pages 1105 - 1119, XP055381719 * |
See also references of EP3372231A4 * |
Also Published As
Publication number | Publication date |
---|---|
JP6859954B2 (ja) | 2021-04-14 |
ES2894691T3 (es) | 2022-02-15 |
EP3372231B1 (en) | 2021-09-15 |
US20200289505A1 (en) | 2020-09-17 |
US10744134B2 (en) | 2020-08-18 |
EP3372231A1 (en) | 2018-09-12 |
EP3372231A4 (en) | 2019-06-12 |
US20180318295A1 (en) | 2018-11-08 |
JPWO2017078049A1 (ja) | 2018-08-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7189870B2 (ja) | Vista及びpd-1経路の二重阻害剤 | |
AU2016369537B2 (en) | Antibody molecules to PD-1 and uses thereof | |
JP2020114836A (ja) | 免疫療法のための化合物及び組成物 | |
JPWO2020130125A1 (ja) | 抗体−薬物コンジュゲートとキナーゼ阻害剤の組み合わせ | |
JP6757959B2 (ja) | 抗がん剤 | |
JP2017535528A (ja) | 組み合わせ治療 | |
AU2015207757A1 (en) | N-azaspirocycloalkane substituted n-heteroaryl compounds and compositions for inhibiting the activity of SHP2 | |
US10973834B2 (en) | EP4 inhibitors and use thereof | |
CN111386128A (zh) | 用于免疫调节的联合疗法 | |
US20200289505A1 (en) | Pharmaceutical composition for cancer immunotherapy and/or immunological activation containing diamino heterocyclic carboxamide compound as active ingredient | |
BR112020008537A2 (pt) | inibidores duplos de vias da tim-3 e da pd-1 | |
CA3107023A1 (en) | Ep4 inhibitors and synthesis thereof | |
TW201914592A (zh) | 阿帕替尼和c-Met抑制劑聯合在製備治療腫瘤的藥物中的用途 | |
JP2018531278A (ja) | 癌のための併用療法 | |
KR20210079313A (ko) | 암 치료에서 면역 조절을 위한 조합 | |
JP2023105077A (ja) | 標的治療剤を含む併用療法 | |
KR20220026588A (ko) | 높은 간질압을 갖는 종양 피험자의 암을 치료하기 위한 소분자 억제제 | |
WO2015153978A1 (en) | Methods for the treatment of tumors | |
US11878958B2 (en) | MEK inhibitors and uses thereof | |
TW202210071A (zh) | 用於治療癌症的pd-1/pd-l1相互作用的小分子抑制劑和抗pd-1抗體的組合 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16862109 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2017548795 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15773225 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2016862109 Country of ref document: EP |