KR20220154344A - Cancer immunotherapy composition comprising a statin as an active ingredient - Google Patents
Cancer immunotherapy composition comprising a statin as an active ingredient Download PDFInfo
- Publication number
- KR20220154344A KR20220154344A KR1020210061747A KR20210061747A KR20220154344A KR 20220154344 A KR20220154344 A KR 20220154344A KR 1020210061747 A KR1020210061747 A KR 1020210061747A KR 20210061747 A KR20210061747 A KR 20210061747A KR 20220154344 A KR20220154344 A KR 20220154344A
- Authority
- KR
- South Korea
- Prior art keywords
- cancer
- immuno
- statin
- present
- cells
- Prior art date
Links
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 title claims abstract description 46
- 239000004480 active ingredient Substances 0.000 title claims abstract description 14
- 239000000203 mixture Substances 0.000 title abstract description 18
- 238000002619 cancer immunotherapy Methods 0.000 title 1
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 44
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 32
- 201000011510 cancer Diseases 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 13
- 201000001441 melanoma Diseases 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 15
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 15
- 201000005202 lung cancer Diseases 0.000 claims description 15
- 208000020816 lung neoplasm Diseases 0.000 claims description 15
- 229960002855 simvastatin Drugs 0.000 claims description 15
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 15
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 10
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 10
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 10
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims description 10
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims description 10
- 229960005370 atorvastatin Drugs 0.000 claims description 10
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 10
- 108090000623 proteins and genes Proteins 0.000 claims description 7
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 6
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 6
- 229960003765 fluvastatin Drugs 0.000 claims description 6
- 229960004844 lovastatin Drugs 0.000 claims description 6
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 6
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 6
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 claims description 5
- 229950009116 mevastatin Drugs 0.000 claims description 5
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 claims description 5
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 claims description 5
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 4
- 229960005110 cerivastatin Drugs 0.000 claims description 4
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 claims description 4
- 229960002965 pravastatin Drugs 0.000 claims description 4
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 208000017604 Hodgkin disease Diseases 0.000 claims description 3
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 201000010536 head and neck cancer Diseases 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 229960002797 pitavastatin Drugs 0.000 claims description 3
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 claims description 3
- 229960000672 rosuvastatin Drugs 0.000 claims description 3
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- 206010044412 transitional cell carcinoma Diseases 0.000 claims 2
- 210000004027 cell Anatomy 0.000 abstract description 49
- 102000008096 B7-H1 Antigen Human genes 0.000 abstract description 41
- 230000014509 gene expression Effects 0.000 abstract description 26
- 230000000694 effects Effects 0.000 abstract description 17
- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 9
- 230000036737 immune function Effects 0.000 abstract description 5
- 230000002147 killing effect Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 description 15
- 229940079593 drug Drugs 0.000 description 12
- 239000002253 acid Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 6
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 210000002865 immune cell Anatomy 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 5
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 5
- -1 alkaline earth metal salt Chemical class 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 3
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 244000299461 Theobroma cacao Species 0.000 description 2
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 2
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 235000014121 butter Nutrition 0.000 description 2
- 235000001046 cacaotero Nutrition 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000000174 gluconic acid Substances 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012457 nonaqueous media Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000000123 paper Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- BNNMDMGPZUOOOE-UHFFFAOYSA-N 4-methylbenzenesulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1 BNNMDMGPZUOOOE-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000282817 Bovidae Species 0.000 description 1
- 101150091609 CD274 gene Proteins 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 229940123239 Cholesterol synthesis inhibitor Drugs 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 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
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101100407305 Homo sapiens CD274 gene Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 108010015268 Integration Host Factors 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000024799 Thyroid disease Diseases 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 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
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 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
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 208000026758 coronary atherosclerosis Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000008004 immune attack Effects 0.000 description 1
- 230000005746 immune checkpoint blockade Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 239000000314 lubricant Substances 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
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- GXHMMDRXHUIUMN-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O GXHMMDRXHUIUMN-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 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
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- DFVFTMTWCUHJBL-BQBZGAKWSA-N statine Chemical compound CC(C)C[C@H](N)[C@@H](O)CC(O)=O DFVFTMTWCUHJBL-BQBZGAKWSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 208000021510 thyroid gland disease Diseases 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 스타틴을 유효성분으로 포함하는 면역항암제 조성물에 관한 것이다.The present invention relates to an immuno-anticancer composition comprising a statin as an active ingredient.
면역항암제는 암세포가 인체의 면역체계를 회피하지 못하도록 하거나 면역세포가 암세포를 더 잘 인식하여 공격하도록 하는 약물이다. 인체의 면역체계를 통해 작용하기 때문에, 기존의 항암제들이 가졌던 부작용은 상대적으로 높지 않으나, 면역 체계의 변화로 인한 갑상선질환, 폐렴, 장염 등이 보고되었으며, 면역항암제의 종류로는 면역관문억제제, 면역세포치료제, 항암바이러스치료제 등이 있다.Immuno-anticancer drugs are drugs that prevent cancer cells from evading the body's immune system or allow immune cells to better recognize and attack cancer cells. Because they act through the body's immune system, the side effects of existing anticancer drugs are relatively low, but thyroid disease, pneumonia, and enteritis have been reported due to changes in the immune system. There are cell therapies, anticancer virus therapies, and the like.
인체 면역기능은 항원인지와 동시에 이러한 동시자극과 동시 억제 신호의 조절을 통하여 전체적인 T세포 기능이 조절된다. 면역세포들은 인체의 감염조직 및 변형조직 등 변화로 인해 발현되는 항원을 감지하고 이러한 조직들을 제거한다. 하지만 암세포는 면역공격을 회피하기 위하여 종양미세환경을 변화시켜 면역기능을 억제하거나 T세포 면역관용 또는 면역편집 등을 통하여 면역회피를 추구한다. 이 회피전략의 하나로 면역관문 기능을 변화시켜 T세포의 기능을 억제한다. 즉, 면역관문은 암세포 파괴를 방해하는 단백질로 암은 면역관문 (immune checkpoint)을 활성화시켜 T세포의 공격을 회피한다.The human body's immune function controls antigen recognition and overall T cell function through the regulation of co-stimulatory and co-inhibitory signals. Immune cells detect antigens that are expressed due to changes such as infected and transformed tissues in the body and remove these tissues. However, cancer cells suppress immune function by changing the tumor microenvironment in order to evade immune attack, or seek immune evasion through T cell immune tolerance or immunoediting. One of these evasion strategies is to suppress the function of T cells by changing the function of the immune checkpoint. In other words, the immune checkpoint is a protein that interferes with the destruction of cancer cells, and cancer activates the immune checkpoint to evade the attack of T cells.
즉, 면역관문억제제 (immune checkpoint inhibitor)는 면역반응 회피 신호를 억제해 면역세포가 감염 및 변형 조직을 공격하게 하는 원리로, 면역반응을 자극시키는 단백질을 증진시키거나 면역반응을 억제하는 단백질 (PD-1, PD-L1)을 차단해 인체의 면역반응을 조절한다.In other words, an immune checkpoint inhibitor is a principle that suppresses immune response evasion signals to allow immune cells to attack infected and transformed tissues. -1, PD-L1) to regulate the body's immune response.
다양한 종류의 암세포에서 PD-L1 단백질의 발현이 증가되어 있으며, 암세포에서 발현되는 PD-L1 단백질은 세포독성 T세포의 PD-1 단백질과 결합을 통해 면역세포에 의한 암세포사멸로부터 회피할 수 있으며, 악성종양으로 성장하고 다른 장기로 전이될 수 있다.Expression of PD-L1 protein is increased in various types of cancer cells, and PD-L1 protein expressed in cancer cells can avoid cancer cell death by immune cells through binding to PD-1 protein of cytotoxic T cells. It can grow as a malignant tumor and metastasize to other organs.
이러한 암세포의 PD-L1과 세포독성 T세포의 PD-1 단백질간의 상호결합을 제어하는 항체 의약품으로써 다양한 면역관문억제제들이 개발되었으며, 현재 항암치료제로 널리 사용되고 있다.Various immune checkpoint inhibitors have been developed as antibody drugs that control the interaction between PD-L1 of these cancer cells and PD-1 protein of cytotoxic T cells, and are currently widely used as anticancer drugs.
한편, 스타틴 (statin)이란 콜레스테롤 합성 저해제 (cholesterol synthesis inhibitor)로서, 콜레스테롤 합성 경로의 율속효소인 히드록시메틸글루타릴-CoA 환원효소 (HMG-CoA 환원효소)의 총칭이며, 각종 스타틴은 기본구조로서 같은 구조를 가지고 있다. 이 화합물은 분자 내에 HMG-CoA환원효소의 기질인 HMG-CoA와 유사한 구조를 하며, 경합 저해에 의해 메발론산으로의 변환을 억제하고, 이를 통하여 총 콜레스테롤 수치와 저밀도 지방단백질 (low density lipoprotein; LDL)의 수치를 낮출 수 있기 때문에, 고지혈증, 고콜레스테롤혈증, 고혈압, 협심증 등의 치료제로서 널리 사용되고 있으며, 이외에도 협심증, 심근경색증과 같은 관상동맥경화증으로 인한 심장병의 예방 및 치료에 있어서 일차 선택 약으로 사용되고 있다. 현재는 세계에서 하루 3천만명 이상 복용하고 있는 일반화된 약물이다. 그러나 스타틴의 면역관문억제를 통한 암 치료 효과에 대해서는 전혀 연구된 바가 없다.On the other hand, statin is a cholesterol synthesis inhibitor, and is a generic term for hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase), which is a rate-limiting enzyme in the cholesterol synthesis pathway. Various statins have a basic structure has the same structure as This compound has a structure similar to HMG-CoA, a substrate of HMG-CoA reductase in the molecule, and inhibits conversion to mevalonic acid by inhibiting competition, thereby reducing total cholesterol level and low density lipoprotein (LDL). ), it is widely used as a treatment for hyperlipidemia, hypercholesterolemia, hypertension, angina pectoris, etc. In addition, it is used as a first-choice drug in the prevention and treatment of heart disease caused by coronary atherosclerosis such as angina pectoris and myocardial infarction. have. It is now a common drug that is taken by more than 30 million people a day worldwide. However, no studies have been conducted on the cancer treatment effect of statins through immune checkpoint inhibition.
본 발명의 목적은 스타틴 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역항암제 조성물을 제공하는 데 있다.An object of the present invention is to provide an immuno-anticancer composition comprising a statin or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명의 다른 목적은 스타틴 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역항암제 조성물을 인간을 제외한 개체에 투여하는 단계를 포함하는 암 치료 방법을 제공하는 데 있다.Another object of the present invention is to provide a cancer treatment method comprising the step of administering an immuno-anticancer composition comprising a statin or a pharmaceutically acceptable salt thereof as an active ingredient to a non-human subject.
상기와 같은 목적을 달성하기 위해, 본 발명은 스타틴 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역항암제 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides an immuno-anticancer pharmaceutical composition comprising a statin or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 상기 스타틴은 심바스타틴 (simvastatin), 아토르바스타틴 (atorvastatin), 로바스타틴 (lovastatin), 플루바스타틴 (fluvastatin), 로슈바스타틴 (rosuvastatin), 피타바스타틴 (pitavastatin), 프라바스타틴 (pravastatin), 세리바스타틴 (cerivastatin) 및 메바스타틴 (mevastatin)으로 이루어진 군에서 선택된 어느 하나인 것일 수 있다.In addition, the statins include simvastatin, atorvastatin, lovastatin, fluvastatin, rosuvastatin, pitavastatin, pravastatin, cerivastatin ( cerivastatin) and mevastatin (mevastatin) may be any one selected from the group consisting of.
또한, 상기 면역항암제 약학 조성물은 면역관문억제제 (immune checkpoint inhibitor)일 수 있다.In addition, the immuno-anticancer pharmaceutical composition may be an immune checkpoint inhibitor.
이어서, 본 발명은 스타틴 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역항암제를 인간을 제외한 개체에 투여하는 단계를 포함하는 암 치료 방법을 제공한다.Then, the present invention provides a cancer treatment method comprising the step of administering an immuno-anticancer agent comprising a statin or a pharmaceutically acceptable salt thereof as an active ingredient to a non-human subject.
본 발명의 스타틴 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역항암제 조성물은 PD-L1 (Programmed death-ligand 1)의 발현을 억제하여 PD-L1과 PD-1이 결합하지 못하도록 막음으로써 T세포의 면역 기능이 유지시켜 암 세포를 사멸하는 효과가 있다.The immuno-anticancer composition containing the statin or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient suppresses the expression of programmed death-ligand 1 (PD-L1) and blocks the binding between PD-L1 and PD-1. It has the effect of killing cancer cells by maintaining the immune function of T cells.
도 1은 인간폐암세포에서 스타틴에 대한 PD-L1 단백질 발현 변화를 나타낸 도이다.
도 2는 인간흑색종세포에서 스타틴에 대한 PD-L1 단백질 발현 변화를 나타낸 도이다.
도 3은 인간흑색종세포에서 스타틴 처리 후 시간에 따른 PD-L1 단백질 발현 변화를 나타낸 도이다.
도 4는 인간흑색종세포 및 인간폐암세포에서 스타틴에 대한 PD-L1 유전자 발현 변화를 나타낸 도이다.1 is a diagram showing changes in PD-L1 protein expression in response to statins in human lung cancer cells.
2 is a diagram showing changes in PD-L1 protein expression in response to statins in human melanoma cells.
3 is a diagram showing changes in PD-L1 protein expression over time after statin treatment in human melanoma cells.
4 is a diagram showing changes in PD-L1 gene expression in response to statins in human melanoma cells and human lung cancer cells.
이하, 첨부된 도면을 참조하여 본 발명의 실시예로 본 발명을 상세히 설명하기로 한다. 다만, 하기 실시예는 본 발명에 대한 예시로 제시되는 것으로, 당업자에게 주지 저명한 기술 또는 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우에는 그 상세한 설명을 생략할 수 있고, 이에 의해 본 발명이 제한되지는 않는다. 본 발명은 후술하는 특허 청구범위의 기재 및 그로부터 해석되는 균등 범주 내에서 다양한 변형 및 응용이 가능하다.Hereinafter, the present invention will be described in detail by embodiments of the present invention with reference to the accompanying drawings. However, the following examples are presented as examples of the present invention, and if it is determined that detailed descriptions of well-known techniques or configurations may unnecessarily obscure the gist of the present invention, the detailed descriptions may be omitted. , the present invention is not limited thereby. Various modifications and applications of the present invention are possible within the description of the claims described later and equivalent scopes interpreted therefrom.
또한, 본 명세서에서 사용되는 용어 (terminology)들은 본 발명의 바람직한 실시 예를 적절히 표현하기 위해 사용된 용어들로서, 이는 사용자, 운용자의 의도 또는 본 발명이 속하는 분야의 관례 등에 따라 달라질 수 있다. 따라서 본 용어들에 대한 정의는 본 명세서 전반에 걸친 내용을 토대로 내려져야 할 것이다. 명세서 전체에서, 어떤 부분이 어떤 구성요소를 “포함”한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In addition, the terms (terminology) used in this specification are terms used to appropriately express preferred embodiments of the present invention, which may vary according to the intention of a user or operator or customs in the field to which the present invention belongs. Therefore, definitions of these terms should be made based on the contents throughout this specification. Throughout the specification, when a certain component is said to "include", it means that it may further include other components without excluding other components unless otherwise stated.
본 명세서 전체에 걸쳐, 특정 물질의 농도를 나타내기 위하여 사용되는 '%'는 별도의 언급이 없는 경우, 고체/고체는 (w/w) %, 고체/액체는 (w/v) %, 그리고 액체/액체는 (v/v) %이다.Throughout this specification, '%' used to indicate the concentration of a particular substance is solid/solid (w/w) %, solid/liquid (w/v) %, and Liquid/liquid is (v/v) %.
본 발명은 스타틴 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역항암제 약학 조성물을 제공한다.The present invention provides an immuno-anticancer pharmaceutical composition comprising a statin or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일실시예에 있어서, 상기 스타틴은 심바스타틴 (simvastatin), 아토르바스타틴 (atorvastatin), 로바스타틴 (lovastatin), 플루바스타틴 (fluvastatin), 로슈바스타틴 (rosuvastatin), 피타바스타틴 (pitavastatin), 프라바스타틴 (pravastatin), 세리바스타틴 (cerivastatin) 및 메바스타틴 (mevastatin)으로 이루어진 군에서 선택된 어느 하나인 것일 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, the statin is simvastatin, atorvastatin, lovastatin, fluvastatin, rosuvastatin, pitavastatin, pravastatin ( It may be any one selected from the group consisting of pravastatin, cerivastatin, and mevastatin, but is not limited thereto.
본 발명의 일실시예에 있어서, 상기 심바스타틴 (simvastatin)은 하기 화학식 1로 표시되는 것일 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, the simvastatin may be represented by Chemical Formula 1 below, but is not limited thereto.
본 발명의 일실시예에 있어서, 상기 아토르바스타틴 (atorvastatin)은 하기 화학식 2로 표시되는 것일 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, the atorvastatin may be represented by Chemical Formula 2 below, but is not limited thereto.
본 발명의 일실시예에 있어서, 상기 로바스타틴 (lovastatin)은 하기 화학식 3으로 표시되는 것일 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, the lovastatin may be represented by Chemical Formula 3 below, but is not limited thereto.
본 발명의 일실시예에 있어서, 상기 플루바스타틴 (fluvastatin)은 하기 화학식 4로 표시되는 것일 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, the fluvastatin may be represented by Chemical Formula 4 below, but is not limited thereto.
본 발명의 스타틴은 당해 기술분야에서 통상적인 방법에 따라 약학적으로 허용 가능한 염으로 제조될 수 있다.The statin of the present invention can be prepared as a pharmaceutically acceptable salt according to a conventional method in the art.
본 발명의 염으로는 약학적으로 허용 가능한 염으로는 유리산 (free acid)에 의해 형성된 산부가염이 유용하다. 산부가염은 통상의 방법, 예를 들면 화합물을 과량의 산 수용액에 용해시키고, 이 염을 메탄올, 에탄올, 아세톤 또는 아세토니트릴과 같은 수혼화성 유기 용매를 사용하여 침전시켜서 제조한다. 동일한 몰량의 화합물 및 물중의 산 또는 알코올 (예, 글리콜 모노메틸에테르)을 가열하고 이어서 상기 혼합물을 증발시켜서 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.As the salt of the present invention, an acid addition salt formed by a free acid is useful as a pharmaceutically acceptable salt. Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an aqueous solution of excess acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and an acid or alcohol (eg, glycol monomethyl ether) in water can be heated and then the mixture evaporated to dryness, or the precipitated salt can be suction filtered.
이 때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아 세트산, 시트르산, 말레인산 (maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산 (propionic acid), 구연산 (citric acid), 젖산 (lactic acid), 글리콜산 (glycollic acid), 글루콘산 (gluconic acid), 갈락투론산, 글루탐산, 글루타르산 (glutaric acid), 글루쿠론산 (glucuronic acid), 아스파르트산, 아스코르빈산, 카본산, 바닐릭산 및 히드로 아이오딕산 등을 사용할 수 있다.At this time, organic acids and inorganic acids can be used as free acids, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid can be used as organic acids. , citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, and the like can be used.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리토 금속염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리토 금속 수산화물 용액 중에 용해하고, 비 용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하며, 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리토 금속염을 적당한 은염 (예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable for pharmaceutically to prepare a sodium, potassium or calcium salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
본 발명의 스타틴의 약학적으로 허용 가능한 염은, 달리 지시되지 않는 한, 본 발명의 화합물에 존재할 수 있는 산성 또는 염기성기의 염을 포함한다. 예를 들면, 약학적으로 허용 가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨염이 포함되며, 아미노기의 기타 약학적으로 허용 가능한 염으로는 하이드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄설포 네이트 (메실레이트) 및 p-톨루엔설포네이트 (토실레이트) 염이 있으며, 당업계에서 알려진 염의 제조 방법이나 제조과정을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the statins of the present invention include, unless otherwise indicated, salts of acidic or basic groups that may be present in the compounds of the present invention. For example, pharmaceutically acceptable salts include the sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and methods or processes for preparing salts known in the art can be produced through
또한, 본 발명의 스타틴 및 이의 약학적으로 허용 가능한 염뿐만 아니라, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 이성질체, 광학 이성질체 및 R 또는 S형 입체 이성질체 및 이들의 혼합물 등을 모두 포함한다. 예를 들어, 거울상 이성질체 형태로 존재할 수 있다. 본 발명은 라세미체, 하나 이상의 거울상 이성질체 형태, 하나 이상의 부분 입체 이성질체 형태 또는 이들의 혼합물의 용도를 포함하며, 당업계에서 알려진 이성질체의 분리 방법이나 제조과정을 포함한다.In addition, the statin of the present invention and its pharmaceutically acceptable salts, as well as possible solvates, hydrates, isomers, optical isomers, R or S stereoisomers and mixtures thereof that can be prepared therefrom are included. For example, they may exist in enantiomeric forms. The present invention includes the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof, and includes methods for isomer separation or preparation known in the art.
본 발명의 스타틴 또는 이의 약학적으로 허용가능한 염은 당업계에 잘 알려진 실리카겔 컬럼, 및 재결정법을 이용한 정제과정을 반복수행하는 분리 방법 및 정제방법으로부터 분리하는 방법 또는 화학적으로 합성하여 제조하거나, 상업적으로 구입가능하다.The statin or a pharmaceutically acceptable salt thereof of the present invention is prepared by separating from a separation method and purification method in which a silica gel column well-known in the art and a recrystallization method are repeatedly performed, or chemically synthesized, or commercially available. can be purchased with
본 발명의 일실시예에 있어서, 면역항암제는 면역관문억제제 (immune checkpoint inhibitor)일 수 있다.In one embodiment of the present invention, the immuno-anticancer agent may be an immune checkpoint inhibitor.
본 발명의 일실시예에 있어서, 상기 면역관문억제제는 PD-L1 유전자 또는 단백질을 억제하는 것일 수 있다.In one embodiment of the present invention, the immune checkpoint inhibitor may inhibit the PD-L1 gene or protein.
본 발명에서 사용되는 용어 “면역항암제”는 면역항암제는 암세포가 인체의 면역체계를 회피하지 못하도록 하거나 면역세포가 암세포를 더 잘 인식하여 공격하도록 하는 약물을 의미한다. 면역항암제의 종류로는 면역관문억제제, 면역세포치료제, 항암바이러스치료제 등이 있다.As used herein, the term "immuno-anticancer agent" refers to a drug that prevents cancer cells from evading the body's immune system or allows immune cells to better recognize and attack cancer cells. Types of immuno-anticancer agents include immune checkpoint inhibitors, immune cell therapy agents, and anticancer virus therapy agents.
본 발명에서 사용되는 용어 “면역관문억제제 (immune checkpoint inhibitor)”는 T 세포 억제에 관여하는 면역체크포인트 단백질 (immune checkpoint protein)의 활성을 차단하여 T 세포를 활성화시켜 암세포를 공격하는 약제를 말한다. 면역체크포인트 단백질은 대표적으로 CTLA-4, PD-1, PD-L1이 있다.As used herein, the term "immune checkpoint inhibitor" refers to a drug that attacks cancer cells by activating T cells by blocking the activity of immune checkpoint proteins involved in T cell suppression. Representative immune checkpoint proteins include CTLA-4, PD-1, and PD-L1.
본 발명의 일실시예에 있어서, 상기 암은 흑색종, 폐암, 요로상피암, 유방암, 방광암, 신장암, 호지킨림프종, 두경부암 및 위암으로 이루어진 군에서 선택되는 것일 수 있으나, PD-L1을 발현하는 암 또는 종양이라면 제한되지 않고 사용될 수 있다.In one embodiment of the present invention, the cancer may be selected from the group consisting of melanoma, lung cancer, urinary tract cancer, breast cancer, bladder cancer, kidney cancer, Hodgkin's lymphoma, head and neck cancer, and stomach cancer, but expressing PD-L1 It can be used without limitation if it is a cancer or tumor.
본 발명의 일실시예에 있어서, 상기 스타틴은 2 μM 이상의 농도로 포함되는 것일 수 있고, 바람직하게는 2 내지 10 μM의 농도로 포함되는 것일 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, the statin may be included at a concentration of 2 μM or more, and preferably may be included at a concentration of 2 to 10 μM, but is not limited thereto.
본 발명의 일실시예에 있어서, 본 발명의 면역항암제는 암 예방 또는 치료용 약학적 조성물로 사용될 수 있다.In one embodiment of the present invention, the immuno-anticancer agent of the present invention can be used as a pharmaceutical composition for preventing or treating cancer.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에서 사용되는 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여, 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" means an amount that is sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is the patient's health The condition, type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and excretion rate, duration of treatment, factors including drugs used in combination or concurrently, and other factors well known in the medical field can be determined according to The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. Considering all of the above factors, it is important to administer the amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
본 발명에서 "개체"는 암을 예방 또는 치료를 목적으로 하는 개체이면 특별히 한정되지 않고, 인간을 포함하는 동물, 예를 들어 비-영장류 (예를 들면, 소, 돼지, 말, 고양이, 개, 래트 및 마우스) 및 영장류 (예를 들면, 원숭이, 예를 들어 사이노몰구스 (cynomolgous) 원숭이 및 침팬지)를 비롯한 포유동물을 나타낸다. 때에 따라서는 인간을 제외하는 개체일 수 있다.In the present invention, "individual" is not particularly limited as long as it is an individual for the purpose of preventing or treating cancer, and animals including humans, such as non-primates (eg, cows, pigs, horses, cats, dogs, rats and mice) and primates (eg, monkeys such as cynomolgous monkeys and chimpanzees). In some cases, it may be an entity excluding humans.
본 발명에 따른 조성물은 약학적으로 유효한 양의 스타틴 또는 이의 약학적으로 허용가능한 염을 단독으로 포함하거나 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 포함할 수 있다. 상기에서 약학적으로 유효한 양이란 면역질환의 증상을 예방, 개선 및 치료하기에 충분한 양을 말한다. 상기에서 "약학적으로 허용되는"이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. The composition according to the present invention may include a pharmaceutically effective amount of a statin or a pharmaceutically acceptable salt thereof alone or may include one or more pharmaceutically acceptable carriers, excipients or diluents. In the above, the pharmaceutically effective amount refers to an amount sufficient to prevent, improve, and treat symptoms of immune diseases. In the above, "pharmaceutically acceptable" refers to a composition that is physiologically acceptable and does not cause allergic reactions such as gastrointestinal disorders and dizziness or similar reactions when administered to humans.
또한, 약학적으로 허용 가능한 담체를 포함하는 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 상기 담체, 부형제 및 희석제로는 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 생리식염수, 메틸히드록시벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유, 덱스트린, 칼슘카보네이트, 프로필렌글리콜 및 리퀴드 파라핀으로 이루어진 군에서 선택된 하나 이상일 수 있으나, 이에 한정되는 것은 아니며, 통상의 담체, 부형제 또는 희석제 모두 사용 가능하다. 상기 성분들은 상기 유효성분인 스타틴 또는 이의 약학적으로 허용가능한 염에 독립적으로 또는 조합하여 추가될 수 있다.In addition, the composition including a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. When formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. The carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, It may be at least one selected from the group consisting of polyvinyl pyrrolidone, physiological saline, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, dextrin, calcium carbonate, propylene glycol, and liquid paraffin. It is not limited, and all conventional carriers, excipients or diluents can be used. These components may be added independently or in combination with the active ingredient, statine or a pharmaceutically acceptable salt thereof.
또한, 경구 투여를 위한 고형제제에는 정제환제, 산제, 과립제, 캡슐제 등이 포함될 수 있으며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로오스 (sucrose) 또는 락토오스 (lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.In addition, solid preparations for oral administration may include tablets, pills, powders, granules, capsules, etc., and such solid preparations may contain at least one excipient, for example, starch, calcium carbonate, sucrose, etc., in one or more compounds. Alternatively, it may be prepared by mixing lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. have.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, freeze-dried formulations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used.
또한, 본 발명의 약학적 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.In addition, the pharmaceutical composition of the present invention is a group consisting of tablets, pills, powders, granules, capsules, suspensions, internal solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. It may have any one formulation selected from. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여 (예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양하다. 상기 스타틴계 약물 및 윈트 신호 전달 조절제 조합의 일일 투여량은 스타틴의 경우 약 10~80㎎/㎏이 바람직하나 임상실험결과에 따라 가감될 수 있으며, 하루 일회 내지 수회에 나누어 투여하는 것이 바람직하다.The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) depending on the desired method, and the dosage is determined by the patient's body weight, age, sex, The range varies according to health status, diet, administration time, administration method, excretion rate, and severity of disease. The daily dose of the combination of the statin drug and the Wint signal transduction regulator is preferably about 10 to 80 mg/kg in the case of statin, but may be increased or decreased according to clinical trial results, and is preferably administered once or several times a day.
본 발명의 약학적 조성물은 암의 예방 또는 치료 효과를 위하여 단독으로, 또는 수술, 호르몬 치료, 약물 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modifiers for the prevention or treatment of cancer.
이어서, 본 발명은 스타틴 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역항암제를 인간을 제외한 개체에 투여하는 단계를 포함하는 암 치료 방법을 제공한다.Then, the present invention provides a cancer treatment method comprising the step of administering an immuno-anticancer agent comprising a statin or a pharmaceutically acceptable salt thereof as an active ingredient to a non-human subject.
상기 암 치료 방법은 상술한 스타틴 또는 이의 약학적으로 허용 가능한 염을 포함하기 때문에, 상술한 본 발명의 스타틴 또는 이의 약학적으로 허용 가능한 염과 중복된 내용은 중복된 내용의 기재에 의한 본 명세서의 과도한 복잡성을 피하기 위하여 그 기재를 생략한다.Since the cancer treatment method includes the above-described statin or pharmaceutically acceptable salt thereof, the contents overlapping with the above-described statin or pharmaceutically acceptable salt thereof of the present invention are described in the present specification according to the overlapping contents. Its description is omitted to avoid undue complexity.
본 발명의 상기 예방 또는 치료 방법은 구체적으로, 암이 발병하였거나 발병할 위험이 있는 개체에 상기 면역항암제를 약학적으로 유효한 양으로 투여하는 단계를 포함할 수 있다.Specifically, the preventive or therapeutic method of the present invention may include administering the immuno-anticancer agent in a pharmaceutically effective amount to a subject who has or is at risk of developing cancer.
본 발명에서 사용되는 용어, "개체"란, 암이 발병되었거나 발병할 가능성이 있는 인간을 포함한 모든 동물을 의미할 수 있다. 상기 동물은 인간뿐만 아니라 이와 유사한 증상의 치료를 필요로 하는 소, 말, 양, 돼지, 염소, 낙타, 영양, 개, 고양이 등의 포유동물일 수 있으나, 이에 제한되지는 않는다.As used herein, the term "subject" may refer to all animals, including humans, who have or are likely to develop cancer. The animal may be not only humans but also mammals such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, and cats that require treatment for similar symptoms, but are not limited thereto.
본 발명에서 사용되는 용어 “약학적으로 유효한 양”은 치료되어야 할 특정 질환의 발병 또는 진행을 지연하거나 전적으로 중지시키는 데 필요한 양을 의미한다. 이 양은 치료되어야 할 대상체의 건강과 물리적 상태, 치료되어야 할 대상체의 분류적 군, 목적하는 보호의 정도, 의학적 상황의 평가 및 기타 관련인자, 예컨대, 조합할 타겟 숙주인자의 종류와 바이러스 단백질의 종류, 제형의 종류, 환자의 연령, 체중, 일반 건강상태, 간의 손상정도, 성별 및 식이, 투여 시간, 투여 경로, 투여 횟수 및 치료 기간, 병용투여제 등에 따라 달라진다. 이 양은 통상적인 시도를 통해 측정될 수 있는 비교적 광범위한 범위에 속할 것이다.As used herein, the term “pharmaceutically effective amount” refers to an amount necessary to delay or completely stop the onset or progression of a particular disease to be treated. This quantity depends on the health and physical condition of the subject to be treated, the taxonomic group of subjects to be treated, the degree of protection desired, the assessment of the medical situation, and other relevant factors, such as the type of target host factor and the type of viral protein to be combined. , Depending on the type of dosage form, patient's age, weight, general health condition, degree of liver damage, gender and diet, administration time, administration route, administration frequency and treatment period, concomitant administration, etc. This amount will fall within a relatively broad range that can be determined through routine experimentation.
본 발명에서 사용된 용어, "투여"는 어떠한 적절한 방법으로 환자에게 본 발명의 약학적 조성물을 도입하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다.As used herein, the term "administration" means introducing the pharmaceutical composition of the present invention to a patient by any suitable method, and the route of administration of the composition of the present invention is oral or parenteral as long as it can reach the target tissue. It can be administered through various routes.
이하, 본 발명의 실시예를 첨부된 도면을 참고하여 보다 상세하게 설명하도록 한다. 그러나, 하기의 실시예는 본 발명의 내용을 구체화하기 위한 것일 뿐, 이에 의해 본 발명이 한정되는 것은 아닐 것이다.Hereinafter, embodiments of the present invention will be described in more detail with reference to the accompanying drawings. However, the following examples are only for specifying the contents of the present invention, and the present invention will not be limited thereby.
<실시예 1> 인간폐암세포에서 스타틴이 PD-L1 발현에 미치는 영향<Example 1> Effect of statins on PD-L1 expression in human lung cancer cells
1-1. 농도별 PD-L1 단백질 발현 측정1-1. Measurement of PD-L1 protein expression by concentration
폐암세포에서 스타틴이 PD-L1 발현에 미치는 영향을 알아보기 위해 인간폐암세포에서 스타틴 처리에 따른 PD-L1 단백질 발현량을 측정하였다. 구체적으로는, 인간폐암세포 Calu-1 세포에 simvastatin, atorvastatin, lovastatin 그리고 fluvastatin을 1, 2, 5, 10 μM의 농도로 처리하고, 인간폐암세포 NCI-H460 세포에 simvastatin을 1, 2, 5, 10 μM의 농도로 처리하였다. 12 시간 후 각 약물을 처리한 세포에서 PD-L1 단백질을 발현을 웨스턴 블롯 (Western blotting)을 통해 측정하였으며, 대조군 단백질로 b-actin을 확인하였다. 그 결과는 도 1에 나타내었다.To investigate the effect of statins on PD-L1 expression in lung cancer cells, the amount of PD-L1 protein expression according to statin treatment was measured in human lung cancer cells. Specifically, human lung cancer cell Calu-1 cells were treated with simvastatin, atorvastatin, lovastatin, and fluvastatin at concentrations of 1, 2, 5, and 10 μM, and human lung cancer cell NCI-H460 cells were treated with simvastatin at 1, 2, 5, It was treated at a concentration of 10 μM. After 12 hours, PD-L1 protein expression in cells treated with each drug was measured by Western blotting, and b-actin was identified as a control protein. The results are shown in Figure 1.
도 1에 나타낸 바와 같이, 인간폐암세포 Calu-1의 경우 약 5uM농도의 simvastatin, atorvastatin, lovastatin에서 PD-L1 단백질 억제효과를 보였으며, 2uM 농도의 fluvastatin에서 강력한 PD-L1단백질 억제효과를 확인하였다 (도 1A). 또한, 인간폐암세포 NCI-H460에서도 마찬가지로 약 10uM 농도의 simvastatin에 의해서 PD-L1단백질이 감소하는 것을 확인하였다.As shown in Figure 1, in the case of human lung cancer cell Calu-1, simvastatin, atorvastatin, and lovastatin at a concentration of about 5uM showed an inhibitory effect on PD-L1 protein, and a strong PD-L1 protein inhibitory effect was confirmed at a concentration of 2uM fluvastatin. (Fig. 1A). In addition, it was also confirmed that PD-L1 protein was decreased by simvastatin at a concentration of about 10uM similarly in human lung cancer cell NCI-H460.
<실시예 2> 인간흑색종세포에서 스타틴이 PD-L1 발현에 미치는 영향<Example 2> Effect of statins on PD-L1 expression in human melanoma cells
2-1. 농도별 PD-L1 단백질 발현 측정2-1. Measurement of PD-L1 protein expression by concentration
흑색종세포에서 스타틴이 PD-L1 발현에 미치는 영향을 알아보기 위해 인간흑색종세포에서 스타틴 처리에 따른 PD-L1 단백질 발현량을 측정하였다. 구체적으로는, 인간흑색종세포 A2058와 A375세포에 simvastatin 및 atorvastatin을 1, 2, 5, 10 μM의 농도로 처리하고, 12 시간 후 각 약물을 처리한 세포에서 PD-L1 단백질을 발현을 웨스턴 블롯 (Western blotting)을 통해 측정하였으며, 대조군 단백질로 b-actin을 확인하였다. 그 결과는 도 2에 나타내었다.In order to examine the effect of statins on PD-L1 expression in melanoma cells, the amount of PD-L1 protein expression according to statin treatment was measured in human melanoma cells. Specifically, human melanoma cells A2058 and A375 were treated with simvastatin and atorvastatin at concentrations of 1, 2, 5, and 10 μM, and after 12 hours, PD-L1 protein expression was measured in cells treated with each drug by Western blot. (Western blotting), and b-actin was identified as a control protein. The results are shown in Figure 2.
도 2에 나타낸 바와 같이, 악성흑색종세포인 A2058과 A375세포에서 simvastatin (도 2A)과 Atorvastatin (도 2B)에 의한 PD-L1 단백질의 발현이 감소하는 것을 확인하였다. As shown in FIG. 2, it was confirmed that the expression of PD-L1 protein was decreased by simvastatin (FIG. 2A) and atorvastatin (FIG. 2B) in malignant melanoma cells A2058 and A375 cells.
2-2. 시간에 따른 PD-L1 단백질 발현 측정2-2. Determination of PD-L1 protein expression over time
흑색종세포에서 스타틴이 PD-L1 발현에 미치는 영향을 알아보기 위해 인간흑색종세포에서 스타틴 처리 후 시간에 따른 PD-L1 단백질 발현량을 측정하였다. 구체적으로는, 구체적으로는, 인간흑색종세포 A2058와 A375세포에 simvastatin을 2 μM의 농도로 처리하고, 4, 8, 12, 24 시간 후 각 약물을 처리한 세포에서 PD-L1 단백질을 발현을 웨스턴 블롯 (Western blotting)을 통해 측정하였으며, 대조군 단백질로 b-actin을 확인하였다. 그 결과는 도 3에 나타내었다.To investigate the effect of statins on PD-L1 expression in melanoma cells, the amount of PD-L1 protein expression over time was measured in human melanoma cells after statin treatment. Specifically, human melanoma cells A2058 and A375 were treated with simvastatin at a concentration of 2 μM, and 4, 8, 12, and 24 hours later, PD-L1 protein was expressed in the cells treated with each drug. It was measured through Western blotting, and b-actin was identified as a control protein. The results are shown in Figure 3.
도 3에 나타낸 바와 같이, 인간악성흑색종세포 A375와 A2058에 simvastatin을 4, 8, 12, 24시간 각각 처리한 결과 simvastatin을 처리한 후 8 시간 정도 경과하였을 때 PD-L1 단백질이 감소하는 것으로 나타났다.As shown in Figure 3, as a result of treating human malignant melanoma cells A375 and A2058 with simvastatin for 4, 8, 12, and 24 hours, respectively, PD-L1 protein decreased when about 8 hours elapsed after treatment with simvastatin. .
<실시예 3> 스타틴의 PD-L1 유전자 발현에 미치는 영향<Example 3> Effect of statin on PD-L1 gene expression
폐암세포 및 흑색종세포에서 스타틴이 PD-L1 발현에 미치는 영향을 알아보기 위해 각 세포에 스타틴 처리에 따른 PD-L1 유전자 발현량을 측정하였다. 구체적으로는, 인간흑색종세포 A2058과 인간폐암세포 NCI-H460과 Calu-1에 5 μM농도의 simvastatin과atorvastatin을 각각 12시간 처리하였다. 각 스타틴을 처리한 세포에서 RNA를 추출하여 PD-L1 단백질을 코딩하고 있는 CD274 유전자의 발현을 quantitative real-time PCR을 통해 확인하였다. 그 결과는 도 4에 나타내었다.To investigate the effect of statin on PD-L1 expression in lung cancer cells and melanoma cells, the expression level of PD-L1 gene according to statin treatment was measured in each cell. Specifically, human melanoma cells A2058 and human lung cancer cells NCI-H460 and Calu-1 were treated with 5 µM simvastatin and atorvastatin for 12 hours, respectively. RNA was extracted from cells treated with each statin, and the expression of the CD274 gene encoding the PD-L1 protein was confirmed through quantitative real-time PCR. The results are shown in FIG. 4 .
도 4에 나타낸 바와 같이, 악성흑색종세포 A2058과 폐암세포 NCI-H460, Calu-1에 simvastatin과 atorvastatin을 각각 5 uM 농도로 처리하고 12시간 배양했을 때 PD-L1의 유전자인 CD274가 감소하는 것을 확인하였다.As shown in Figure 4, when malignant melanoma cells A2058 and lung cancer cells NCI-H460 and Calu-1 were treated with simvastatin and atorvastatin at a concentration of 5 uM, respectively, and cultured for 12 hours, CD274, a gene of PD-L1, decreased. Confirmed.
상기 결과를 종합해보면, 스타틴은 암세포에서 면역관문단백질 중 하나인 PD-L1의 발현을 감소시키는 작용을 하며, 이러한 작용을 통해 PD-L1과 PD-1이 결합하지 못하도록 막음으로써 T세포의 면역 기능이 유지시켜 암 세포를 사멸하는 효과가 있다는 것을 의미한다.Summarizing the above results, statins act to reduce the expression of PD-L1, one of the immune checkpoint proteins, in cancer cells, and through this action, prevent the binding of PD-L1 and PD-1, thereby preventing the immune function of T cells. This means that it has the effect of killing cancer cells by maintaining it.
이상에서 살펴본 바와 같이, 본 발명의 구체적인 실시예를 상세하게 설명되었으나, 본 발명의 사상을 이해하는 당업자는 동일한 사상의 범위 내에서 다른 구성요소를 추가, 변경, 삭제 등을 통하여, 퇴보적인 다른 발명이나 본 발명 사상의 범위 내에 포함되는 다른 실시예를 용이하게 제안할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상술한 상세한 설명보다는 후술하는 특허청구의 범위에 의하여 나타내어지며, 특허청구의 범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.As described above, the specific embodiments of the present invention have been described in detail, but those skilled in the art who understand the spirit of the present invention may add, change, delete, etc. other components within the scope of the same idea, and other degenerate inventions. However, other embodiments included within the scope of the present invention can be easily suggested. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting. The scope of the present invention is indicated by the claims to be described later rather than the detailed description above, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts thereof are included in the scope of the present invention. should be interpreted as
Claims (7)
An immuno-anticancer pharmaceutical composition comprising a statin or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 스타틴은 심바스타틴 (simvastatin), 아토르바스타틴 (atorvastatin), 로바스타틴 (lovastatin), 플루바스타틴 (fluvastatin), 로슈바스타틴 (rosuvastatin), 피타바스타틴 (pitavastatin), 프라바스타틴 (pravastatin), 세리바스타틴 (cerivastatin) 및 메바스타틴 (mevastatin)으로 이루어진 군에서 선택된 어느 하나인, 면역항암제 약학 조성물.
According to claim 1,
The statins include simvastatin, atorvastatin, lovastatin, fluvastatin, rosuvastatin, pitavastatin, pravastatin, and cerivastatin. And any one selected from the group consisting of mevastatin (mevastatin), immuno-anticancer pharmaceutical composition.
상기 면역항암제는 면역관문억제제 (immune checkpoint inhibitor)인 것을 특징으로 하는, 면역항암제 약학 조성물.
According to claim 1,
The immuno-anticancer agent is characterized in that the immune checkpoint inhibitor (immune checkpoint inhibitor), immuno-anticancer pharmaceutical composition.
상기 면역관문억제제는 PD-L1 유전자 또는 단백질을 억제하는 것을 특징으로 하는, 면역항암제 약학 조성물.
According to claim 3,
The immuno-anticancer pharmaceutical composition, characterized in that the immune checkpoint inhibitor inhibits the PD-L1 gene or protein.
상기 암은 흑색종, 폐암, 요로상피암, 유방암, 방광암, 신장암, 호지킨림프종, 두경부암 및 위암으로 이루어진 군에서 선택되는 것을 특징으로 하는, 면역항암제 약학 조성물.
According to claim 1,
The cancer is characterized in that selected from the group consisting of melanoma, lung cancer, urothelial cancer, breast cancer, bladder cancer, kidney cancer, Hodgkin's lymphoma, head and neck cancer and gastric cancer, immuno-anticancer pharmaceutical composition.
A cancer treatment method comprising administering to a non-human subject an immuno-anticancer agent comprising a statin or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 암은 흑색종, 폐암, 요로상피암, 유방암, 방광암, 신장암, 호지킨림프종, 두경부암 및 위암으로 이루어진 군에서 선택되는 것을 특징으로 하는, 암 치료 방법.According to claim 6,
Wherein the cancer is selected from the group consisting of melanoma, lung cancer, urothelial cancer, breast cancer, bladder cancer, kidney cancer, Hodgkin's lymphoma, head and neck cancer, and stomach cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020210061747A KR20220154344A (en) | 2021-05-13 | 2021-05-13 | Cancer immunotherapy composition comprising a statin as an active ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020210061747A KR20220154344A (en) | 2021-05-13 | 2021-05-13 | Cancer immunotherapy composition comprising a statin as an active ingredient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20220154344A true KR20220154344A (en) | 2022-11-22 |
Family
ID=84236490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020210061747A KR20220154344A (en) | 2021-05-13 | 2021-05-13 | Cancer immunotherapy composition comprising a statin as an active ingredient |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR20220154344A (en) |
-
2021
- 2021-05-13 KR KR1020210061747A patent/KR20220154344A/en not_active Application Discontinuation
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2021073314A (en) | Combination of histone deacetylase inhibition medicine and immunomodulator | |
| JP6952602B2 (en) | Treatment of leukemia with histone deacetylase inhibitors | |
| JP6491089B2 (en) | Methods for using cyclodextrins | |
| TW200401768A (en) | Methods of treatment with CETP inhibitors and antihypertensive agents | |
| US20150105383A1 (en) | HDAC Inhibitors, Alone Or In Combination With PI3K Inhibitors, For Treating Non-Hodgkin's Lymphoma | |
| US20150105409A1 (en) | Hdac inhibitors, alone or in combination with btk inhibitors, for treating nonhodgkin's lymphoma | |
| US20210069192A1 (en) | Use of neutrophil elastase inhibitors in liver disease | |
| WO2017184774A1 (en) | Hdac inhibitors, alone or in combination with btk inhibitors, for treating chronic lymphocytic leukemia | |
| JP2010506900A (en) | Food extract containing N-methylnicotinamide for the treatment of lipoprotein abnormalities and skin diseases and disorders | |
| EP3681481A1 (en) | Compositions and methods for preventing and treating heterotopic ossification and pathologic calcification | |
| TW200306853A (en) | Therapeutic agent for glomerular disease | |
| KR20220154344A (en) | Cancer immunotherapy composition comprising a statin as an active ingredient | |
| EP2968219A1 (en) | Novel therapy for prostate carcinoma | |
| CA2424060A1 (en) | Preventives and remedies for complications of diabetes | |
| TW202019891A (en) | Use of aminoalkylbenzothiazepine derivatives | |
| CA2524175C (en) | Sugar intake-ability enhancer | |
| US9345671B2 (en) | Adiponectin production enhancer | |
| CN113271931A (en) | New application of carbamate beta phenylethanolamine analogue in enhancing clearance of intracellular LDL cholesterol and combination with statins | |
| US20180303802A1 (en) | Methods for treating synovial sarcoma | |
| US20220287993A1 (en) | Pharmaceutical composition comprising hdac inhibitor and anti-pd1 antibody or anti pd-l1 antibody | |
| US10064843B2 (en) | Bis-amide derivative and use thereof | |
| JP7485311B2 (en) | Cancer cell proliferation inhibitors and cancer cell proliferation inhibitor enhancers | |
| TW201121560A (en) | Radiosensitizer composition comprising schisandra chinensis (Turcz.) Baill and methods for use | |
| JP2005232150A (en) | Adiponectin production-reinforcing agent | |
| JP2005232151A (en) | Sugar uptake ability-reinforcing agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| E902 | Notification of reason for refusal | ||
| E601 | Decision to refuse application |