TW202126330A - Pharmaceutical composition for treatment of systemic scleroderma - Google Patents
Pharmaceutical composition for treatment of systemic scleroderma Download PDFInfo
- Publication number
- TW202126330A TW202126330A TW109133327A TW109133327A TW202126330A TW 202126330 A TW202126330 A TW 202126330A TW 109133327 A TW109133327 A TW 109133327A TW 109133327 A TW109133327 A TW 109133327A TW 202126330 A TW202126330 A TW 202126330A
- Authority
- TW
- Taiwan
- Prior art keywords
- pharmaceutical composition
- antibody
- composition according
- skin
- sclerosis
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 77
- 201000009594 Systemic Scleroderma Diseases 0.000 title claims abstract description 70
- 206010042953 Systemic sclerosis Diseases 0.000 title claims abstract description 70
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 59
- 102000013691 Interleukin-17 Human genes 0.000 claims abstract description 61
- 108050003558 Interleukin-17 Proteins 0.000 claims abstract description 61
- 208000034189 Sclerosis Diseases 0.000 claims abstract description 55
- 239000003112 inhibitor Substances 0.000 claims abstract description 50
- 230000037361 pathway Effects 0.000 claims abstract description 49
- 101710186083 Interleukin-17 receptor A Proteins 0.000 claims abstract description 35
- 102100035018 Interleukin-17 receptor A Human genes 0.000 claims abstract description 35
- 239000005557 antagonist Substances 0.000 claims abstract description 33
- 102100036672 Interleukin-23 receptor Human genes 0.000 claims abstract description 15
- 108040001844 interleukin-23 receptor activity proteins Proteins 0.000 claims abstract description 15
- 239000004480 active ingredient Substances 0.000 claims abstract description 10
- 229950002853 bimekizumab Drugs 0.000 claims abstract description 7
- 229950009342 brazikumab Drugs 0.000 claims abstract description 7
- 229950009792 mirikizumab Drugs 0.000 claims abstract description 7
- 229940121307 netakimab Drugs 0.000 claims abstract description 7
- 229960004540 secukinumab Drugs 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims description 20
- 229940124597 therapeutic agent Drugs 0.000 claims description 12
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 8
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 239000003018 immunosuppressive agent Substances 0.000 claims description 8
- 230000001919 adrenal effect Effects 0.000 claims description 7
- 239000003246 corticosteroid Substances 0.000 claims description 7
- 229960001334 corticosteroids Drugs 0.000 claims description 7
- 238000007920 subcutaneous administration Methods 0.000 claims description 7
- 229940118365 Endothelin receptor antagonist Drugs 0.000 claims description 6
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 6
- 229940126409 proton pump inhibitor Drugs 0.000 claims description 6
- 239000000612 proton pump inhibitor Substances 0.000 claims description 6
- 239000005541 ACE inhibitor Substances 0.000 claims description 5
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 5
- 230000003510 anti-fibrotic effect Effects 0.000 claims description 5
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 5
- 150000003180 prostaglandins Chemical class 0.000 claims description 5
- 229940122820 Cannabinoid receptor antagonist Drugs 0.000 claims description 4
- 239000003536 cannabinoid receptor antagonist Substances 0.000 claims description 4
- 230000000750 progressive effect Effects 0.000 abstract description 10
- 239000012634 fragment Substances 0.000 abstract description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 abstract 2
- 238000000034 method Methods 0.000 description 53
- 150000001413 amino acids Chemical group 0.000 description 29
- 208000024891 symptom Diseases 0.000 description 15
- 230000000694 effects Effects 0.000 description 9
- 230000006872 improvement Effects 0.000 description 7
- 230000027455 binding Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 210000000068 Th17 cell Anatomy 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 210000003414 extremity Anatomy 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 230000001766 physiological effect Effects 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 101710117290 Aldo-keto reductase family 1 member C4 Proteins 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- -1 belastostat Chemical compound 0.000 description 3
- 244000309466 calf Species 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 208000006111 contracture Diseases 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 230000005750 disease progression Effects 0.000 description 3
- 210000000245 forearm Anatomy 0.000 description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 3
- 229940125721 immunosuppressive agent Drugs 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 208000037821 progressive disease Diseases 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- 206010062575 Muscle contracture Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 241000219061 Rheum Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229960002170 azathioprine Drugs 0.000 description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- 229960003735 brodalumab Drugs 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000003363 dihydroorotate dehydrogenase inhibitor Substances 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- 230000001861 immunosuppressant effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000004199 lung function Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 206010033675 panniculitis Diseases 0.000 description 2
- 208000000689 peptic esophagitis Diseases 0.000 description 2
- 238000009520 phase I clinical trial Methods 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 238000012797 qualification Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 210000004304 subcutaneous tissue Anatomy 0.000 description 2
- 210000003813 thumb Anatomy 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- YCHYFHOSGQABSW-RTBURBONSA-N (6ar,10ar)-1-hydroxy-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene-9-carboxylic acid Chemical compound C1C(C(O)=O)=CC[C@H]2C(C)(C)OC3=CC(C(C)(C)CCCCCC)=CC(O)=C3[C@@H]21 YCHYFHOSGQABSW-RTBURBONSA-N 0.000 description 1
- XPRDUGXOWVXZLL-UHFFFAOYSA-N 2-[[2-fluoro-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid Chemical compound COC1=CC=CC(C=2C=C(F)C(NC(=O)C=3CCCC=3C(O)=O)=CC=2)=C1 XPRDUGXOWVXZLL-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000032081 Cabezas type X-linked intellectual disability Diseases 0.000 description 1
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 1
- 108050007331 Cannabinoid receptor Proteins 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 1
- 208000034657 Convalescence Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010015278 Erythrodermic psoriasis Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101000690301 Homo sapiens Aldo-keto reductase family 1 member C4 Proteins 0.000 description 1
- 101001019598 Homo sapiens Interleukin-17 receptor A Proteins 0.000 description 1
- 101001116548 Homo sapiens Protein CBFA2T1 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010037575 Pustular psoriasis Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 206010062553 Scleroderma renal crisis Diseases 0.000 description 1
- 206010050207 Skin fibrosis Diseases 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010065604 Suicidal behaviour Diseases 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960002414 ambrisentan Drugs 0.000 description 1
- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 229940090047 auto-injector Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229960003065 bosentan Drugs 0.000 description 1
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229950001524 clinprost Drugs 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960004770 esomeprazole Drugs 0.000 description 1
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 1
- 210000003811 finger Anatomy 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000004247 hand Anatomy 0.000 description 1
- 102000043448 human IL17RA Human genes 0.000 description 1
- 102000054751 human RUNX1T1 Human genes 0.000 description 1
- 229960002240 iloprost Drugs 0.000 description 1
- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 description 1
- 229960001195 imidapril Drugs 0.000 description 1
- KLZWOWYOHUKJIG-BPUTZDHNSA-N imidapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(O)=O)=O)CC1=CC=CC=C1 KLZWOWYOHUKJIG-BPUTZDHNSA-N 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000009177 immunoglobulin therapy Methods 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 229940121290 lenabasum Drugs 0.000 description 1
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 description 1
- 229960001039 macitentan Drugs 0.000 description 1
- JGCMEBMXRHSZKX-UHFFFAOYSA-N macitentan Chemical compound C=1C=C(Br)C=CC=1C=1C(NS(=O)(=O)NCCC)=NC=NC=1OCCOC1=NC=C(Br)C=N1 JGCMEBMXRHSZKX-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- QIGRQPVOWVHYBT-KABTVRTISA-N methyl 5-[(3as,5r,6r,6as)-5-hydroxy-6-[(e,3s)-3-hydroxyoct-1-enyl]-1,3a,4,5,6,6a-hexahydropentalen-2-yl]pentanoate Chemical compound C1=C(CCCCC(=O)OC)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 QIGRQPVOWVHYBT-KABTVRTISA-N 0.000 description 1
- 229950000844 mizoribine Drugs 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 1
- 229960004378 nintedanib Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 229960003073 pirfenidone Drugs 0.000 description 1
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 201000001872 syndromic X-linked intellectual disability Cabezas type Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 229960005032 treprostinil Drugs 0.000 description 1
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229950010644 vidofludimus Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
-
- 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
- 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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
-
- 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
-
- 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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Endocrinology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
作為用以治療可伴隨進行性皮膚硬化之全身性硬化症患者之新穎技術，本發明提供一種可伴隨進行性皮膚硬化之全身性硬化症治療用醫藥組合物，其含有IL-17路徑抑制劑作為有效成分。IL-17路徑抑制劑可為選自IL-17RA拮抗劑及IL-23R拮抗劑中之任一種以上，尤其是可為選自由布羅達單抗、蘇金單抗、伊西貝單抗、奈塔基單抗(Netakimab)、Bimekizumab、尤特克單抗、蒂爾他昔單抗、瑞莎珠單抗、Mirikizumab、Brazikumab及古塞庫單抗所組成之群中之任一種以上抗體或其片段。As a novel technology for treating patients with systemic sclerosis that can be accompanied by progressive skin sclerosis, the present invention provides a pharmaceutical composition for the treatment of systemic sclerosis that can be accompanied by progressive skin sclerosis, which contains an IL-17 pathway inhibitor as Active ingredients. The IL-17 pathway inhibitor may be any one or more selected from the group consisting of IL-17RA antagonists and IL-23R antagonists, and in particular, may be selected from the group consisting of brodazumab, secukinumab, ishibezumab, and naphthalene. Takimab (Netakimab), Bimekizumab, Utekinumab, Tiltaximab, Resalizumab, Mirikizumab, Brazikumab, and Gosekuumab consisting of any one or more of the antibodies or Fragment.
Description
本發明係關於一種含有IL-17路徑抑制劑作為有效成分之用於治療全身性硬化症之醫藥組合物。本發明係關於一種使用IL-17路徑抑制劑之用於全身性硬化症之治療方法。The present invention relates to a pharmaceutical composition containing IL-17 pathway inhibitor as an effective ingredient for the treatment of systemic sclerosis. The present invention relates to a treatment method for systemic sclerosis using IL-17 pathway inhibitors.
全身性硬化症係一種慢性進行性疾病，其特徵在於皮膚或內臟變硬。全身性硬化症分為以下2種類型：皮膚硬化除了面部以外亦延伸到四肢附近(上臂、大腿)或軀幹之「彌漫性皮膚硬化型全身性硬化症」(dcSSc)、與皮膚硬化侷限於四肢遠端(前臂、小腿)或面部之「局部皮膚硬化型全身性硬化症」(lcSSc)。於彌漫性皮膚硬化型全身性硬化症患者中，皮膚硬化在發病後6年以內進展，並且隨著皮膚硬化之進展，肺、消化道、腎及心臟等之器官病變或關節屈曲攣縮亦進展。又，據報告70%之重症皮膚硬化發生於發病後3年以內。Systemic sclerosis is a chronic progressive disease characterized by hardening of the skin or internal organs. Systemic sclerosis is divided into the following two types: "diffuse skin sclerosis type systemic sclerosis" (dcSSc), which extends to the limbs (upper arms, thighs) or trunk in addition to the face, and skin sclerosis confined to the limbs Distal (forearm, calf) or "partial skin sclerosis systemic sclerosis" (lcSSc) on the face. In patients with diffuse skin sclerosis type systemic sclerosis, skin sclerosis progresses within 6 years after onset, and as skin sclerosis progresses, lung, digestive tract, kidney, heart and other organ diseases or joint flexion contractures also progress. In addition, it is reported that 70% of severe skin sclerosis occurs within 3 years after the onset.
全身性硬化症係一種進行性疾病，其發病機制尚不明確，尚無針對皮膚硬化之治療法，需要長期療養。因此，通常情況下，主要治療係對症治療或使用抑制疾病進展之藥劑。進而，由於病變部位(器官)會因每個患者之疾病進展程度而有所不同，因此亦根據每個患者之症狀而選擇治療法。作為針對各器官之代表性治療法，可列舉：少量內服腎上腺皮質類固醇(針對皮膚硬化)、環磷醯胺(針對肺纖維化症)、質子泵抑制劑(針對反流性食管炎)、前列腺環素衍生物(針對血管病變)、血管收縮素轉化酶抑制劑(針對硬皮性腎危症)、及內皮素受體拮抗劑(針對肺性高血壓)等。對於皮膚硬化，通常進行使用腎上腺皮質類固醇或免疫抑制劑之藥物療法，但由於該等藥物療法中存在因長期投予導致副作用之顧慮，故期待確立新的治療法。Systemic sclerosis is a progressive disease. Its pathogenesis is still unclear. There is no cure for skin sclerosis and it requires long-term convalescence. Therefore, under normal circumstances, the main treatment is symptomatic treatment or the use of drugs that inhibit disease progression. Furthermore, since the diseased location (organ) varies with the degree of disease progression of each patient, the treatment method is also selected according to the symptoms of each patient. Representative treatments for each organ include: small amounts of oral adrenal corticosteroids (for skin sclerosis), cyclophosphamide (for pulmonary fibrosis), proton pump inhibitors (for reflux esophagitis), prostate Cyclin derivatives (for vascular disease), angiotensin converting enzyme inhibitors (for scleroderma renal crisis), and endothelin receptor antagonists (for pulmonary hypertension), etc. For skin sclerosis, drug therapies using adrenal corticosteroids or immunosuppressive agents are usually performed. However, there are concerns about side effects caused by long-term administration in these drug therapies, and new treatment methods are expected to be established.
關於全身性硬化症，提示了皮膚纖維化及病情進展可能與Th17細胞及由Th17細胞產生之IL-17A有關。全身性硬化症患者之血中Th17細胞數及IL-17A濃度高於健康成人，認為其明顯與皮膚硬化相關(非專利文獻1-4)。於博來黴素誘導之全身性硬化症小鼠模型中亦確認了Th17細胞數及IL-17A濃度之上升、與皮膚及肺之炎症及硬化具有相關性(非專利文獻5、6)。已知於全身性硬化症患者之病變部皮膚中，IL-17RA之mRNA及蛋白質之表現量上升(非專利文獻7)。Regarding systemic sclerosis, it is suggested that skin fibrosis and disease progression may be related to Th17 cells and IL-17A produced by Th17 cells. The number of Th17 cells and the concentration of IL-17A in the blood of patients with systemic sclerosis are higher than those of healthy adults, and it is believed that these are obviously related to skin sclerosis (Non-Patent Documents 1-4). In a mouse model of bleomycin-induced systemic sclerosis, it was also confirmed that the increase in the number of Th17 cells and the concentration of IL-17A is correlated with inflammation and sclerosis of the skin and lungs (Non-Patent Documents 5 and 6). It is known that the expression levels of IL-17RA mRNA and protein increase in the skin of lesions of patients with systemic sclerosis (Non-Patent Document 7).
布羅達單抗係一種IgG2單株抗體，其與人類IL-17RA結合，並阻斷IL-17A、IL-17F、IL-17A/F異源二聚物、及IL-17E(IL-25)之生物活性(非專利文獻8-10)。在日本，布羅達單抗被批准作為針對於既有治療中效果不充分之尋常性牛皮癬、關節性牛皮癬、膿皰性牛皮癬及紅皮病型牛皮癬之適應症之治療藥。 先前技術文獻 專利文獻Brodazumab is an IgG2 monoclonal antibody that binds to human IL-17RA and blocks IL-17A, IL-17F, IL-17A/F heterodimer, and IL-17E (IL-25 ) Of biological activity (Non-Patent Documents 8-10). In Japan, brodazumab is approved as a therapeutic drug for the indications of psoriasis vulgaris, articular psoriasis, pustular psoriasis, and erythrodermic psoriasis, which are not sufficiently effective in existing treatments. Prior art literature Patent literature
專利文獻1：國際公開第2008/054603號 [非專利文獻]Patent Document 1: International Publication No. 2008/054603 [Non-Patent Literature]
非專利文獻1：Arthritis Rheum、2000年、第43卷、第2455-2463頁
非專利文獻2：Eur Cytokine Netw、2012年、第23卷、第128-139頁
非專利文獻3：Arthritis Res Ther、2013年、第15卷、R151
非專利文獻4：Arthritis Res Ther、2014年、第16卷、R4
非專利文獻5：Clin Exp Rheumatol、2016年、第34卷、Suppl 100 第14-22頁
非專利文獻6：Arthritis Rheum、2012年、第64卷、第3726-3735頁
非專利文獻7：Human Immunology、2015年、第76卷、第22-29頁
非專利文獻8：Immunity、2008年、第28卷、第4號、第454-467頁
非專利文獻9：J Allergy Clin Immunol、2007年、第120卷、第6號、第1324-1331頁
非專利文獻10：J Immunol、2005年、第175卷、第1號、第404-412頁Non-Patent Document 1: Arthritis Rheum, 2000, Volume 43, Pages 2455-2463
Non-Patent Document 2: Eur Cytokine Netw, 2012, Volume 23, Pages 128-139
Non-Patent Document 3: Arthritis Res Ther, 2013,
[發明所欲解決之問題][The problem to be solved by the invention]
本發明之主要目的在於提供一種可用以治療可伴隨進行性皮膚硬化之全身性硬化症的新穎技術。 [解決問題之技術手段]The main purpose of the present invention is to provide a novel technique that can be used to treat systemic sclerosis that can be accompanied by progressive skin sclerosis. [Technical means to solve the problem]
為了解決上述課題，本發明提供以下之[1]～[45]。 [1]一種全身性硬化症治療用醫藥組合物，其含有IL-17路徑抑制劑作為有效成分。 [2]一種伴隨進行性皮膚硬化之全身性硬化症治療用醫藥組合物，其含有IL-17路徑抑制劑作為有效成分。 [3]如[1]或[2]之醫藥組合物，其中IL-17路徑抑制劑係選自IL-17RA拮抗劑及IL-23R拮抗劑中之任一種以上。 [4]如[1]至[3]中任一項之醫藥組合物，其中IL-17路徑抑制劑係抗體或抗體片段。 [5]如[4]之醫藥組合物，其中上述抗體係抗IL-17RA抗體、抗IL-17A抗體、抗IL-17A/F抗體、抗IL-23p40次單元抗體及/或抗IL-23p19次單元抗體，尤其是選自由布羅達單抗、蘇金單抗、伊西貝單抗、奈塔基單抗(Netakimab)、Bimekizumab、尤特克單抗、蒂爾他昔單抗、瑞莎珠單抗、Mirikizumab、Brazikumab及古塞庫單抗所組成之群中之任一種以上。 [6]如[5]之醫藥組合物，其中上述抗體係布羅達單抗。 [7]如[1]至[6]中任一項之醫藥組合物，其中上述全身性硬化症係彌漫性皮膚硬化型全身性硬化症(dcSSc)。 [8]如[1]至[7]中任一項之醫藥組合物，其用以使患者之皮膚評分(mRSS)在投予開始後12週前，比治療前降低3以上。 [9]如[1]至[8]中任一項之醫藥組合物，其用以使患者之皮膚評分(mRSS)在投予開始後24週前，比治療前降低5以上。 [10]如[1]至[9]中任一項之醫藥組合物，其用以使患者之皮膚評分(mRSS)在投予開始後52週前，比治療前降低7以上。 [11]如[1]至[10]中任一項之醫藥組合物，其用於治療前之皮膚評分(mRSS)為20以上且未達30之患者。 [12]如[1]至[11]中任一項之醫藥組合物，其中上述IL-17路徑抑制劑之1次投予用量為70 mg、140 mg、210 mg、或280 mg。 [13]如[1]至[12]中任一項之醫藥組合物，其中上述IL-17路徑抑制劑之1次投予量為210 mg，於第1天、1週後、2週後進行皮下投予，其後，每2週進行1次皮下投予。 [14]如[1]至[13]中任一項之醫藥組合物，其用於與IL-17路徑抑制劑以外之第2治療劑組合使用。 [15]如[14]之醫藥組合物，其中上述第2治療劑係選自由腎上腺皮質類固醇、抗纖維化藥、免疫抑制劑、質子泵抑制劑、前列腺環素衍生物、血管收縮素轉化酶抑制劑、內皮素受體拮抗劑及Ⅱ型大麻素受體拮抗劑所組成之群中之至少1種以上。 [16]一種醫藥組合物，其係含有IL-17路徑抑制劑作為有效成分之全身性硬化症治療用醫藥組合物，且 上述全身性硬化症係彌漫性皮膚硬化型全身性硬化症(dcSSc)， 上述IL-17路徑抑制劑係布羅達單抗，其1次投予量為210 mg，於第1天、1週後、2週後進行皮下投予，其後，每2週進行1次皮下投予。In order to solve the above-mentioned problems, the present invention provides the following [1] to [45]. [1] A pharmaceutical composition for the treatment of systemic sclerosis, which contains an IL-17 pathway inhibitor as an active ingredient. [2] A pharmaceutical composition for the treatment of systemic sclerosis accompanied by progressive skin sclerosis, which contains an IL-17 pathway inhibitor as an active ingredient. [3] The pharmaceutical composition according to [1] or [2], wherein the IL-17 pathway inhibitor is selected from any one or more of IL-17RA antagonists and IL-23R antagonists. [4] The pharmaceutical composition according to any one of [1] to [3], wherein the IL-17 pathway inhibitor is an antibody or an antibody fragment. [5] The pharmaceutical composition according to [4], wherein the aforementioned antibody system is anti-IL-17RA antibody, anti-IL-17A antibody, anti-IL-17A/F antibody, anti-IL-23p40 subunit antibody and/or anti-IL-23p19 Subunit antibodies, especially selected from the group consisting of bridalizumab, secukinumab, ixibizumab, netakimab, Bimekizumab, utekizumab, tiltaximab, and Reza Any one or more of the group consisting of benzumab, mirikizumab, brazikumab, and guseculumab. [6] The pharmaceutical composition according to [5], wherein the above-mentioned anti-system brodazumab. [7] The pharmaceutical composition according to any one of [1] to [6], wherein the above-mentioned systemic sclerosis is diffuse skin sclerosis type systemic sclerosis (dcSSc). [8] The pharmaceutical composition according to any one of [1] to [7], which is used to reduce the patient's skin score (mRSS) by more than 3 before 12 weeks after the start of administration. [9] The pharmaceutical composition according to any one of [1] to [8], which is used to reduce the patient's skin score (mRSS) by more than 5 or more before 24 weeks after the start of administration. [10] The pharmaceutical composition according to any one of [1] to [9], which is used to reduce the patient's skin score (mRSS) by more than 7 weeks after the start of administration, compared to before treatment. [11] The pharmaceutical composition according to any one of [1] to [10], which is used for patients whose pre-treatment skin score (mRSS) is 20 or more and less than 30. [12] The pharmaceutical composition according to any one of [1] to [11], wherein the dose of the IL-17 pathway inhibitor for one administration is 70 mg, 140 mg, 210 mg, or 280 mg. [13] The pharmaceutical composition according to any one of [1] to [12], wherein the single administration amount of the IL-17 pathway inhibitor is 210 mg, on the first day, after 1 week, and after 2 weeks Subcutaneous administration was performed, and thereafter, subcutaneous administration was performed once every 2 weeks. [14] The pharmaceutical composition according to any one of [1] to [13], which is used in combination with a second therapeutic agent other than an IL-17 pathway inhibitor. [15] The pharmaceutical composition of [14], wherein the second therapeutic agent is selected from the group consisting of adrenal corticosteroids, antifibrotic drugs, immunosuppressive agents, proton pump inhibitors, prostaglandin derivatives, and angiotensin converting enzymes At least one of the group consisting of inhibitors, endothelin receptor antagonists and type II cannabinoid receptor antagonists. [16] A pharmaceutical composition containing an IL-17 pathway inhibitor as an active ingredient for the treatment of systemic sclerosis, and The above-mentioned systemic sclerosis is diffuse skin sclerosis type systemic sclerosis (dcSSc), The above-mentioned IL-17 pathway inhibitor is brodazumab, which is administered at a dose of 210 mg once, and is administered subcutaneously on the first day, one week later, and two weeks later, and thereafter, once every two weeks Administer subcutaneously.
[17]一種IL-17路徑抑制劑，其用於治療全身性硬化症。 [18]一種IL-17路徑抑制劑，其用於治療伴隨進行性皮膚硬化之全身性硬化症。 [19]如[17]或[18]之IL-17路徑抑制劑，其係選自IL-17RA拮抗劑及IL-23R拮抗劑中之任一種以上。 [20]如[17]至[19]中任一項之IL-17路徑抑制劑，其係抗體或抗體片段。 [21]如[20]之IL-17路徑抑制劑，其係抗IL-17RA抗體、抗IL-17A抗體、抗IL-17A/F、抗IL-23p40次單元抗體及/或抗IL-23p19次單元抗體或其等之片段，尤其是選自由布羅達單抗、蘇金單抗、伊西貝單抗、奈塔基單抗(Netakimab)、Bimekizumab、尤特克單抗、蒂爾他昔單抗、瑞莎珠單抗、Mirikizumab、Brazikumab及古塞庫單抗所組成之群中之任一種以上之抗體或其片段。 [22]如[21]之IL-17路徑抑制劑，其係布羅達單抗。 [23]如[17]至[22]中任一項之IL-17路徑抑制劑，其中上述全身性硬化症係彌漫性皮膚硬化型全身性硬化症(dcSSc)。[17] An IL-17 pathway inhibitor for the treatment of systemic sclerosis. [18] An IL-17 pathway inhibitor for the treatment of systemic sclerosis accompanied by progressive skin sclerosis. [19] The IL-17 pathway inhibitor according to [17] or [18], which is selected from any one or more of IL-17RA antagonists and IL-23R antagonists. [20] The IL-17 pathway inhibitor according to any one of [17] to [19], which is an antibody or antibody fragment. [21] The IL-17 pathway inhibitor as in [20], which is an anti-IL-17RA antibody, an anti-IL-17A antibody, an anti-IL-17A/F, an anti-IL-23p40 subunit antibody and/or an anti-IL-23p19 Subunit antibodies or fragments thereof, especially selected from the group consisting of brodazumab, secukinumab, ishibizumab, netakimab, Bimekizumab, utekizumab, tiltaxib Any one or more of antibodies or fragments thereof from the group consisting of monoclonal antibodies, risacizumab, mirikizumab, brazikumab, and gusecumumab. [22] The IL-17 pathway inhibitor of [21], which is brodazumab. [23] The IL-17 pathway inhibitor according to any one of [17] to [22], wherein the above-mentioned systemic sclerosis is diffuse skin sclerosis type systemic sclerosis (dcSSc).
[24]一種IL-17路徑抑制劑之用途，其用於製造全身性硬化症治療用醫藥組合物。 [25]一種IL-17路徑抑制劑之用途，其用於製造伴隨進行性皮膚硬化之全身性硬化症治療用醫藥組合物。 [26]如[24]或[25]之用途，其中IL-17路徑抑制劑係選自IL-17RA拮抗劑及IL-23R拮抗劑中之任一種以上。 [27]如[24]至[26]中任一項之用途，其中IL-17路徑抑制劑係抗體或抗體片段。 [28]如[27]之用途，其中上述抗體係抗IL-17RA抗體、抗IL-17A抗體、抗IL-17A/F抗體、抗IL-23p40次單元抗體及/或抗IL-23p19次單元抗體，尤其是選自由布羅達單抗、蘇金單抗、伊西貝單抗、奈塔基單抗(Netakimab)、Bimekizumab、尤特克單抗、蒂爾他昔單抗、瑞莎珠單抗、Mirikizumab、Brazikumab及古塞庫單抗所組成之群中之任一種以上。 [29]如[28]之用途，其中上述抗體係布羅達單抗。 [30]如[24]至[29]中任一項之用途，其中上述全身性硬化症係彌漫性皮膚硬化型全身性硬化症(dcSSc)。[24] The use of an IL-17 pathway inhibitor for the manufacture of a pharmaceutical composition for the treatment of systemic sclerosis. [25] The use of an IL-17 pathway inhibitor for the manufacture of a pharmaceutical composition for the treatment of systemic sclerosis accompanied by progressive skin sclerosis. [26] The use of [24] or [25], wherein the IL-17 pathway inhibitor is selected from any one or more of IL-17RA antagonists and IL-23R antagonists. [27] The use according to any one of [24] to [26], wherein the IL-17 pathway inhibitor is an antibody or antibody fragment. [28] The use of [27], wherein the above-mentioned anti-IL-17RA antibody, anti-IL-17A antibody, anti-IL-17A/F antibody, anti-IL-23p40 subunit antibody and/or anti-IL-23p19 subunit Antibodies, especially selected from the group consisting of bridalizumab, secukinumab, issibezumab, netakimab, bimekizumab, utekizumab, tiltaximab, risabizumab Any one or more of the group consisting of anti, Mirikizumab, Brazikumab, and Gusecumumab. [29] The use of [28], wherein the above-mentioned anti-system brodazumab. [30] The use according to any one of [24] to [29], wherein the above-mentioned systemic sclerosis is diffuse skin sclerosis type systemic sclerosis (dcSSc).
[31]一種全身性硬化症之治療方法，其包括如下之程序：向對象投予含有IL-17路徑抑制劑作為有效成分之醫藥組合物。 [32]一種伴隨進行性皮膚硬化之全身性硬化症之治療方法，其包括如下之程序：向對象投予含有IL-17路徑抑制劑作為有效成分之醫藥組合物。 [33]如[31]或[32]之治療方法，其中IL-17路徑抑制劑係選自IL-17RA拮抗劑及IL-23R拮抗劑中之任一種以上。 [34]如[31]至[33]中任一項之治療方法，其中IL-17路徑抑制劑係抗體或抗體片段。 [35]如[34]之治療方法，其中上述抗體係抗IL-17RA抗體、抗IL-17A抗體、抗IL-17A/F抗體、抗IL-23p40次單元抗體及/或抗IL-23p19次單元抗體或其等之片段，尤其是選自由布羅達單抗、蘇金單抗、伊西貝單抗、奈塔基單抗(Netakimab)、Bimekizumab、尤特克單抗、蒂爾他昔單抗、瑞莎珠單抗、Mirikizumab、Brazikumab及古塞庫單抗所組成之群中之任一種以上。 [36]如[35]之治療方法，其中上述抗體係布羅達單抗。 [37]如[31]至[36]中任一項之治療方法，其中上述全身性硬化症係彌漫性皮膚硬化型全身性硬化症(dcSSc)。 [38]如[31]至[37]中任一項之治療方法，其中上述對象之皮膚評分(mRSS)於投予開始後12週前，比治療前降低3以上。 [39]如[31]至[38]中任一項之治療方法，其中上述對象之皮膚評分(mRSS)於投予開始後24週前，比治療前降低5以上。 [40]如[31]至[39]中任一項之治療方法，其中上述對象之皮膚評分(mRSS)於投予開始後52週前，比治療前降低7以上。 [41]如[31]至[40]中任一項之治療方法，其中上述對象之治療前之皮膚評分(mRSS)為20以上且未達30。 [42]如[31]至[41]中任一項之治療方法，其中上述IL-17路徑抑制劑之1次投予用量為70 mg、140 mg、210 mg、或280 mg。 [43]如[31]至[42]中任一項之治療方法，其中上述IL-17路徑抑制劑之1次投予量為210 mg，於第1天、1週後、2週後進行皮下投予，其後，每2週進行1次皮下投予。 [44]如[31]至[43]中任一項之治療方法，其進而包括如下之程序：投予IL-17路徑抑制劑以外之第2治療劑。 [45]如[44]之治療方法，其中上述第2治療劑係選自由腎上腺皮質類固醇、抗纖維化藥、免疫抑制劑、質子泵抑制劑、前列腺環素衍生物、血管收縮素轉化酶抑制劑、內皮素受體拮抗劑及Ⅱ型大麻素受體拮抗劑所組成之群中之至少1種以上。 [發明之效果][31] A treatment method for systemic sclerosis, which includes the following procedure: administering to a subject a pharmaceutical composition containing an IL-17 pathway inhibitor as an active ingredient. [32] A treatment method for systemic sclerosis accompanied by progressive skin sclerosis, which includes the following procedure: administering to a subject a pharmaceutical composition containing an IL-17 pathway inhibitor as an active ingredient. [33] The treatment method of [31] or [32], wherein the IL-17 pathway inhibitor is selected from any one or more of IL-17RA antagonists and IL-23R antagonists. [34] The treatment method according to any one of [31] to [33], wherein the IL-17 pathway inhibitor is an antibody or an antibody fragment. [35] The treatment method of [34], wherein the above-mentioned anti-IL-17RA antibody, anti-IL-17A antibody, anti-IL-17A/F antibody, anti-IL-23p40 subunit antibody and/or anti-IL-23p19 times Unit antibodies or fragments thereof, especially selected from the group consisting of bridalizumab, secukinumab, isibeibezumab, netakimab, Bimekizumab, utekizumab, tiltaximab Any one or more of the group consisting of anti-resalizumab, mirikizumab, brazikumab and gusekuumab. [36] The method of treatment according to [35], wherein the above-mentioned anti-system brodazumab. [37] The treatment method according to any one of [31] to [36], wherein the above-mentioned systemic sclerosis is diffuse skin sclerosis type systemic sclerosis (dcSSc). [38] The treatment method according to any one of [31] to [37], wherein the skin score (mRSS) of the subject is lowered by more than 3 before 12 weeks after the start of the administration. [39] The treatment method according to any one of [31] to [38], wherein the skin score (mRSS) of the above-mentioned subject is lowered by 5 or more than before the treatment 24 weeks after the start of the administration. [40] The treatment method according to any one of [31] to [39], wherein the skin score (mRSS) of the above-mentioned subject is reduced by more than 7 before 52 weeks after the start of the administration. [41] The treatment method according to any one of [31] to [40], wherein the pre-treatment skin score (mRSS) of the above-mentioned subject is 20 or more and less than 30. [42] The treatment method according to any one of [31] to [41], wherein the dose of the IL-17 pathway inhibitor for one administration is 70 mg, 140 mg, 210 mg, or 280 mg. [43] The treatment method according to any one of [31] to [42], wherein the single administration of the IL-17 pathway inhibitor is 210 mg, which is performed on the first day, after 1 week, and after 2 weeks Subcutaneous administration, and thereafter, subcutaneous administration once every 2 weeks. [44] The treatment method of any one of [31] to [43], which further includes the following procedure: administering a second therapeutic agent other than the IL-17 pathway inhibitor. [45] The treatment method of [44], wherein the second therapeutic agent is selected from the group consisting of adrenal corticosteroids, antifibrotic drugs, immunosuppressants, proton pump inhibitors, prostaglandin derivatives, and angiotensin converting enzyme inhibitors At least one of the group consisting of an agent, an endothelin receptor antagonist, and a type II cannabinoid receptor antagonist. [Effects of Invention]
根據本發明，提供一種可有效地治療可伴隨進行性皮膚硬化之全身性硬化症的新穎技術。According to the present invention, there is provided a novel technique that can effectively treat systemic sclerosis that can be accompanied by progressive skin sclerosis.
以下，對用於實施本發明之較佳形態加以說明。再者，以下所說明之實施方式表示本發明之代表性實施方式之一例，並非由此限制性地解釋本發明之範圍。Hereinafter, a preferred mode for carrying out the present invention will be described. In addition, the embodiment described below represents an example of a representative embodiment of the present invention, and is not intended to limit the scope of the present invention.
本發明係關於一種可伴隨進行性皮膚硬化之全身性硬化症患者之治療用醫藥組合物，其含有IL-17路徑抑制劑作為有效成分。The present invention relates to a pharmaceutical composition for the treatment of patients with systemic sclerosis that can be accompanied by progressive skin sclerosis, which contains an IL-17 pathway inhibitor as an active ingredient.
又，本發明中亦包括一種全身性硬化症患者之治療方法，其包括如下之程序：向可伴隨進行性皮膚硬化之全身性硬化症之患者投予IL-17路徑抑制劑。In addition, the present invention also includes a treatment method for patients with systemic sclerosis, which includes the following procedure: administering an IL-17 pathway inhibitor to patients with systemic sclerosis that may be accompanied by progressive skin sclerosis.
全身性硬化症係一種慢性進行性疾病，其特徵在於皮膚或內臟變硬。全身性硬化症分為以下2種類型：皮膚硬化除了面部以外延伸到四肢附近(上臂、大腿)或軀幹之「彌漫性皮膚硬化型全身性硬化症」(dcSSc)、與皮膚硬化侷限於四肢遠端(前臂、小腿)或面部之「局部皮膚硬化型全身性硬化症」(lcSSc)。Systemic sclerosis is a chronic progressive disease characterized by hardening of the skin or internal organs. Systemic sclerosis is divided into the following two types: "diffuse skin sclerosis type systemic sclerosis" (dcSSc), which extends to the vicinity of the limbs (upper arms, thighs) or trunk except for the face, and skin sclerosis confined to the extremities. "Local Skin Sclerosis Systemic Sclerosis" (lcSSc) on the end (forearm, calf) or face.
作為本發明之醫藥組合物或治療方法之對象的全身性硬化症並不限定於彌漫性皮膚硬化型全身性硬化症與局部皮膚硬化型全身性硬化症之任一者，較佳為彌漫性皮膚硬化型全身性硬化症。The systemic sclerosis that is the object of the pharmaceutical composition or treatment method of the present invention is not limited to either diffuse skin sclerosis type systemic sclerosis and local skin sclerosis type systemic sclerosis, and it is preferably diffuse skin Sclerosing systemic sclerosis.
作為本發明之醫藥組合物或治療方法之對象的全身性硬化症患者亦可為除了皮膚硬化之症狀以外，亦伴隨有肺、消化道、腎或心臟之器官病變或者關節屈曲攣縮之症狀的患者。A patient with systemic sclerosis who is the subject of the pharmaceutical composition or treatment method of the present invention may also be a patient who, in addition to the symptoms of skin sclerosis, is also accompanied by organ diseases of the lung, digestive tract, kidney, or heart, or symptoms of joint flexion contracture .
全身性硬化症之皮膚硬化之重症度可利用公知之方法進行評價。例如，改良的Rodnan總皮膚厚度評分(modified Rodnan total skin thickness score，mRSS)可利用記載於日本皮膚科學會指南中之以下之方法進行評價。 將身體分為17個部位(兩手指、兩手背、兩前臂、兩上臂、臉、前胸部、腹部、兩大腿、兩小腿、兩足背)，對各部位，以0～3之4個等級進行皮膚之硬化程度之評價(0＝正常、1＝輕度、2＝中度、3＝高度，並以總計0～51分進行皮膚評分。於進行評價時，利用兩拇指夾住皮膚，觀察皮膚之厚度與皮下組織之可動性。將皮膚完全缺乏與皮下組織之可動性之情形判定為3，將雖沒有明顯之皮膚硬化但手感些許厚重之情形判定為1，將介於兩者中間之情形判定為2。關於皮膚硬化之重症度，在日本根據mRSS之總計分類為：0(正常：0)、1～9(輕度：1)、10～19(中等：2)、20～29(嚴重：3)、30以上(非常嚴重：4)(日本皮膚科學會雜誌、126(10)、1831-1896、2016)。關於mRSS之測定法，亦揭示於J Rheumatol，1993；20(11)：第1892-1896頁與J Rheumatol，1995；22：第1281-1285頁中。The severity of skin sclerosis in systemic sclerosis can be evaluated by known methods. For example, the modified Rodnan total skin thickness score (mRSS) can be evaluated using the following method described in the guidelines of the Japanese Society of Dermatology. Divide the body into 17 parts (two fingers, two backs of hands, two forearms, two upper arms, face, front chest, abdomen, two thighs, two calves, and back of two feet). For each part, use 4 levels from 0 to 3 Carry out the evaluation of the degree of skin hardening (0=normal, 1=mild, 2=moderate, 3=high, and score the skin with a total of 0 to 51 points. During the evaluation, use both thumbs to hold the skin and observe The thickness of the skin and the mobility of the subcutaneous tissue. The case where the skin is completely lacking in the mobility of the subcutaneous tissue is judged as 3, and the case where there is no obvious skin hardening but the hand feeling is judged as 1, and it is between the two The situation is judged to be 2. The severity of skin sclerosis is classified in Japan according to the total mRSS: 0 (normal: 0), 1-9 (mild: 1), 10-19 (medium: 2), 20-29 (Severe: 3), 30 or more (very serious: 4) (Journal of the Japanese Society of Dermatology, 126(10), 1831-1896, 2016). The measurement method of mRSS is also disclosed in J Rheumatol, 1993; 20(11 ): pages 1892-1896 and J Rheumatol, 1995; 22: pages 1281-1285.
作為本發明之醫藥組合物或治療方法之對象的皮膚硬化之重症度無特別限定，mRSS較佳為10以上，更佳為20以上，最佳為20以上且未達30。即，皮膚硬化之重症度較佳為中度以上，更佳為重度以上，最佳為中度至重度。The severity of skin sclerosis that is the subject of the pharmaceutical composition or treatment method of the present invention is not particularly limited. The mRSS is preferably 10 or more, more preferably 20 or more, and most preferably 20 or more and less than 30. That is, the severity of skin sclerosis is preferably moderate or higher, more preferably severe or higher, and most preferably moderate to severe.
本發明之醫藥組合物或治療方法之對象亦可為於既有治療中效果不充分之全身性硬化症患者。 本發明之醫藥組合物或治療方法之對象亦可為於既有治療中效果不充分之具有皮膚硬化之全身性硬化症患者。 本發明之醫藥組合物或治療方法之對象亦可為具有中症至重症皮膚硬化的全身性硬化症患者。 本發明之醫藥組合物或治療方法之對象亦可為具有發病初期之皮膚硬化的全身性硬化症患者。所謂發病初期，係指發病後6年以內。 本發明之醫藥組合物或治療方法之對象亦可為具有可逆性皮膚硬化的全身性硬化症患者。所謂可逆性皮膚硬化，係指皮膚之狀態表現為浮腫及硬化，未達到萎縮之狀態。The subject of the pharmaceutical composition or treatment method of the present invention can also be a patient with systemic sclerosis whose effect in the existing treatment is insufficient. The subject of the pharmaceutical composition or the treatment method of the present invention can also be a patient with systemic sclerosis who has skin hardening whose effect is insufficient in the existing treatment. The subject of the pharmaceutical composition or treatment method of the present invention can also be a patient with systemic sclerosis with moderate to severe skin sclerosis. The subject of the pharmaceutical composition or treatment method of the present invention can also be a systemic sclerosis patient with skin hardening at an early stage of onset. The so-called early onset refers to within 6 years after onset. The subject of the pharmaceutical composition or treatment method of the present invention can also be a patient with systemic sclerosis who has reversible skin sclerosis. The so-called reversible hardening of the skin refers to the state of the skin showing swelling and hardening, which has not reached the state of atrophy.
皮膚硬化之改善只要利用公知之方法進行確認即可。例如，於投予本發明之醫藥組合物之後，經時性地測定mRSS，確認相較於治療前而言mRSS有所降低，藉此可確認皮膚硬化之改善。The improvement of skin hardening only needs to be confirmed by a known method. For example, after administering the pharmaceutical composition of the present invention, the mRSS is measured over time to confirm that the mRSS is reduced compared to before the treatment, thereby confirming the improvement of skin hardening.
所謂皮膚硬化之症狀之改善，係指自投予醫藥組合物或開始治療方法經過特定之時間後，mRSS比治療前降低1、2、3、4、5、6、7、8、9、或10以上。關於mRSS，在投予本發明之醫藥組合物或開始治療方法後，於8週前可降低2以上、於12週前可降低3以上、於16週前可降低3以上、於20週前可降低4以上、於24週前可降低5以上、於40週前可降低6以上、於52週前可降低7以上。The so-called improvement of the symptoms of skin sclerosis refers to the reduction of mRSS by 1, 2, 3, 4, 5, 6, 7, 8, 9, or after a certain period of time since the administration of the pharmaceutical composition or the beginning of the treatment method. 10 or more. Regarding mRSS, after administering the pharmaceutical composition of the present invention or starting the treatment method, it can be reduced by more than 2 before 8 weeks, by more than 3 by 12 weeks, by more than 3 by 16 weeks, and by more than 20 weeks. A reduction of 4 or more, a reduction of 5 or more before 24 weeks, a reduction of 6 or more before 40 weeks, and a reduction of 7 or more before 52 weeks.
本發明之醫藥組合物及治療方法除了可改善或治療皮膚硬化之症狀以外，亦可改善或治療選自肺、消化道、腎或心臟之器官病變或者關節屈曲攣縮之症狀中至少1種症狀。又，本發明之醫藥組合物及治療方法可改善或治療基於全身性或局部性纖維化之諸症狀。各症狀之改善可利用公知之方法進行評價。例如，關於肺中之纖維化相關之肺功能之改善，可藉由利用肺活量計對肺功能進行評分而進行評價。關於消化道中之反流性食管炎之症狀之改善，可藉由使用FSSG(Frequency Scale for the Symptoms of GERD)特異性問卷對患者症狀進行評分而進行評價。In addition to improving or treating the symptoms of skin sclerosis, the pharmaceutical composition and treatment method of the present invention can also ameliorate or treat at least one symptom selected from lung, digestive tract, kidney, or heart organ diseases or joint flexion contracture symptoms. In addition, the pharmaceutical composition and treatment method of the present invention can improve or treat various symptoms based on systemic or local fibrosis. The improvement of each symptom can be evaluated by a known method. For example, the improvement of lung function related to fibrosis in the lung can be evaluated by scoring the lung function using a spirometer. Regarding the improvement of the symptoms of reflux esophagitis in the digestive tract, it can be evaluated by scoring the patient's symptoms using the FSSG (Frequency Scale for the Symptoms of GERD) specific questionnaire.
本說明書中所使用之術語「投予」係指一次投予或複數次投予(以下，亦記載為「連續投予」)。The term "injection" used in this manual refers to one-time injection or multiple injections (hereinafter, also referred to as "continuous injection").
本發明中所使用之IL-17路徑抑制劑之每1次之投予量無特別限定，只要參照各抑制劑之說明書等，以可進行臨床應用之用量使用即可。具體而言，於IL-17路徑抑制劑係布羅達單抗之情形時，1次投予用量較佳為70 mg以上，更佳為140 mg以上，最佳為210 mg。投予量於上述治療劑之連續投予中亦可適當增加或減少。典型而言，1次投予用量為70 mg、140 mg、210 mg、或280 mg。The dosage of the IL-17 pathway inhibitor used in the present invention is not particularly limited, as long as it refers to the instructions of each inhibitor, etc., and can be used in an amount that can be used in clinical applications. Specifically, when the IL-17 pathway inhibitor is brodazumab, the dosage for one administration is preferably 70 mg or more, more preferably 140 mg or more, and most preferably 210 mg. The dosage can also be appropriately increased or decreased in the continuous administration of the above-mentioned therapeutic agents. Typically, the dosage for one administration is 70 mg, 140 mg, 210 mg, or 280 mg.
醫藥組合物之投予間隔無特別限定，例如，於第1天(以下，亦記載為第0週)、第1週及第2週進行投予，且其後每2週進行1次投予或每4週進行1次投予。投予間隔可適當地延長或縮短。投予間隔較理想為於第1天、第1週、第2週進行投予，其後每2週進行1次投予。 投予量及投予間隔特佳為以1次投予量為210 mg，於第1天、1週後、2週後進行1次投予，其後每2週進行1次投予。The administration interval of the pharmaceutical composition is not particularly limited. For example, the administration is carried out on the first day (hereinafter, also referred to as week 0), the first week and the second week, and the administration is carried out every two weeks thereafter. Or once every 4 weeks. The interval of administration can be appropriately extended or shortened. The interval of administration is ideally to be administered on the first day, first week, and second week, and then once every two weeks. The dosage and interval between administrations are particularly preferred as a single administration of 210 mg, one administration on the first day, one week later, and two weeks later, and one administration every two weeks thereafter.
醫藥組合物之投予期間無特別限定，例如可設為投予開始後8、10、12、16、20、24、36、48或52週進行投予，或者亦可長於52週。投予期間較佳為長於52週。亦可於投予期間內包含停藥期。The administration period of the pharmaceutical composition is not particularly limited. For example, it may be administered at 8, 10, 12, 16, 20, 24, 36, 48, or 52 weeks after the start of the administration, or may be longer than 52 weeks. The administration period is preferably longer than 52 weeks. It is also possible to include a withdrawal period during the administration period.
本發明中之IL-17路徑抑制劑包含各種可阻礙IL-17RA與IL-17RA配體(IL-17A、IL-17F、IL-17A/F、IL-17E等)之間之相互作用、且阻斷生理活性訊號之物質。以下，將阻礙IL-17RA與IL-17RA配體之間之相互作用、且阻斷生理活性訊號之物質稱為「IL-17RA拮抗劑」。
已知IL-23會誘發產生IL-17RA配體之Th17細胞，且位於IL-17路徑之上游(Nature Reviews Drug Discovery 2015，第14卷，第11-12頁)。因此，本發明之IL-17路徑抑制劑中亦包含可阻礙IL-23與IL-23R之相互作用、且阻斷生理活性訊號之物質。以下，將阻礙IL-23與IL-23R之相互作用、且阻斷生理活性訊號之物質稱為「IL-23R拮抗劑」。
IL-17RA拮抗劑例如可為：具有阻礙IL-17RA與IL-17RA配體結合之活性的拮抗劑、具有阻礙因IL-17RA配體之結合而開始之IL-17RA活化之活性的拮抗劑、或具有阻礙IL-17RA與形成異源二聚物之受體之間之締合之活性的拮抗劑。
IL-23R拮抗劑例如可為：具有阻礙IL-23R與IL-23結合之活性的拮抗劑、具有阻礙作為IL-23之次單元的p19與p40締合之活性的拮抗劑。The IL-17 pathway inhibitors of the present invention include various interactions between IL-17RA and IL-17RA ligands (IL-17A, IL-17F, IL-17A/F, IL-17E, etc.), and A substance that blocks the signal of physiological activity. Hereinafter, substances that inhibit the interaction between IL-17RA and IL-17RA ligands and block physiological activity signals are referred to as "IL-17RA antagonists."
It is known that IL-23 induces Th17 cells that produce IL-17RA ligand and is located upstream of the IL-17 pathway (Nature Reviews Drug Discovery 2015,
IL-17RA拮抗劑及IL-23R拮抗劑例如可為：低分子、抗體或該抗體片段、siRNA、反義寡核苷酸。IL-17RA拮抗劑及IL-23R拮抗劑較佳為抗體或抗體片段。The IL-17RA antagonist and IL-23R antagonist may be, for example, low molecules, antibodies or fragments of the antibodies, siRNA, and antisense oligonucleotides. The IL-17RA antagonist and IL-23R antagonist are preferably antibodies or antibody fragments.
作為IL-17RA拮抗劑之抗體，其具體例可列舉：抗IL-17RA抗體、抗IL-17A抗體、抗IL-17F抗體、抗IL-17A/F抗體、抗IL-17E抗體及其等之片段。As IL-17RA antagonist antibodies, specific examples thereof include: anti-IL-17RA antibody, anti-IL-17A antibody, anti-IL-17F antibody, anti-IL-17A/F antibody, anti-IL-17E antibody, and the like Fragment.
作為IL-17RA拮抗劑之低分子，其具體例可列舉：二氫乳清酸去氫酶抑制劑。作為二氫乳清酸去氫酶抑制劑，可列舉：Vidofludimus。As a low molecular weight IL-17RA antagonist, specific examples thereof include dihydroorotate dehydrogenase inhibitors. Examples of dihydroorotate dehydrogenase inhibitors include Vidofludimus.
作為IL-23R拮抗劑之抗體，其具體例可列舉：抗IL-23p40次單元抗體及抗IL-23p19次單元抗體。As IL-23R antagonist antibodies, specific examples thereof include anti-IL-23p40 subunit antibodies and anti-IL-23p19 subunit antibodies.
作為抗IL-23p40次單元抗體之具體例，可列舉：尤特克單抗。作為抗IL-23p19次單元抗體之具體例，可列舉：蒂爾他昔單抗、瑞莎珠單抗、Mirikizumab、Brazikumab及古塞庫單抗。As a specific example of the anti-IL-23p40 subunit antibody, utekimab can be cited. Specific examples of anti-IL-23p19 subunit antibodies include tiltaciximab, risalizumab, mirikizumab, brazikumab, and gusekuumab.
IL-17路徑抑制劑較佳為IL-17RA拮抗劑及IL-23R拮抗劑，更佳為IL-17RA拮抗劑。IL-17RA拮抗劑較佳為作為抗IL-17RA抗體之布羅達單抗，作為抗IL-17A抗體之奈塔基單抗(Netakimab)、蘇金單抗或伊西貝單抗，及作為抗IL-17A/F抗體之Bimekizumab，最佳為布羅達單抗。The IL-17 pathway inhibitor is preferably an IL-17RA antagonist and an IL-23R antagonist, and more preferably an IL-17RA antagonist. The IL-17RA antagonist is preferably bridalumab as an anti-IL-17RA antibody, Netakimab, secukimab or isibeibezumab as an anti-IL-17A antibody, and as an anti-IL-17A antibody. The best IL-17A/F antibody is Bimekizumab.
本發明之醫藥組合物或治療方法可與第2治療劑或第2治療方法組合使用。 第2治療劑例如為：腎上腺皮質類固醇、抗纖維化藥、免疫抑制劑、質子泵抑制劑、血管收縮素轉化酶抑制劑、內皮素受體拮抗劑前列腺環素衍生物或Ⅱ型大麻素受體拮抗劑。 作為腎上腺皮質類固醇，例如可列舉：潑尼松龍。 作為抗纖維化藥，例如可列舉：吡非尼酮及尼達尼布。 作為免疫抑制劑，例如可列舉：環磷醯胺、麥考酚酸酯、環孢素、他克莫司、硫唑嘌呤、咪唑立賓及甲胺喋呤。 作為質子泵抑制劑，例如可列舉：奧美拉唑、蘭索拉唑、雷貝拉唑及埃索美拉唑。 作為血管收縮素轉化酶抑制劑，例如可列舉：卡托普利、依那普利、阿拉普利、咪達普利及替莫普利。 作為內皮素受體拮抗劑，例如可列舉：波生坦、安立生坦及馬西替坦。 作為前列腺環素衍生物，例如可列舉：伊洛前列素、貝拉司特、曲前列環素、依前列醇或克林前列素。 作為Ⅱ型大麻素受體拮抗劑，例如可列舉：Lenabasum。 作為第2治療方法，例如可列舉：大量靜脈注射免疫球蛋白之療法(IVIG)或光線療法。 於本發明之醫藥組合物或治療方法中，IL-17路徑抑制劑亦可將2種以上組合使用。 於本發明之醫藥組合物及治療方法中，於使用IL-17路徑抑制劑與第2治療劑之情形時，可向患者同時或分時地進行投予。因此，本發明之醫藥組合物或治療方法中亦包括與第2治療劑併用之態樣。The pharmaceutical composition or treatment method of the present invention can be used in combination with the second therapeutic agent or the second treatment method. The second therapeutic agent is, for example, adrenal corticosteroids, antifibrotic drugs, immunosuppressive agents, proton pump inhibitors, angiotensin converting enzyme inhibitors, endothelin receptor antagonists, prostaglandin derivatives, or type II cannabinoid receptors. Body antagonist. Examples of adrenocorticoids include prednisolone. Examples of antifibrotic drugs include pirfenidone and nintedanib. Examples of immunosuppressants include cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, azathioprine, mizoribine, and methotrexate. Examples of proton pump inhibitors include omeprazole, lansoprazole, rabeprazole, and esomeprazole. Examples of angiotensin converting enzyme inhibitors include captopril, enalapril, alapril, imidapril, and temopril. Examples of endothelin receptor antagonists include bosentan, ambrisentan, and macitentan. Examples of prostaglandin derivatives include iloprost, belastostat, treprostinil, epoprostol, or clinprost. Examples of type II cannabinoid receptor antagonists include Lenabasum. As the second treatment method, for example, a large amount of intravenous immunoglobulin therapy (IVIG) or phototherapy can be cited. In the pharmaceutical composition or treatment method of the present invention, the IL-17 pathway inhibitor can also be used in combination of two or more kinds. In the pharmaceutical composition and treatment method of the present invention, when the IL-17 pathway inhibitor and the second therapeutic agent are used, they can be administered to the patient at the same time or at different times. Therefore, the pharmaceutical composition or treatment method of the present invention also includes the aspect of combined use with the second therapeutic agent.
本發明中所使用之抗體可為單株抗體、多株抗體之任一種，較佳為結合於單一表位之單株抗體。The antibody used in the present invention may be either a monoclonal antibody or a multi-strain antibody, and is preferably a monoclonal antibody that binds to a single epitope.
抗體可為由融合瘤產生之單株抗體，或者，亦可為利用基因重組技術製得之基因重組抗體。基因重組抗體之例包括：小鼠抗體、大鼠抗體、人類嵌合抗體(以下，簡稱為「嵌合抗體」)、人源化抗體(亦稱為人源互補決定區(complementarity determining region)(CDR)移植抗體)、及人類抗體。對於人類而言，為了降低免疫原性，較佳為使用嵌合抗體、人源化抗體、或人類抗體。The antibody may be a monoclonal antibody produced by a fusion tumor, or it may be a genetically recombinant antibody produced by genetic recombination technology. Examples of genetically recombinant antibodies include mouse antibodies, rat antibodies, human chimeric antibodies (hereinafter referred to as "chimeric antibodies"), and humanized antibodies (also referred to as human complementarity determining regions) ( CDR) grafted antibodies), and human antibodies. For humans, in order to reduce immunogenicity, it is preferable to use chimeric antibodies, humanized antibodies, or human antibodies.
具體而言，作為本發明中所使用之單株抗體，可列舉選自以下之(A)～(F)中之抗體及該抗體片段。 (A)抗體之重鏈可變區(記為VH)之CDR1、CDR2、及CDR3分別包含序列編號1、2、及3所示之胺基酸序列，且抗體之輕鏈可變區(記為VL)之CDR1、CDR2、及CDR3分別包含序列編號4、5、及6所示之胺基酸序列之單株抗體； (B)抗體之VH包含序列編號7所示之胺基酸序列，且抗體之VL包含序列編號8所示之胺基酸序列之單株抗體； (C)抗體之重鏈(H鏈)包含序列編號9所示之胺基酸序列，且抗體之L鏈包含序列編號10所示之胺基酸序列之單株抗體； (D)與選自上述(A)～(C)中任一抗體競爭，並結合於IL-17RA之抗體； (E)與存在於IL-17RA中之表位結合之抗體，且該IL-17RA結合有選自上述(A)～(C)中任一抗體；及 (F)與選自上述(A)～(C)中任一抗體所具有之胺基酸序列具有90%以上之序列同一性，且具有與該抗體同等之結合特異性以及結合活性之抗體。Specifically, as the monoclonal antibody used in the present invention, an antibody selected from the following (A) to (F) and the antibody fragment can be cited. (A) The CDR1, CDR2, and CDR3 of the variable region of the heavy chain of the antibody (denoted as VH) contain the amino acid sequences shown in SEQ ID NOS 1, 2, and 3 respectively, and the variable region of the light chain of the antibody (denoted as It is a monoclonal antibody in which CDR1, CDR2, and CDR3 of VL) contain the amino acid sequence shown in SEQ ID NO: 4, 5, and 6, respectively; (B) A monoclonal antibody in which the VH of the antibody includes the amino acid sequence shown in SEQ ID NO: 7 and the VL of the antibody includes the amino acid sequence shown in SEQ ID NO: 8; (C) A monoclonal antibody in which the heavy chain (H chain) of the antibody contains the amino acid sequence shown in SEQ ID NO: 9 and the L chain of the antibody contains the amino acid sequence shown in SEQ ID NO: 10; (D) An antibody that competes with any antibody selected from (A) to (C) above and binds to IL-17RA; (E) an antibody that binds to an epitope present in IL-17RA, and the IL-17RA binds to any antibody selected from the above (A) to (C); and (F) An antibody that has 90% or more sequence identity with an amino acid sequence possessed by any antibody selected from the above (A) to (C), and has the same binding specificity and binding activity as the antibody.
於本發明中，關於抗體之VH之CDR1、CDR2、及CDR3分別包含序列編號1、2、及3所示之胺基酸序列、且抗體之VL之CDR1、CDR2、及CDR3分別包含序列編號4、5、及6所示之胺基酸序列之單株抗體，或抗體之VH包含序列編號7所示之胺基酸序列、且抗體之VL包含序列編號8所示之胺基酸序列之單株抗體，其等之一實施方式係抗人類IL-17RA人類單株抗體AMH
14/AML
14(專利文獻1)及基因重組抗人類IL-17RA人類抗體布羅達單抗。In the present invention, the CDR1, CDR2, and CDR3 of the VH of the antibody respectively include the amino acid sequences shown in
於本發明中，所謂「單株抗體」係指由單克隆抗體形成細胞分泌出之抗體，其係僅識別1個表位(抗原決定基)、且構成單株抗體之胺基酸序列(一級結構)較均勻之抗體。In the present invention, the so-called "monoclonal antibody" refers to the antibody secreted by monoclonal antibody-forming cells, which recognizes only one epitope (epitope) and constitutes the amino acid sequence (primary Structure) relatively uniform antibody.
所謂「表位」係指由單株抗體識別以進行結合的單一胺基酸序列；包含胺基酸序列之立體結構；結合有糖鏈、糖脂質、多糖脂質、胺基、羧基、磷酸及硫酸等修飾殘基之胺基酸序列；及包含結合有該修飾殘基之胺基酸序列之立體結構。所謂「立體結構」係指天然存在之蛋白質所具有之立體結構，係指由於細胞內或細胞膜上表現之蛋白質構成之立體結構。The so-called "epitope" refers to a single amino acid sequence recognized by a monoclonal antibody for binding; a three-dimensional structure containing an amino acid sequence; combined with sugar chains, glycolipids, polysaccharide lipids, amine groups, carboxyl groups, phosphoric acid and sulfuric acid The amino acid sequence of the modified residue; and the three-dimensional structure containing the amino acid sequence of the modified residue. The so-called "three-dimensional structure" refers to the three-dimensional structure possessed by naturally occurring proteins, and refers to the three-dimensional structure composed of proteins expressed in cells or on cell membranes.
於本發明中，抗體分子亦被稱為免疫球蛋白(以下，記為Ig)。根據分子結構間之差異，將人類抗體分類為：IgA1、IgA2、IgD、IgE、IgG1、IgG2、IgG3、IgG4、及IgM之同型。亦將胺基酸序列之同源性比較高之IgG1、IgG2、IgG3、及IgG4總稱為IgG。 作為本發明中所使用之抗體種型，較佳為IgG種型，更佳為選自IgG1、IgG2、IgG4及該同型抗體之Fc區域中之1個或2個以上之胺基酸殘基被置換之Fc改型體中之IgG種型。In the present invention, antibody molecules are also referred to as immunoglobulins (hereinafter referred to as Ig). According to the differences in molecular structure, human antibodies are classified into IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. IgG1, IgG2, IgG3, and IgG4 with relatively high amino acid sequence homology are also collectively referred to as IgG. The antibody type used in the present invention is preferably an IgG type, and more preferably one or more amino acid residues selected from the Fc region of IgG1, IgG2, IgG4, and antibodies of the same type. The IgG type in the replaced Fc variant.
於本發明中，抗體分子包含被稱為重鏈(H鏈)及輕鏈(L鏈)之多肽。In the present invention, antibody molecules include polypeptides called heavy chains (H chains) and light chains (L chains).
進而，於H鏈中，自N末端側起包含VH及H鏈恆定區(亦記為CH)，於L鏈中，自N末端側其分別包含VL及L鏈恆定區(亦記為CL)。Furthermore, in the H chain, the VH and H chain constant regions (also referred to as CH) are included from the N-terminal side, and in the L chain, they respectively include the VL and L-chain constant regions (also referred to as CL) from the N-terminus side. .
所謂「嵌合抗體」係指包含源自人類以外之動物的抗體之VH及VL、及人類抗體之CH及CL之抗體。關於源自可變區之動物之種類，只要是小鼠、大鼠、倉鼠、兔子等可用於製作融合瘤之動物即可，並無特別限定。The so-called "chimeric antibody" refers to antibodies including VH and VL of antibodies derived from animals other than humans, and CH and CL of human antibodies. Regarding the type of animal derived from the variable region, as long as it is a mouse, rat, hamster, rabbit, etc., which can be used to produce fusion tumors, it is not particularly limited.
所謂「人源化抗體」係指藉由將源自非人類動物抗體之VH及VL之CDR移植至人類抗體之VH及VL之適當位置而獲得之抗體(人源CDR移植抗體)。The so-called "humanized antibody" refers to an antibody (human CDR grafted antibody) obtained by grafting CDRs of VH and VL derived from non-human animal antibodies to appropriate positions of VH and VL of human antibodies.
所謂「人類抗體」係指可天然地存在於人類體內之抗體或包含由人類基因編碼之胺基酸序列之抗體。人類抗體亦包括基於基因工學、細胞工學、發育工學之方法製作之，由人類抗體噬菌體庫或產生人類抗體轉基因動物獲得之抗體。The so-called "human antibody" refers to antibodies that can naturally exist in humans or antibodies that contain amino acid sequences encoded by human genes. Human antibodies also include antibodies produced by methods based on genetic engineering, cell engineering, and developmental engineering, and obtained from human antibody phage libraries or transgenic animals that produce human antibodies.
於本發明中，抗體片段之類型無特別限定，例如可列舉：Fab、Fab'、F(ab')2 、scFv、雙功能抗體(diabody)、dsFv、含有CDR之肽等。In the present invention, the types of antibody fragments are not particularly limited, and examples include Fab, Fab', F(ab') 2 , scFv, diabody, dsFv, CDR-containing peptides, and the like.
本發明之醫藥組合物可為僅含有作為有效成分之IL-17路徑抑制劑者，通常情況下，較佳為以與藥理學上容許之1種以上載體一起混合，且利用製劑學之技術領域中眾所周知之任意方法進行製造而得之醫藥製劑之形式提供。醫藥製劑之具體例包括：包含140 mg/mL之基因重組抗人類IL-17RA人類抗體布羅達單抗作為有效成分，且使用10 mmol/L之L-麩胺酸、3%(w/v)之L-脯胺酸、及0.010%(w/v)之聚山梨糖醇酯20等作為添加劑而進行調製之醫藥製劑等。又，醫藥製劑亦包括：包含140 mg/mL之基因重組抗人類IL-17RA人類抗體布羅達單抗，進而包含30 mmol/L之L-麩胺酸、2.4%(w/v)之L-脯胺酸、及0.01%(w/v)之聚山梨糖醇酯20作為添加劑的pH值4.8之醫藥製劑。醫藥製劑例如可利用國際公開第2011/088120號中所記載之方法進行生產。The pharmaceutical composition of the present invention may contain only the IL-17 pathway inhibitor as an active ingredient. Generally, it is preferably mixed with one or more pharmacologically acceptable carriers and utilizes the technical field of pharmacology It is provided in the form of a pharmaceutical preparation obtained by any method well known in the art. Specific examples of pharmaceutical preparations include: genetically recombinant anti-human IL-17RA human antibody brodalumab containing 140 mg/mL as the active ingredient, and the use of 10 mmol/L L-glutamic acid, 3% (w/v ) L-proline and 0.010% (w/v) polysorbate 20 as additives to prepare pharmaceutical preparations, etc. In addition, the pharmaceutical preparations also include: genetically recombinant anti-human IL-17RA human antibody brodalumab containing 140 mg/mL, and further containing 30 mmol/L L-glutamic acid, 2.4% (w/v) L -Proline and 0.01% (w/v) polysorbate 20 as an additive to a pharmaceutical preparation with a pH of 4.8. The pharmaceutical preparation can be produced by the method described in International Publication No. 2011/088120, for example.
本發明之醫藥組合物或治療方法中之IL-17路徑抑制劑之投予路徑較佳為當進行治療時最為有效之路徑。投予路徑之具體例包括：經口投予，或者口腔內、氣管內、直腸內、皮下、肌內或靜脈內等非經口投予，較佳為皮下或靜脈內投予，更佳為皮下投予。投予形態之例包括：噴霧劑、膠囊劑、錠劑、散劑、顆粒劑、糖漿劑、乳劑、栓劑、注射劑、軟膏、貼劑等，且較佳為注射劑。The route of administration of the IL-17 pathway inhibitor in the pharmaceutical composition or treatment method of the present invention is preferably the most effective route during treatment. Specific examples of the route of administration include: oral administration, or parenteral administration such as intraoral, intratracheal, intrarectal, subcutaneous, intramuscular, or intravenous, preferably subcutaneous or intravenous administration, more preferably Administer subcutaneously. Examples of the administration form include sprays, capsules, tablets, powders, granules, syrups, emulsions, suppositories, injections, ointments, patches, etc., and injections are preferred.
本發明之治療劑之投予裝置可於治療期間恰當地進行選擇。作為投予裝置，例示有預填充式注射器及自動注射器，但並不受該等限定。 實施例The device for administration of the therapeutic agent of the present invention can be appropriately selected during treatment. As the administration device, a pre-filled syringe and an auto-injector are exemplified, but they are not limited to these. Example
[試驗例1：重組抗人類IL-17RA人類抗體布羅達單抗的以全身性硬化症患者為對象之I期臨床試驗] (1)試驗概要 將重組抗人類IL-17RA人類抗體布羅達單抗的以具有中度～重度皮膚硬化之全身性硬化症患者作為對象之I期臨床試驗(以下，亦簡稱為「臨床試驗」)之概要示於表1。作為臨床試驗之受試者，選擇滿足表2所示之條件的全身性硬化症患者，對投予布羅達單抗時之安全性及有效性等進行評價。對各受試者，於第1天、第1週、及第2週、並且其後於第50週前每2週進行1次210 mg之布羅達單抗之皮下投予。[Test Example 1: Phase I clinical trial of recombinant anti-human IL-17RA human antibody brodazumab targeting patients with systemic sclerosis] (1) Test summary Summary of Phase I clinical trial (hereinafter, also referred to as "clinical trial") for the recombinant anti-human IL-17RA human antibody brodazumab for patients with systemic sclerosis with moderate to severe skin sclerosis于表1。 In Table 1. As the subjects of clinical trials, patients with systemic sclerosis who meet the conditions shown in Table 2 were selected to evaluate the safety and effectiveness of brodazumab when administered. Each subject was administered 210 mg of bridalumab subcutaneously every two weeks on the first day, the first week, and the second week, and every two weeks before the 50th week.
布羅達單抗以具有專利文獻1中所記載之抗體可變區胺基酸序列之源自CHO(Chinese hamsters Ovary，中國倉鼠卵巢)細胞之重組人類抗體之形式，依據慣例進行製作。Brodazumab is produced in the form of a recombinant human antibody derived from CHO (Chinese hamsters Ovary) cells with the amino acid sequence of the variable region of the antibody described in Patent Document 1, according to conventional practices.
[表1]
[表2]
(2)試驗結果 對參加臨床試驗之受試者，自首次投予布羅達單抗開始經時性地測定表示皮膚硬化程度之皮膚評分(mRSS)。將所獲得之結果示於圖1及圖2。關於mRSS，由醫生利用兩拇指夾住全身17處皮膚，對各部位以0～3之4個等級進行皮膚硬化程度之評價(0＝正常、1＝輕度、2＝中度、3＝高度、總計0～51分)。mRSS之皮膚重症度以總計分類為0＝正常、1～9＝輕度、10～19＝中等、20～29＝嚴重、30以上＝非常嚴重。(2) Test results For subjects participating in the clinical trial, the skin score (mRSS), which indicates the degree of skin hardening, was measured over time since the first administration of bridalumab. The results obtained are shown in Figs. 1 and 2. Regarding mRSS, the doctor clamps 17 skins on the whole body with two thumbs, and evaluates the degree of skin hardening in 4 levels from 0 to 3 (0=normal, 1=mild, 2=moderate, 3=high , A total of 0 to 51 points). The skin severity of mRSS is classified as 0=normal, 1-9=mild, 10-19=moderate, 20-29=severe, 30+=very severe.
將參加臨床試驗之受試者之資訊示於表3。如表中所示，8例具有中度～重度皮膚硬化之全身性硬化症患者中，7例為重度(mRSS：20～29)皮膚硬化。The information of the subjects participating in the clinical trial is shown in Table 3. As shown in the table, of 8 patients with systemic sclerosis with moderate to severe skin sclerosis, 7 had severe (mRSS: 20-29) skin sclerosis.
[表3]
如圖1所示，8例具有中度～重度皮膚硬化之全身性硬化症患者均於投予開始後12週之時間點，mRSS自基線(治療開始時之mRSS)降低3以上。同樣地，於投予開始後24週之時間點，mRSS自基線降低5以上，並於投予開始後52週之時間點，mRSS自基線降低7以上。可知對於具有中度～重度皮膚硬化之全身性硬化症患者，藉由利用布羅達單抗之治療，於治療開始後12週、24週或者52週之較早之階段可獲得顯著之皮膚評分降低。As shown in Figure 1, the 8 patients with systemic sclerosis with moderate to severe skin sclerosis all had their mRSS decreased by more than 3 from baseline (mRSS at the beginning of treatment) at 12 weeks after the start of the administration. Similarly, at the time point 24 weeks after the start of the administration, the mRSS decreased by more than 5 from the baseline, and at the time point 52 weeks after the start of the administration, the mRSS decreased by more than 7 from the baseline. It can be seen that for patients with systemic sclerosis with moderate to severe skin sclerosis, by treatment with brodazumab, significant skin scores can be obtained at the earlier stage of 12 weeks, 24 weeks or 52 weeks after the start of treatment reduce.
先前應用於全身性硬化症中之皮膚硬化的利用腎上腺皮質類固醇之治療(地塞米松靜脈注射脈衝療法)中，為了使mRSS自基線降低4.5(平均值)，需要6個月之時間(Rhcumatol lnt，1994，14，91-94)。又，報告了即便係先前利用作為免疫抑制劑之環磷醯胺之治療中，於治療開始12個月後，mRSS自基線之降低亦止步於3.6(N Engl J Med，2006，354，2655-66)，同樣地，於先前利用作為免疫抑制劑之硫唑嘌呤之治療中，即便於治療開始18個月後，亦未觀察到皮膚硬化之改善(C in Rhcumatol，2006，25，205-212)。 另一方面，於利用布羅達單抗之治療中，包括7名具有重度皮膚硬化之患者在內之具有中度～重度皮膚硬化之全身性硬化症患者均可於治療開始後12週、24週或者52週達成mRSS之顯著降低。其結果表示布羅達單抗適用於伴隨中度～重度皮膚硬化之全身性硬化症，且與先前之藥劑相比而言，可於非常早期之階段發揮治療效果。 [序列表非關鍵文字]In the treatment with adrenal corticosteroids (dexamethasone intravenous pulse therapy) previously applied to skin sclerosis in systemic sclerosis, in order to reduce mRSS from baseline by 4.5 (average), it takes 6 months (Rhcumatol lnt , 1994, 14, 91-94). Furthermore, it was reported that even in the previous treatment with cyclophosphamide as an immunosuppressant, the decrease in mRSS from baseline stopped at 3.6 after 12 months from the start of treatment (N Engl J Med, 2006, 354, 2655) 66). Similarly, in the previous treatment with azathioprine as an immunosuppressant, no improvement in skin sclerosis was observed even 18 months after the start of the treatment (C in Rhcumatol, 2006, 25, 205-212 ). On the other hand, in the treatment with brodazumab, patients with systemic sclerosis with moderate to severe skin sclerosis, including 7 patients with severe skin sclerosis, can be treated at 12 weeks and 24 weeks after the start of treatment. A significant reduction in mRSS was reached in weeks or 52 weeks. The results show that brodazumab is suitable for systemic sclerosis accompanied by moderate to severe skin sclerosis, and can exert a therapeutic effect at a very early stage compared with previous drugs. [Sequence List Non-Key Text]
序列編號1：布羅達單抗_HCDR1之胺基酸序列 序列編號2：布羅達單抗_HCDR2之胺基酸序列 序列編號3：布羅達單抗_HCDR3之胺基酸序列 序列編號4：布羅達單抗_LCDR1之胺基酸序列 序列編號5：布羅達單抗_LCDR2之胺基酸序列 序列編號6：布羅達單抗_LCDR3之胺基酸序列 序列編號7：布羅達單抗_VH之胺基酸序列 序列編號8：布羅達單抗_VL之胺基酸序列 序列編號9：布羅達單抗_H鏈之胺基酸序列 序列編號10：布羅達單抗_L鏈之胺基酸序列SEQ ID NO:1: The amino acid sequence of Brodazumab_HCDR1 SEQ ID NO: 2: The amino acid sequence of Brodazumab_HCDR2 SEQ ID NO: 3: Amino acid sequence of brodazumab_HCDR3 Sequence number 4: the amino acid sequence of brodazumab_LCDR1 Sequence number 5: the amino acid sequence of brodazumab_LCDR2 SEQ ID NO: 6: The amino acid sequence of brodazumab_LCDR3 SEQ ID NO: 7: Amino acid sequence of brodazumab_VH SEQ ID NO: 8: Amino acid sequence of brodazumab_VL SEQ ID NO: 9: Amino acid sequence of brodazumab_H chain SEQ ID NO: 10: Brodazumab_L chain amino acid sequence
圖1係表示治療開始後各患者之皮膚評分(mRSS：modified Rodnan total skin thickness score，改良的Rodnan總皮膚厚度評分)變化之曲線圖。縱軸表示mRSS(治療開始時為0)。橫軸表示自首次投予布羅達單抗以來之時間(週)。 圖2係表示治療開始後各患者之mRSS變化之平均值之曲線圖。縱軸表示mRSS(治療開始時為0)。橫軸表示自首次投予布羅達單抗以來之時間(週)。Figure 1 is a graph showing the changes in the skin score (mRSS: modified Rodnan total skin thickness score) of each patient after the start of treatment. The vertical axis represents mRSS (0 at the beginning of treatment). The horizontal axis represents the time (weeks) since the first administration of brodazumab. Figure 2 is a graph showing the average value of mRSS changes in each patient after the start of treatment. The vertical axis represents mRSS (0 at the beginning of treatment). The horizontal axis represents the time (weeks) since the first administration of brodazumab.
Claims (14)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019-174734 | 2019-09-25 | ||
| JP2019174734 | 2019-09-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW202126330A true TW202126330A (en) | 2021-07-16 |
| TWI870471B TWI870471B (en) | 2025-01-21 |
Family
ID=75166206
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW109133327A TWI870471B (en) | 2019-09-25 | 2020-09-25 | Pharmaceutical composition for treating systemic sclerosis |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP7093940B2 (en) |
| KR (1) | KR20220070244A (en) |
| CN (1) | CN114423455A (en) |
| TW (1) | TWI870471B (en) |
| WO (1) | WO2021060425A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2024282654A1 (en) | 2023-05-30 | 2025-12-04 | Paragon Therapeutics, Inc. | Alpha4beta7 integrin antibody compositions and methods of use |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0417487D0 (en) * | 2004-08-05 | 2004-09-08 | Novartis Ag | Organic compound |
| US7767206B2 (en) | 2006-10-02 | 2010-08-03 | Amgen Inc. | Neutralizing determinants of IL-17 Receptor A and antibodies that bind thereto |
| AU2015241373B2 (en) * | 2014-03-31 | 2020-11-05 | Amgen K-A, Inc. | Methods of treating nail and scalp psoriasis |
| CN107236041B (en) * | 2016-03-29 | 2020-07-24 | 舒泰神（北京）生物制药股份有限公司 | IL-17 antibody |
| CN113603777B (en) * | 2018-02-12 | 2022-10-21 | 原启生物科技(上海)有限责任公司 | IL17 antibodies and uses thereof |
-
2020
- 2020-09-25 JP JP2021549013A patent/JP7093940B2/en active Active
- 2020-09-25 WO PCT/JP2020/036156 patent/WO2021060425A1/en not_active Ceased
- 2020-09-25 CN CN202080066358.8A patent/CN114423455A/en active Pending
- 2020-09-25 KR KR1020227013178A patent/KR20220070244A/en active Pending
- 2020-09-25 TW TW109133327A patent/TWI870471B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| JP7093940B2 (en) | 2022-07-01 |
| WO2021060425A1 (en) | 2021-04-01 |
| TWI870471B (en) | 2025-01-21 |
| CN114423455A (en) | 2022-04-29 |
| KR20220070244A (en) | 2022-05-30 |
| JPWO2021060425A1 (en) | 2021-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7434456B2 (en) | Method for treating diseases in which IL-13 activity is harmful using anti-IL-13 antibodies | |
| JP7119114B2 (en) | How to treat ulcerative colitis | |
| JP6554155B2 (en) | Methods of treating generalized pustular psoriasis (GPP) using an IL-17 antagonist | |
| US20250161440A1 (en) | Compositions and methods for treatment of psoriasis | |
| JP2022126791A (en) | Methods of treating incipient plaque-type psoriasis with an IL-17 antagonist | |
| KR20210122286A (en) | Treatment of skin lesions and pruritus in patients with prurigo nodosa | |
| EP3185902B1 (en) | Method for treating psoriasis patient which received anti-tnf-alpha antibody therapy | |
| TWI870471B (en) | Pharmaceutical composition for treating systemic sclerosis | |
| WO2020119707A1 (en) | Anti-il-17a antibody and use thereof | |
| CN109641053A (en) | Dosage regimen | |
| KR20230084166A (en) | How to treat OX40 related disorders | |
| ES3049513T3 (en) | Nemolizumab in the treatment of atopic dermatitis with moderate to severe excoriation | |
| HK40072099A (en) | Pharmaceutical composition for treatment of systemic scleroderma | |
| WO2021018191A1 (en) | Method for treating autoimmune disease by il-17 antagonist | |
| JP2022512721A (en) | Pan-ELR + CXC chemokine antibody for the treatment of hidradenitis suppurativa | |
| US20250066467A1 (en) | Methods for the treatment of myasthenia gravis | |
| JP2021526529A (en) | Methods for improving circulation and treating cardiovascular disease | |
| HK40072292A (en) | Methods of treatment of diseases in which il-13 activity is detrimental using anti-il-13 antibodies | |
| JP2025537966A (en) | How to Treat Ulcerative Colitis | |
| CN118339186A (en) | Anti-GD2 Dosing Regimen | |
| HK40052952A (en) | Compositions and methods for treatment of psoriasis | |
| HK40004820A (en) | Methods of treatment of diseases in which il-13 activity is detrimental using anti-il-13 antibodies |