JP2019507755A5 - - Google Patents

Info

Publication number

JP2019507755A5

JP2019507755A5 JP2018544332A JP2018544332A JP2019507755A5 JP 2019507755 A5 JP2019507755 A5 JP 2019507755A5 JP 2018544332 A JP2018544332 A JP 2018544332A JP 2018544332 A JP2018544332 A JP 2018544332A JP 2019507755 A5 JP2019507755 A5 JP 2019507755A5

Authority

JP

Japan

Prior art keywords

day

level

smad7

patient

tnfα

Prior art date

2017-02-24

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Pending

Links

• Espacenet
• Global Dossier
• Discuss

• 238000000034 method Methods 0.000 claims description 418
• 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 311
• 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 311
• 102000049873 Smad7 Human genes 0.000 claims description 308
• 102000004889 Interleukin-6 Human genes 0.000 claims description 303
• 108090001005 Interleukin-6 Proteins 0.000 claims description 303
• 229940100601 interleukin-6 Drugs 0.000 claims description 296
• 102000004887 Transforming Growth Factor beta Human genes 0.000 claims description 253
• 108090001012 Transforming Growth Factor beta Proteins 0.000 claims description 253
• ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims description 253
• 230000007781 signaling event Effects 0.000 claims description 236
• 208000015943 Coeliac disease Diseases 0.000 claims description 210
• 108091034117 Oligonucleotide Proteins 0.000 claims description 111
• 239000000074 antisense oligonucleotide Substances 0.000 claims description 103
• 238000012230 antisense oligonucleotides Methods 0.000 claims description 103
• 239000003112 inhibitor Substances 0.000 claims description 103
• 230000001965 increasing effect Effects 0.000 claims description 39
• 210000004027 cell Anatomy 0.000 claims description 25
• 108020004999 messenger RNA Proteins 0.000 claims description 25
• 230000000968 intestinal effect Effects 0.000 claims description 23
• 239000002773 nucleotide Substances 0.000 claims description 23
• 125000003729 nucleotide group Chemical group 0.000 claims description 23
• 208000021329 Refractory celiac disease Diseases 0.000 claims description 22
• 230000011664 signaling Effects 0.000 claims description 21
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 19
• 231100000682 maximum tolerated dose Toxicity 0.000 claims description 16
• RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 16
• 108700031279 Smad7 Proteins 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• 239000012491 analyte Substances 0.000 claims description 10
• 210000001519 tissue Anatomy 0.000 claims description 10
• 102000003812 Interleukin-15 Human genes 0.000 claims description 9
• 108090000172 Interleukin-15 Proteins 0.000 claims description 9
• 102000013691 Interleukin-17 Human genes 0.000 claims description 9
• 108050003558 Interleukin-17 Proteins 0.000 claims description 9
• 230000003247 decreasing effect Effects 0.000 claims description 9
• 230000000694 effects Effects 0.000 claims description 9
• 230000002829 reductive effect Effects 0.000 claims description 9
• CDKIEBFIMCSCBB-UHFFFAOYSA-N 1-(6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)-3-(1-methyl-2-phenylpyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one;hydrochloride Chemical compound Cl.C1C=2C=C(OC)C(OC)=CC=2CCN1C(=O)C=CC(C1=CC=CN=C1N1C)=C1C1=CC=CC=C1 CDKIEBFIMCSCBB-UHFFFAOYSA-N 0.000 claims description 8
• CKTSBUTUHBMZGZ-ULQXZJNLSA-N 4-amino-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-tritiopyrimidin-2-one Chemical compound O=C1N=C(N)C([3H])=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-ULQXZJNLSA-N 0.000 claims description 8
• 235000006694 eating habits Nutrition 0.000 claims description 8
• 230000000391 smoking effect Effects 0.000 claims description 8
• 210000004369 blood Anatomy 0.000 claims description 7
• 239000008280 blood Substances 0.000 claims description 7
• 210000002966 serum Anatomy 0.000 claims description 7
• 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 claims description 6
• 101000652166 Homo sapiens Mothers against decapentaplegic homolog 7 Proteins 0.000 claims description 6
• 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 claims description 6
• 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 claims description 6
• 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 claims description 6
• 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 claims description 6
• 102000046299 Transforming Growth Factor beta1 Human genes 0.000 claims description 6
• 102000011117 Transforming Growth Factor beta2 Human genes 0.000 claims description 6
• 101800002279 Transforming growth factor beta-1 Proteins 0.000 claims description 6
• 101800000304 Transforming growth factor beta-2 Proteins 0.000 claims description 6
• 102000056172 Transforming growth factor beta-3 Human genes 0.000 claims description 6
• 108090000097 Transforming growth factor beta-3 Proteins 0.000 claims description 6
• 102000044356 human SMAD7 Human genes 0.000 claims description 6
• 230000002401 inhibitory effect Effects 0.000 claims description 6
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
• 208000011231 Crohn disease Diseases 0.000 claims description 4
• 101710143112 Mothers against decapentaplegic homolog 4 Proteins 0.000 claims description 4
• 102100025725 Mothers against decapentaplegic homolog 4 Human genes 0.000 claims description 4
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 239000002702 enteric coating Substances 0.000 claims description 4
• 238000009505 enteric coating Methods 0.000 claims description 4
• GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 claims description 4
• 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 4
• 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 4
• 210000005087 mononuclear cell Anatomy 0.000 claims description 4
• 210000004400 mucous membrane Anatomy 0.000 claims description 4
• 210000001842 enterocyte Anatomy 0.000 claims description 3
• 229940099456 transforming growth factor beta 1 Drugs 0.000 claims description 2
• 229940072041 transforming growth factor beta 2 Drugs 0.000 claims description 2
• 239000000203 mixture Substances 0.000 claims 25
• 101700026522 SMAD7 Proteins 0.000 description 294
• 238000002965 ELISA Methods 0.000 description 12
• 238000004458 analytical method Methods 0.000 description 9
• 230000002708 enhancing effect Effects 0.000 description 6
• 238000012544 monitoring process Methods 0.000 description 6
• 210000002381 plasma Anatomy 0.000 description 6
• 230000026683 transduction Effects 0.000 description 5
• 238000010361 transduction Methods 0.000 description 5
• 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
• 108020004635 Complementary DNA Proteins 0.000 description 3
• 238000010804 cDNA synthesis Methods 0.000 description 3
• 210000001072 colon Anatomy 0.000 description 3
• 239000002299 complementary DNA Substances 0.000 description 3
• 230000007423 decrease Effects 0.000 description 3
• 230000002183 duodenal effect Effects 0.000 description 3
• 102000004169 proteins and genes Human genes 0.000 description 3
• 108090000623 proteins and genes Proteins 0.000 description 3
• 230000002441 reversible effect Effects 0.000 description 3
• 102000007469 Actins Human genes 0.000 description 2
• 108010085238 Actins Proteins 0.000 description 2
• 239000003814 drug Substances 0.000 description 2
• 230000001131 transforming effect Effects 0.000 description 2
• 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
• 208000030990 Impulse-control disease Diseases 0.000 description 1
• 102100040247 Tumor necrosis factor Human genes 0.000 description 1
• JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
• 238000000137 annealing Methods 0.000 description 1
• 230000000692 anti-sense effect Effects 0.000 description 1
• 238000001574 biopsy Methods 0.000 description 1
• 238000004925 denaturation Methods 0.000 description 1
• 230000036425 denaturation Effects 0.000 description 1
• 201000010099 disease Diseases 0.000 description 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
• 229940079593 drug Drugs 0.000 description 1
• 238000005516 engineering process Methods 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 238000012986 modification Methods 0.000 description 1
• 230000004048 modification Effects 0.000 description 1