TWI439285B - Il-23激動劑及拮抗劑之用途及相關試劑 - Google Patents
Il-23激動劑及拮抗劑之用途及相關試劑 Download PDFInfo
- Publication number
- TWI439285B TWI439285B TW100126443A TW100126443A TWI439285B TW I439285 B TWI439285 B TW I439285B TW 100126443 A TW100126443 A TW 100126443A TW 100126443 A TW100126443 A TW 100126443A TW I439285 B TWI439285 B TW I439285B
- Authority
- TW
- Taiwan
- Prior art keywords
- cancer
- tumor
- cells
- antibody
- cell
- Prior art date
Links
- 239000005557 antagonist Substances 0.000 title description 32
- 239000000556 agonist Substances 0.000 title description 28
- 239000003153 chemical reaction reagent Substances 0.000 title description 14
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 110
- 108010065637 Interleukin-23 Proteins 0.000 claims description 72
- 102000013264 Interleukin-23 Human genes 0.000 claims description 72
- 201000011510 cancer Diseases 0.000 claims description 49
- 238000009739 binding Methods 0.000 claims description 38
- 230000027455 binding Effects 0.000 claims description 37
- 239000012634 fragment Substances 0.000 claims description 23
- 206010006895 Cachexia Diseases 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 18
- 239000000427 antigen Substances 0.000 claims description 13
- 108091007433 antigens Proteins 0.000 claims description 13
- 102000036639 antigens Human genes 0.000 claims description 13
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 230000033115 angiogenesis Effects 0.000 claims description 8
- 206010061428 decreased appetite Diseases 0.000 claims description 8
- 208000022531 anorexia Diseases 0.000 claims description 7
- 230000004614 tumor growth Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 210000000750 endocrine system Anatomy 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 3
- 210000004994 reproductive system Anatomy 0.000 claims description 3
- 210000002345 respiratory system Anatomy 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 56
- 230000000694 effects Effects 0.000 abstract description 32
- 238000011282 treatment Methods 0.000 abstract description 31
- 102000004127 Cytokines Human genes 0.000 abstract description 30
- 108090000695 Cytokines Proteins 0.000 abstract description 30
- 229940124829 interleukin-23 Drugs 0.000 description 69
- 210000004027 cell Anatomy 0.000 description 54
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 46
- 241000699670 Mus sp. Species 0.000 description 38
- 239000000203 mixture Substances 0.000 description 36
- 102100036672 Interleukin-23 receptor Human genes 0.000 description 34
- 150000007523 nucleic acids Chemical class 0.000 description 34
- 102000005962 receptors Human genes 0.000 description 32
- 108020003175 receptors Proteins 0.000 description 32
- 108090000623 proteins and genes Proteins 0.000 description 31
- 108040001844 interleukin-23 receptor activity proteins Proteins 0.000 description 29
- 102000039446 nucleic acids Human genes 0.000 description 28
- 108020004707 nucleic acids Proteins 0.000 description 28
- 108090000765 processed proteins & peptides Proteins 0.000 description 22
- 108010065805 Interleukin-12 Proteins 0.000 description 21
- 102000004169 proteins and genes Human genes 0.000 description 21
- 239000003446 ligand Substances 0.000 description 20
- 102000004196 processed proteins & peptides Human genes 0.000 description 19
- 208000024891 symptom Diseases 0.000 description 16
- 229920001184 polypeptide Polymers 0.000 description 14
- 150000003384 small molecules Chemical class 0.000 description 14
- 210000001519 tissue Anatomy 0.000 description 14
- 230000004913 activation Effects 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 210000001744 T-lymphocyte Anatomy 0.000 description 10
- 125000003275 alpha amino acid group Chemical group 0.000 description 10
- 230000014509 gene expression Effects 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 229940124597 therapeutic agent Drugs 0.000 description 10
- ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 9
- VFZRZRDOXPRTSC-UHFFFAOYSA-N DMBA Natural products COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 210000000987 immune system Anatomy 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 9
- 101710103841 Interleukin-12 receptor subunit beta-1 Proteins 0.000 description 8
- 102100020790 Interleukin-12 receptor subunit beta-1 Human genes 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 239000012530 fluid Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 108010074328 Interferon-gamma Proteins 0.000 description 7
- 230000028993 immune response Effects 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 230000002062 proliferating effect Effects 0.000 description 7
- 238000010561 standard procedure Methods 0.000 description 7
- 206010058314 Dysplasia Diseases 0.000 description 6
- 108010021466 Mutant Proteins Proteins 0.000 description 6
- 102000008300 Mutant Proteins Human genes 0.000 description 6
- 230000000890 antigenic effect Effects 0.000 description 6
- 230000034994 death Effects 0.000 description 6
- 230000036039 immunity Effects 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 5
- 102100037850 Interferon gamma Human genes 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 241000699660 Mus musculus Species 0.000 description 5
- 108091028043 Nucleic acid sequence Proteins 0.000 description 5
- 108020004459 Small interfering RNA Proteins 0.000 description 5
- 210000000612 antigen-presenting cell Anatomy 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000003745 diagnosis Methods 0.000 description 5
- 239000000032 diagnostic agent Substances 0.000 description 5
- 229940039227 diagnostic agent Drugs 0.000 description 5
- 230000003053 immunization Effects 0.000 description 5
- 238000002649 immunization Methods 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 239000004055 small Interfering RNA Substances 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 101710195550 Interleukin-23 receptor Proteins 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- 108020004711 Nucleic Acid Probes Proteins 0.000 description 4
- 108010043958 Peptoids Proteins 0.000 description 4
- 230000000692 anti-sense effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000008045 co-localization Effects 0.000 description 4
- 210000004443 dendritic cell Anatomy 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 210000002919 epithelial cell Anatomy 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 229920006008 lipopolysaccharide Polymers 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- 210000000822 natural killer cell Anatomy 0.000 description 4
- 210000000440 neutrophil Anatomy 0.000 description 4
- 239000002853 nucleic acid probe Substances 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000009870 specific binding Effects 0.000 description 4
- -1 supercytokines Proteins 0.000 description 4
- 239000013598 vector Substances 0.000 description 4
- 208000016261 weight loss Diseases 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 3
- 101000853012 Homo sapiens Interleukin-23 receptor Proteins 0.000 description 3
- 101000852980 Homo sapiens Interleukin-23 subunit alpha Proteins 0.000 description 3
- 208000006994 Precancerous Conditions Diseases 0.000 description 3
- 208000000453 Skin Neoplasms Diseases 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 238000002659 cell therapy Methods 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 239000013068 control sample Substances 0.000 description 3
- 238000002405 diagnostic procedure Methods 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000011132 hemopoiesis Effects 0.000 description 3
- 239000000833 heterodimer Substances 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 230000004968 inflammatory condition Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 244000144972 livestock Species 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001394 metastastic effect Effects 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 238000009007 Diagnostic Kit Methods 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 102000003814 Interleukin-10 Human genes 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 108010076561 Interleukin-23 Subunit p19 Proteins 0.000 description 2
- 102000011718 Interleukin-23 Subunit p19 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 101150009057 JAK2 gene Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 101000852978 Mus musculus Interleukin-23 subunit alpha Proteins 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 210000004100 adrenal gland Anatomy 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 230000003092 anti-cytokine Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000003124 biologic agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000013060 biological fluid Substances 0.000 description 2
- 238000001815 biotherapy Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 210000003979 eosinophil Anatomy 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 102000057111 human IL23R Human genes 0.000 description 2
- 210000004754 hybrid cell Anatomy 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000015788 innate immune response Effects 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 229940076144 interleukin-10 Drugs 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 210000002429 large intestine Anatomy 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 210000003071 memory t lymphocyte Anatomy 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 210000000066 myeloid cell Anatomy 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 210000001428 peripheral nervous system Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000005740 tumor formation Effects 0.000 description 2
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- SNKDCTFPQUHAPR-UHFFFAOYSA-N 1-fluoropyrimidine-2,4-dione Chemical compound FN1C=CC(=O)NC1=O SNKDCTFPQUHAPR-UHFFFAOYSA-N 0.000 description 1
- UIEQALGRBADZNA-UHFFFAOYSA-N 2,3-dimethyl-1h-benzo[g]indole Chemical compound C1=CC=C2C(NC(=C3C)C)=C3C=CC2=C1 UIEQALGRBADZNA-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-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
- IJJWOSAXNHWBPR-HUBLWGQQSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-(6-hydrazinyl-6-oxohexyl)pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCC(=O)NN)SC[C@@H]21 IJJWOSAXNHWBPR-HUBLWGQQSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- 241000212384 Bifora Species 0.000 description 1
- 239000002028 Biomass Substances 0.000 description 1
- 230000005653 Brownian motion process Effects 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 229920001076 Cutan Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 230000009946 DNA mutation Effects 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 229940122236 Histamine receptor antagonist Drugs 0.000 description 1
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 description 1
- 101001003142 Homo sapiens Interleukin-12 receptor subunit beta-1 Proteins 0.000 description 1
- 102100025305 Integrin alpha-2 Human genes 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010017515 Interleukin-12 Receptors Proteins 0.000 description 1
- 102000004560 Interleukin-12 Receptors Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 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
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 101000853010 Mus musculus Interleukin-23 receptor Proteins 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010029098 Neoplasm skin Diseases 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000004020 Oxygenases Human genes 0.000 description 1
- 108090000417 Oxygenases Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 101150099493 STAT3 gene Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000010399 Wasting Syndrome Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 238000009166 antihormone therapy Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 210000003123 bronchiole Anatomy 0.000 description 1
- 238000005537 brownian motion Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000010370 cell cloning Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 1
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 239000000409 cytokine receptor agonist Substances 0.000 description 1
- 239000000430 cytokine receptor antagonist Substances 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 210000000581 natural killer T-cell Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 201000003733 ovarian melanoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000008560 physiological behavior Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 210000004560 pineal gland Anatomy 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013391 scatchard analysis Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 208000017572 squamous cell neoplasm Diseases 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008427 tissue turnover Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
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
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
- C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
-
- 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
- A61K38/00—Medicinal preparations containing peptides
-
- 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
Description
本發明係關於哺乳動物之細胞激素分子之用途及相關試劑。更詳言之,本發明係關於可用於治療增生性病症之哺乳動物的細胞激素類蛋白質及其抑制劑之識別。
癌症及腫瘤可藉由免疫系統來控制或根除。免疫系統包括幾種類型之淋巴及骨髓細胞,例如單核細胞、巨噬細胞、樹突狀細胞(DC)、嗜曙紅細胞、T細胞、B細胞及嗜中性白細胞。該等淋巴及骨髓細胞產生分泌性訊號蛋白質,該等蛋白質稱為細胞激素。該等細胞激素包括:(例如)介白素-10(IL-10)、干擾素-γ(IFN-γ)、IL-12及IL-23。免疫反應包括發炎,亦即全身性或身體之特殊部位的免疫細胞之積聚。回應於感染劑或外來物質,免疫細胞會分泌細胞激素,而細胞激素又調節免疫細胞之增生、發展、分化或遷移。免疫反應可產生病理後果,例如在涉及過度發炎時,其如同自身免疫性病症的情形,而受損的免疫反應會導致癌症。藉由免疫系統之抗腫瘤回應包括:先天免疫,例如藉由巨噬細胞、NK細胞及嗜中性白細胞來調停之免疫;及適應性免疫,例如藉由抗原遞呈細胞(APC)、T細胞及B細胞來調停之免疫(例如,參見Abbas等人(eds.)(2000)Cellular and Molecular Immunology
,W.B. Saunders Co.,Philadelphia,PA;Oppenheim及Feldmann(eds.)(2001)Cytokine Reference
,Academic Press,San Diego,CA;von Andrian及Mackay(2000)New Engl. J. Med.
343:1020-1034;Davidson及Diamond(2001)New Engl. J. Med.
345:340-350)。
調節免疫反應之方法已用於治療諸如黑素瘤之癌症。該等方法包括以細胞激素或抗細胞激素抗體來進行治療,例如IL-2、IL-12、腫瘤壞死因子-α(TNF-α)、IFN-γ、粒細胞巨噬細胞集落刺激因子(GM-CSF)及轉化生長因子(TGF)。當癌細胞可產生增強其自身生長或其自身存活之細胞激素時,抗細胞激素抗體可作為適當的治療劑(例如,參見Ramirez-Montagut等人(2003)Oncogene
22:3180-3187;Braun等人(2000)J.Immunol.
164:4025-4031;Shaw等人(1998)J. Immunol.
161:2817-2824;Coussens及Werb(2002)Nature
420:860-867;Baxevanis等人(2000)J. Immunol.
164:3902-3912;Shimizu等人(1999)J. Immunol
. 163:5211-5218;Belardelli及Ferrantini(2002)TRENDS Immunol.
23:201-208;Seki等人(2002)J. Immunol.
168:3484-3492;Casares等人(2003)J. Immunol.
171:5931-5939;Oft等人(2002)Nature Cell Biol.
4:487-494)。
介白素-23(IL-23)係由兩個子單元(亦即p19及p40)組成之雜二聚細胞激素。p19子單元在結構上與IL-6、粒細胞集落刺激因子(G-CSF)及IL-12之p35子單元相關。IL-23之p40子單元亦為IL-12之部分,其中IL-12係包含p35及p40之雜二聚細胞激素。IL-23藉由結合至由IL-23R及IL-12β1所組成之雜二聚受體來調停訊號。IL-12β1子單元由IL-12受體共享,該IL-12受體由IL-12β1及IL-12β2組成。大量早期研究證實:遺傳性缺乏p40之生理後果(p40剔除小鼠;p40KO小鼠;p40-/-
小鼠)不同於p35KO小鼠中所發現的生理後果,例如比之更嚴重或更不嚴重。該等結果中有一些結果最終藉由IL-23之探索及p40KO防止IL-12與IL-23二者之表現的發現來解釋(Oppmann等人(2000)Immunity
13:715-725;Wiekowski等人(2001)J. Immunol.
166:7563-7570;Parham等人(2002)J. Immuno1
168,5699-708;Frucht(2002)Sci STKE
2002,E1-E3;Elkins等人(2002)Infection immunity
70:1936-1948;Cua等人(2003)Nature
421:744-748)。
用於治療癌症之本方法並非完全有效,且諸如IL-12或IFN-γ之細胞激素會產生毒副作用(例如,參見Naylor及Hadden(2003)Int. Immunopharmacol.
3:1205-1215;Fernandez等人(1999)J. Immunol.
162:609-617)。本發明藉由提供使用IL-23激動劑及拮抗劑之方法來解決該等問題。
本發明係基於IL-23激動劑或拮抗劑可調節腫瘤生長之探索。
本發明提供一種調節腫瘤生長之方法,該方法包含使腫瘤細胞與有效劑量之IL-23激動劑或拮抗劑接觸。本發明亦提供其中IL-23拮抗劑抑制或防止腫瘤細胞生長之上述方法;及其中腫瘤細胞表現IL-23之上述方法。在另一態樣中,本發明提供其中IL-23激動劑或拮抗劑包含特定結合p19(序列標識號:1、2、3或4)或IL-23R(序列標識號:5或6)之多肽或核酸的結合組合物之上述方法;或其中結合組合物包含下列各物之上述方法:抗體之抗原結合點,IL-23R(序列標識號:5或6)之細胞外區域,小分子,反義核酸或小干擾RNA(siRNA),或可偵測標記;及其中結合組合物包含下列各物之上述方法:多株抗體,單株抗體,人化抗體或其片段,Fab、Fv或F(ab')2
片段,或抗體之類肽物(peptide mimetic)。
而本發明之另一實施例提供一種調節腫瘤生長之方法,該方法包含使腫瘤細胞與有效劑量之IL-23激動劑或拮抗劑接觸;其中,腫瘤細胞為:結腸癌細胞,卵巢癌細胞,乳腺癌細胞或黑素瘤細胞。
在另一態樣中,本發明提供一種治療罹患癌症或腫瘤之患者的方法,該方法包含向患者投予有效劑量之IL-23激動劑或拮抗劑;及其中IL-23拮抗劑具有以下抑制作用之上述方法:抑制癌症或腫瘤之生長,抑制惡病質,抑制厭食症,或抑制血管生成。本發明亦提供其中IL-23拮抗劑包含特定結合p19(序列標識號:1、2、3或4)或IL-23R(序列標識號:5或6)之多肽或核酸的結合組合物之上述方法。而本發明之另一實施例提供其中結合組合物包含下列各物之上述方法:抗體之抗原結合點,IL-23R(序列標識號:5或6)之細胞外區域,反義核酸或或小干擾RNA(siRNA),小分子,或可偵測之標記;及其中結合組合物包含下列各物之上述方法:多株抗體,單株抗體,人化抗體或其片段,Fab、Fv或F(ab')2
片段,或抗體之類肽物。
在另一實施例中,本發明提供其中癌症或腫瘤係以下各物之癌症或腫瘤的上述方法:胃腸道,呼吸道,生殖系統或內分泌系統;以及其中癌症或腫瘤為以下癌症或腫瘤之上述方法:結腸癌,卵巢癌,黑素瘤,或乳腺癌。
本發明之另一態樣提供以下兩種方法:一種診斷癌症或腫瘤之方法,該方法包含使來自受測者之樣本與上述方法之結合組合物接觸;以及其中結合組合物包含特定結合或雜交至序列標識號為1、2或5之聚核苷酸的核酸探針或底塗劑之上述診斷方法。
而本發明之另一實施例提供一種用於診斷癌症或腫瘤之套組,該套組包含上述方法之結合組合物及隔室或者使用或處置說明。本發明亦提供其中結合組合物包含特定結合至p19(序列標識號:1、2、3或4)或IL-23R(序列標識號:5或6)之抗體的上述套組。
如本文所使用,包括隨附申請專利範圍,除非上下文明確另行指出,否則諸如"一(a/an)"及"該(the)"等詞之單數形式包括對其相應之複數的提及。本文所引用的所有文獻均以引用的方式併入本文,該引用的程度就如同已特定地及個別地將各個公開案、專利申請案或專利案之揭示內容以引用的方式併入一般。
當"活化"、"刺激"及"治療"應用於細胞或受體時,其可具有相同的含義,例如,除非上下文或明確另行指出,否則可以配位子來活化、刺激或治療細胞或受體。"配位子"涵蓋天然及合成配位子,例如細胞激素、細胞激素變體、同功異質體(analogue)、突變蛋白質及源於抗體之結合組合物。"配位子"亦涵蓋小分子,例如細胞激素之類肽物及抗體之類肽物。"活化"係指藉由內部機制調控及藉由外部或環境因子調控之細胞活化。"回應",例如細胞、組織或器官之回應,涵蓋生化或生理行為之變化,例如生物隔室內之濃度、密度、黏附力或遷移之變化,基因表現之速率的變化,或分化狀態之變化,其中變化與活化、刺激或治療、或者諸如遺傳程式化之內部機制相關。
分子"活性"可描述或指代:將分子與配位子或受體結合,或催化活性;刺激基因表現或細胞訊號、分化或成熟之能力;抗原活性,對其它分子之活性的調節等。分子"活性"亦可指調節或維持細胞與細胞間的諸如黏附力之相互作用之活性,或維持諸如細胞膜或細胞骨架之細胞結構的活性。"活性"亦可意謂比活性,例如[催化活性]/[毫克蛋白質],或[免疫活性]/[毫克蛋白質],生物隔室中之濃度或其類似物。"增生活性"涵蓋:促進(例如)正常細胞分裂及癌症、腫瘤、發育異常、細胞轉化、轉移、血管生成之活性;或其所必需之活性;或與其特定關聯之活性。
當"投藥"及"治療"應用於動物、人類、實驗對象、細胞、組織、器官或生物流體時,其係指使外因性藥劑、治療劑、診斷劑、化合物或組合物與動物、人類、受測者、細胞、組織、器官或生物流體接觸。"投藥"及"治療"可指(例如)治療方法、安慰劑方法、醫藥動力學方法、診斷方法、研究方法及實驗方法。"細胞治療"涵蓋使試劑與細胞接觸及使試劑與流體接觸,其中該流體係與細胞接觸。"投藥"及"治療"亦意謂藉由試劑、診斷劑、結合組合物或藉由另一細胞來試管內(in vitro)及體外(ex vivo)治療(例如)細胞。當"治療"應用於人類、牲畜或研究對象時,其係指對研究及診斷應用的治療處理、預防性或防止性措施(measure)。當"治療"應用於人類、牲畜或研究對象、或者細胞、組織或器官時,其涵蓋使IL-23激動劑或IL-23拮抗劑與人類或動物受測者、細胞、組織、生理隔室或生理流體接觸。"細胞治療"亦涵蓋如下兩種情形:IL-23激動劑或IL-23拮抗劑接觸IL-23受體(IL-23R及IL-12Rβ1之雜二聚物),例如在流體相或膠體相中;及激動劑或拮抗劑接觸流體,例如流體接觸細胞或受體,但未證實激動劑或拮抗劑接觸細胞或受體之情形。
"結合組合物"係指能夠與目標結合之分子、小分子、巨型分子、抗體、其片段或同功異質體、或可溶性受體。"結合組合物"亦可指能夠與目標結合之下列物質:分子錯合物,例如非共價錯合物;離子化分子;及共價或非共價改質之分子,例如藉由磷酸化、醯化、交聯、環化或有限裂解來改質之分子。"結合組合物"亦可指與安定劑、賦形劑、鹽、緩衝劑、溶劑或添加劑組合之分子。"結合"可定義為結合組合物與目標之締合(association),其中若結合組合物可溶解於或懸浮於溶液中,則該締合會導致結合組合物之正常的布朗運動減少。
"惡病質"係涉及肌肉損耗(肌肉消耗)及脂肪損耗之消耗性綜合症,其由新陳代謝之失調引起。惡病質發生於各種癌症、慢性阻塞性肺病(COPD)、先期(advanced)器官衰竭及AIDS中。"癌症惡病質"為伴隨癌症並發的惡體質。癌症惡體質之特徵在於:例如顯著的體重減輕、厭食、衰弱及貧血。厭食症係由於缺乏進食動機所引起的病症,例如厭惡食物(例如,參見MacDonald等人(2003)J
.Am
.Coll
.Surg
. 197:143-161;Rubin(2003)Proc
.Natl
.Acad
.Sci
.USA
100:5384-5389;Tisdale(2002)Nature Reviews Cancer
2:862:871;Argiles等人(2003)Drug Discovery Today
8:838:844;Lelli等人(2003)J
.Chemother
. 15:220-225;Argiles等人(2003)Curr
.Opin
.Clin
.Nutr
.Metab
.Care
6:401-406)。
"守恒改質之變體(conservatively modified variant)"適用於胺基酸序列及核酸序列二者。就特殊核酸序列而言,守恒改質之變體係指:編碼相同或基本相同之胺基酸序列的核酸;或當核酸並未編碼胺基酸序列時,其係指基本相同之核酸序列。因為遺傳密碼之簡並,所以大量官能性相同之核酸可編碼任意給定之蛋白質。
關於胺基酸序列,熟悉此項技術者將瞭解:替代守恒胺基酸之編碼序列中的胺基酸或小百分比胺基酸之核酸、肽、多肽或蛋白質序列的個別替代物為"守恒改質之變體"。提供官能性相似之胺基酸的守恒替代物表在此項技術中為吾人所熟知。守恒替代物之一實例為將下列各組之一組中的一胺基酸交換成同組中之另一胺基酸(頒予Lee等人的美國專利第5,767,063號;Kyte及Doolittle(1982)J. Mol. Biol
. 157:105-132):
(1) 疏水性:己胺酸、lle、Val、Leu、Phe、Cys或Met;
(2) 中性親水性:Cys、Ser、Thr;
(3) 酸性:Asp、Glu;
(4) 鹼性:Asn、Gln、His、Lys、Arg;
(5) 影響鏈取向之殘餘物:Gly、Pro;
(6) 芳香性:Trp、Tyr、Phe;
(7) 小胺基酸:Gly、Ala、Ser。
"有效劑量"涵蓋足以改善或防止醫學症狀之徵兆或體征之劑量。有效劑量亦意謂足以允許或便於診斷之劑量。特殊患者或牲畜受測者之有效劑量可依各種因素而變化,例如正在治療的症狀、患者之整體健康狀況、投藥方法路徑與劑量及副作用之嚴重程度(例如,參見頒予Netti等人的美國專利第5,888,530號)。有效劑量可為避免顯著副作用或毒性作用之最大劑量或配量方案(dosing protocol)。其效果將導致診斷度量或參數改良至少5%,通常至少10%,更通常至少20%,最通常至少30%,較佳至少40%,更佳至少50%,最佳至少60%,理想上至少70%,更理想至少80%,且最理想至少90%,其中將100%界定為正常受測者所顯示之診斷參數(例如,參見Maynard等人(1996)A Handbook of SOPs for Good Clinical Practice
,Interpharm Press,Boca Raton,FL;Dent(2001)Good Laboratory and Good Clinical Practice
,Urch Publ.,London,UK)。
視上下文,"外因性"係指產生於有機體、細胞或人體外之物質。視上下文,"內因性"係指產生於細胞、有機體或人體內之物質。
"免疫性症狀"或"免疫性病症"涵蓋(例如)病理性發炎、發炎性病症及自身免疫性病症或疾病。"免疫性症狀"亦指感染、持續感染及增生性症狀,例如癌症、腫瘤及血管生成,包括藉由免疫系統抵抗根除(irradication)之感染、腫瘤及癌症。"癌性症狀"包括(例如)癌症、癌細胞、腫瘤、血管生成及諸如發育異常之癌症前期症狀。
"發炎性病症"意謂其中病理係完全或部分由(例如)免疫系統之細胞的數目改變、遷移速率改變或活性改變引起的病症或病理性症狀。免疫系統之細胞包括(例如)T細胞、B細胞、單核細胞或巨噬細胞、抗原遞呈細胞(APC)、樹突狀細胞、小膠質細胞、NK細胞、NKT細胞、嗜中性白細胞、嗜曙紅細胞、肥大細胞或其它與免疫學有特定關聯的細胞,例如產生細胞激素之內皮細胞或上皮細胞。
"抑制劑"及"拮抗劑"或"活化劑"及"激動劑"分別指抑制分子或活化分子,例如,其活化(例如)配位子、受體、輔助因子、基因、細胞、組織或器官。(例如)基因、受體、配位子或細胞之調節劑係改變基因、受體、配位子或細胞之活性的分子,其中可活化、抑制或改變其調控性質之活性。調節劑可單獨作用,或可使用輔助因子,例如蛋白質、金屬離子或小分子。抑制劑係減少、阻斷、防止、延遲活化或滅活、脫敏或向下調控(例如)基因、蛋白質、配位子、受體或細胞之化合物。活化劑係增加、活化、促進、增強活化或敏化或向上調控(例如)基因、蛋白質、配位子、受體或細胞之化合物。抑制劑亦可定義為減少、妨礙或滅活固有活性之組合物。"激動劑"係與目標相互作用以引起或促進目標之活化增加的化合物。"拮抗劑"係與激動劑之作用相反的化合物。拮抗劑防止、降低、抑制或中和激動劑之活性。即使未識別到激動劑,拮抗劑仍可防止、抑制或降低諸如目標受體之目標的固有活性。
例如,為檢查抑制之程度,以勢能(potential)活化劑或抑制劑來處理包含給定(例如)蛋白質、基因、細胞或有機體之樣本或檢定物,並將其與未用抑制劑處理之對照樣本進行比較。對照樣本,亦即不以拮抗劑處理之樣本,被賦予100%的相對活性值。當相對於對照值的活性值為以下值時達成了抑制:約90%或更少,典型為85%或更少,更典型為80%或更少,最典型為75%或更少,一般為70%或更少,更一般為65%或更少,最一般為60%或更少,典型為55%或更少,通常為50%或更少,更通常為45%或更少,最通常為40%或更少,較佳為35%或更少,更佳為30%或更少,再佳為25%或更少,最佳為低於25%。當相對於對照值的活性值為以下值時達成了活化:約110%,一般至少為120%,更一般至少為140%,最一般至少為160%,經常至少為180%,更經常至少為2倍,最經常至少為2.5倍,通常至少為5倍,更通常至少為10倍,較佳至少為20倍,更佳至少為40倍,且最佳超過40倍。
活化或抑制端點可監控如下。例如,對細胞、生理流體、組織、器官及動物或人類受測者之治療的活化、抑制及回應可由端點來監控。端點可包含預定數目或百分比之(例如)發炎、致瘤或細胞脫粒或分泌之標誌,例如細胞激素、毒性氧或蛋白酶之釋放。端點可包含:(例如)預定數目之離子流或傳輸;細胞遷移;細胞黏附;細胞增生;轉移勢能;細胞分化;及表型改變,例如關於發炎、細胞凋亡、轉化、細胞循環或轉移相關之基因表現的改變(例如,參見Knight(2000)Ann. Clin. Lab. Sci.
30:145-158;Hood及Cheresh(2002)Nature Rev. Cancer
2:91-100;Timme等人(2003)Curr. Drug Targets
4:251-261;Robbins及Itzkowitz(2002)Med. Clin. North Am.
86:1467-1495;Grady及Markowitz(2002)Annu. Rev. Genomics Hum. Genet.
3:101-128;Bauer等人(2001)Glia
36:235-243;Stanimirovic及Satoh(2000)Brain Pathol.
10:113-126)。
抑制端點一般為對照值之75%或更少,較佳為對照值之50%或更少,更佳為對照值之25%或更少,且最佳為對照值之10%或更少。一般而言,活化端點為對照值之至少150%,較佳為對照值之至少2倍,更佳為對照值之至少4倍,且最佳為對照值之至少10倍。
藉由光譜方法、光化學方法、生物化學方法、免疫化學方法、同位素方法或化學方法,可直接或間接偵測"經標記"之組合物。例如,可用之標記包括32
P、33
P、35
S、14
C、3
H、125
I、穩定同位素、螢光染料、高電子試劑、受質、抗原決定部位標簽或酶,例如用於酶連接免疫檢定法,或螢光標記物(例如,參見Rozinov及Nolan(1998)Chem. Biol
. 5:713-728)。
"配位子"係指(例如)小分子、肽、多肽及膜相關分子或膜結合分子或者其錯合物,其可充當受體之激動劑或拮抗劑。"配位子"亦涵蓋一藥劑,該藥劑並非激動劑或拮抗劑,但其可與受體結合而不會顯著影響其生物學性質(例如訊號或黏附)。此外,"配位子"包括已藉由(例如)化學或重組方法改變為可溶性型式之膜結合配位子的膜結合配位子。按照慣例,當配位子是結合於第一個細胞的膜上時,受體通常出現於另一個細胞上。第二個細胞可具有與第一細.胞相同或不同之實體。配位子或受體可完全在細胞內,即其可位於細胞液、細胞核或某些其它細胞內隔室中。配位子或受體可改變其位置,例如,從細胞內隔室改變至原生質膜之外面。配位子與受體之錯合物稱為"配位子受體錯合物"。當配位子及受體包含在訊號通道內時,配位子出現在訊號通道之上游位置,而受體出現在訊號通道之下游位置。
提供"小分子"以治療腫瘤及癌症之生理學及病症。將"小分子"界定為分子量小於10 kD、典型地係小於2 kD,而較佳者小於1 kD之分子。小分子包括(但不限於)無機分子、有機分子、含有無機成分之有機分子、包含放射性原子之分子、合成分子、類肽物及類抗體物。作為治療劑而言,小分子比大分子更易透過細胞、更不易降解,且更不易於引起免疫反應。業已描述了小分子,例如抗體及細胞激素之類肽物以及小分子毒素(例如,參見Casset等人(2003)Biochem. Biophys. Res. Commun.
307:198-205;Muyldermans(2001)J. Biotechnol.
74:277-302;Li(2000)Nat. Biotechnol.
18:1251-1256;Apostolopoulos等人(2002)Curr. Med. Chem.
9:411-420;Monfardini等人(2002)Curr. Pharm. Des.
8:2185-2199;Domingues等人(1999)Nat. Struct. Biol.
6:652-656;Sato及Sone(2003)Biochem. J.
371:603-608;頒予Stewart等人的美國專利第6,326,482號)。
當"特定"或"選擇性"結合係指配位子/受體、抗體/抗原或其它結合對時,其表示對蛋白質與其它生物製劑之異類群體中之蛋白質的存在具有決定作用之結合反應。因此,在指定條件下,特定之配位子與特殊受體結合,而不與該樣本中存在之其它蛋白質大量結合。所涵蓋的方法中,抗體或自抗體之抗原結合點衍生的結合組合物與其抗原或變體或突變蛋白質藉由親合力結合,相較於任何其它抗體或自其衍生的結合組合物之親合力,該親合力至少為其2倍,較佳為至少10倍,更佳為至少20倍,且最佳為至少100倍。在一較佳實施例中,(例如)藉由Scatchard分析所測定的抗體之親合力將約大於109
公升/莫耳(Munsen等人(1980)Analyt. Biochem.
107:220-239)。
本發明提供IL-23雜二聚物、p19子單元、p40子單元、IL-23受體雜二聚物、IL-23R子單元或IL-12Rβ1子單元之多肽、核酸、變體、突變蛋白質及擬態物(mimetic)之使用方法。本發明亦提供超細胞素(意即包含(例如)連接至p40子單元之p19子單元的融合蛋白質)及編碼超細胞素之核酸(例如,參見序列標識號:10或11)的使用方法(Oppmann等人supra
;Fischer等人(1997)Nature Biotechnol.
15:142-145;Rakemann等人(1999)J. Biol. Chem.
274:1257-1266;及Peters等人(1998)J. Immunol.
161:3575-3581)。
介白素-23(IL-23,又名IL-B30)係由IL-12之新穎p19子單元(序列標識號:2或4)及p40子單元(序列標識號:8或9)組成之雜二聚細胞激素。如同p35,為了生物活性,p19要求p40之共同表現(Wiekowski等人supra
)。IL-23受體包含結合p19之新穎受體子單元(IL-23R;序列標識號:6)及結合p40之IL-12Rβ1(序列標識號:7)(例如,參見Parham等人(2002)J. Immunol.
168:5699-5708)。該等兩種受體子單元形成功能性訊號錯合物,且其表現在CD4+
CD45Rblo
記憶T細胞及IFN-γ活化骨髓巨噬細胞上(Parham等人supra
)。
抗體可培養(raise)為自然存在(全長)形態或其重組形態(例如,參見序列標識號:2、4、10或11)之各種細胞激素蛋白質,包括單獨、多形態、等位、菌株或種變體及其片段。此外,抗體可培養為天然(或活性)形態或非活性形態(例如,變性形態)之受體蛋白質(例如,參見序列標識號:6)。亦可使用抗個體基因型抗體(anti-idiotypic antibodies)。
投予IL-23激動劑(亦即IL-23或IL-23超細胞素)可誘發(例如)記憶T細胞、PHA胚細胞、CD45RO T細胞、CD45RO T細胞之增生;藉由PHA胚細胞或CD45RO T細胞增強干擾素-γ(IFN-γ)之產生。與IL-12相比,IL-23較優地刺激記憶,此與人類及小鼠中之天然T細胞群相反。IL-23活化大量細胞內細胞訊號分子,例如Jak2、Tyk2、Stat1、Stat2、Stat3及Stat4。IL-12活化同組分子,但Stat4對IL-23之回應相對較弱,而Stat4對IL-12之回應較強(Oppmann等人,supra
;Parham等人(2002)J. Immunol
. 168:5699-5708)。
IL-12及IL-23涉及(engage)類似的訊號轉導機制。銜接(engage)其受體錯合物之IL-23活化Jak2、Tyk2及Stat-1、-3、-4及-5,IL-12亦如此。然而,Stat-4之活化對IL-23之回應顯著地弱於對IL-12之回應。同樣地,與IL-12相比,由IL-23所引起之最突出的Stat為Stat-3(例如,參見Parham等人supra
)。
投予IL-23之p19子單元可導致:(例如)動物的矮化生長、不育及死亡,以及諸如胃腸道、肺部、皮膚及肝臟之發炎性浸潤(infiltrate),及上皮細胞之超常增生、小紅細胞性貧血、嗜中性白細胞計數增加、血清TNFα增加;及肝臟中之急性相基因表現增加;(Wiekowski等人supra
)。增強之IL-23表現出現在永生性非轉化之上皮細胞系中。因此,IL-23可提供活體內潛在腫瘤之早期訊號。
其它研究已證實IL-23調節對感染之免疫反應(例如,參見Pirhonen等人(2002) J. Immunol. 169:5673-5678;Broberg等人(2002)J. Interferon Cytokine Res
. 22:641-651;Elkins等人(2002)Infection Immunity
70:1936-1948;Cooper等人(2002)J. Immunol.
168:1322-1327)。
關於癌症,來自一個體之活體檢視組織中之相對較高量的轉錄產物之存在表明了疾病發展的素因(predisposition),或可提供在出現實際臨床徵兆之前偵測疾病之方法。基因表現資料係在疾病及病理症狀之診斷及治療中之有用工具(例如,參見Li及Wong(2001)Genome Informatics
12:3-13;Lockhart等人(1996)Nature Biotechnol.
14:1675-1680;Homey等人(2000)J. Immunol.
164:3465-3470;Debets等人(2000)J. Immunol
. 165:4950-4956)。
本發明提供IL-23激動劑及拮抗劑之使用方法。IL-23激動劑涵蓋:(例如)IL-23、IL-23變體、突變蛋白質、超細胞素、或類肽物、IL-23R之激動抗體,及將該等激動劑編碼之核酸。IL-23之拮抗劑包括:(例如)IL-23之抗體、IL-23R之阻斷抗體,基於IL-23R之子單元的細胞外區域之可溶性受體、其類肽物,及將該等拮抗劑編碼之核酸。
本發明提供p19、p19與p40之錯合物、IL-23R、及IL-23R與IL-12Rβ1之錯合物的激動劑及拮抗劑之使用方法,包括特定結合至p19、p19與p40之錯合物、IL-23R、及IL-23R與IL-12Rβ1之錯合物的蛋白質及蛋白質錯合物之結合組合物之使用方法。
IL-23超細胞素涵蓋(例如)包含p19及p40之多肽序列之融合蛋白質,其中p19及p40出現在連續多肽鏈中。p19及p40之序列可為任何順序。融合蛋白質可含有連接序列(liker sequence),該連接序列位於一連續多肽鏈中之p19與p40序列之間。
增加抗原性之區域可用於抗體產生。人體p19之增加抗原性區域出現在:(例如) GenBank AAQ89442(gi:37183284)之胺基酸16-28;57-87、110-114、136-154及182-186處。人體IL-23R之增加抗原性區域出現在(例如)GenBank AAM44229(gi:21239252)之胺基酸22-33、57-63、68-74、101-112、117-133、164-177、244-264、294-302、315-326、347-354、444-473、510-530及554-558處。藉由使用Vector NTISuite(Informax,Inc.,Bethesda,MD)之Parker圖來進行分析。本發明亦提供IL-23拮抗劑,其為可溶性受體,意即包含IL-23R之細胞外區域(例如GenBankAAM44229之胺基酸1-353)或其片段,其中細胞外區域或其片段特定結合至IL-23。小鼠IL-23R係GenBank NP_653131(gi:21362353)。涵蓋突變蛋白質及變體,例如聚乙二醇化(pegylation)或突變誘發(mutagenesis)以移除或取代脫醯胺基之天冬醯胺(deamidating Asn)殘餘物。
可製備單株、多株及人化抗體(例如,參見Sheperd及Dean(eds.)(2000)Monoclonal Antibodies
,Oxford Univ. Press,New York,NY;Kontermann及Dubel(eds.)(2001)Antibody Engineering
,Springer-verlag,New York;Harlow及Lane(1988)Antibodies A Laboratory Manual
,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY,第139-243頁;Carpenter等人(2000)J. Immunol.
165:6205;He等人(1998)J. Immunol.
160:1029;Tang等人(1999)J. Biol. Chem.
274:27371-27378;Baca等人(1997)J. Biol. Chem.
272:10678-10684;Chothia等人(1989)Nature
342:877-883;Foote及Winter(1992)J. Mol. Biol.
224:487-499;頒予Vasquez等人的美國專利第6,329,511號)。
對於抗體之產生而言,並非必須純化抗原。可藉由DNA媒介免疫來執行免疫,例如,參見Wang等人(1997)Virology
228:278-284。或者,以攜帶相關抗原之細胞來使動物免疫。於是,脾細胞可自免疫動物單離,且脾細胞可隨骨髓瘤細胞系融合以產生雜種細胞(Meyaard等人(1997)Immunity
7:283-290;Wright等人(2000)Immunity
13:233-242;Preston等人(1997)Eur. J. Immunol.
27:1911-1918)。可藉由官能性檢定或生物檢定,即不取決於是否具有純化抗原之檢定,來篩選所得雜種細胞以產生所要抗體。可證明:對於抗體之產生而言,藉由細胞之免疫優於藉由純化抗原之免疫(Kaithamana等人(1999)J. Immunol.
163:5157-5164)。
抗體對抗原及配位子對受體之結合性質可藉由諸如表面細胞質基因共振(Karlsson等人(1991)J. Immunol. Methods
145:229-240;Neri等人(1997)Nat. Biotechnol.
15:1271-1275;Jonsson等人(1991)Biotechniques
11:620-627)或藉由競爭ELISA(Friguet等人(1985)J. Immunol. Methods
77:305-319;Hubble(1997)Immunol. Today
18:305-306)來量測。抗體可用於親合力純化以單離抗體之目標抗原及關聯結合之蛋白質(associated bound protein),例如,參見Wilchek等人(1984)Meth. Enzymol.
104:3-55。
抗體通常結合至少約10-3
M之KD
,更通常至少10-6
M,典型至少10-7
M,更典型至少10-8
M,較佳至少約10-9
M,且更佳至少約10-10
M,且最佳至少10-11
M(例如,參見Presta等人(2001)Thromb. Haemost.
85:379-389;Yang等人(2001)Crit. Rev. Oncol. Hematol.
38:17-23;Carnahan等人(2003)Clin. Cancer Res.
(Suppl.) 9:3982s-3990s)。
提供包含IL-23或IL-12Rβ1受體多肽之細胞外域的可溶性受體。可溶性受體可根據標準方法來製備及使用(例如,參見Jones等人(2002)Biochim. Biophys. Acta
1592:251-263;Prudhomme等人(2001)Expert Opinion Biol. Ther.
1:359-373;Fernandez-Botran(1999)Crit. Rev. Clin. Lab Sci.
36:165-224)。
本發明提供IL-23及抗IL-23R,其用於(例如)治療增生性症狀及病症,包括癌症、腫瘤、血管生成、惡病質、癌症惡病質、厭食症及癌症前期病症,例如發育異常。亦提供核酸以用於該等治療用途,例如編碼IL-23或IL-23R之核酸、或其抗原片段、相應反義核酸、及其雜種產物。本發明亦提供用於siRNA干擾之組合物(例如,參見Arenz及Schepers(2003)Naturwissenschaften
90:345-359;Sazani 及Kole(2003)J. Clin. Invest.
112:481-486;Pirollo等人(2003)Pharmacol. Therapeutics
99:55-77;Wang等人(2003)Antisense Nucl. Acid Drug Devel.
13:169-189)。
為製備包括IL-23激動劑或拮抗劑之醫藥組合物或無菌組合物,將細胞激素類似物或突變蛋白質、其抗體、或其核酸與醫藥上可接受之載體或賦形劑混合,例如,參見Remington's Pharmaceutical Sciences andU.S. Pharmacopeia
:NationalFormulary
,Mack Publishing Company,Easton,PA(1984)。治療劑及診斷劑之調配物可藉由將其與生理學上可接受之諸如凍乾粉末、漿料、水溶液或懸浮液形式之載體、賦形劑或安定劑混合來製備(例如,參見Hardman等人(2001)Goodman and Gilman's The Pharmacological Basis of Therapeutics
,McGraw-Hill
,New York,NY;Gennaro(2000)Remington: The Science and Practice of Pharmacy
,Lippincott,Williams,and Wilkins,New York,NY;Avis等人(eds.)(1993)Pharmaceutical Dosage Forms: Parenteral Medications
,Marcel Dekker,NY;Lieberman等人(eds.)(1990)Pharmaceutical Dosage Forms: Tablets
,Marcel Dekker,NY;Lieberman等人(eds.)(1990)Pharmaceutical Dosage Forms: Disperse Systems
,Marcel Dekker,NY;Weiner及Kotkoskie(2000)Excipient Toxicity and Safety
,Marcel Dekker,Inc.,New York,NY)。
投藥路徑係藉由(例如)局部或皮膚施用,皮下注射,藉由靜脈內、腹膜內、腦內、肌肉內、眼內、動脈內、腦脊髓內、患處內或肺部路徑之注射或灌輸,或藉由持續釋放系統或植入物。對(例如)中央神經系統之基因轉移媒介已有描述(例如,參見Cua等人(2001)J. Immunol.
166:602-608;Sidman等人(1983)Biopolymers
22:547-556;Langer等人(1981)J. Biomed. Mater. Res.
15:167-277;Langer(1982)Chem. Tech.
12:98-105;Epstein等人(1985)Proc. Natl. Acad. Sci. USA
82:3688-3692;Hwang等人(1980)Proc. Natl. Acad. Sci. USA
77:4030-4034;美國專利第6,350,466號及第6,316,024號)。
治療劑之投藥方式之選擇取決於若干因素,包括疾病單元(entity)之血清或組織周轉率、症兆程度、疾病單元之免疫原性、生物母質中之目標細胞之可接近性(accessibility)。投藥方式較佳使傳遞給患者的符合可接受程度之副作用的治療劑劑量最大化。因此,所傳遞的生物量部分取決於特殊疾病單元及正在治療之症狀的嚴重程度。可以獲得選擇抗體、細胞激素及小分子之適當劑量方面的指導(例如,參見Wawrzynczak(1996)Antibody Therapy
,Bios Scientific Pub. Ltd,Oxfordshire,UK;Kresina(ed.)(1991)Monoclonal Antibodies,Cytokines and Arthritis
,Marcel Dekker,New York,NY;Bach(ed.)(1993)Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases
,Marcel Dekker,New York,NY;Baert等人(2003)New Engl. J. Med.
348:601-608;Milgrom等人(1999)New Engl. J. Med.
341:1966-1973;Slamon等人(2001)New Engl,J. Med.
344:783-792;Beniaminovitz等人(2000)New Engl. J. Med.
342:613-619;Ghosh等人(2003)New Engl J. Med.
348:24-32;Lipsky等人(2000)New Engl. J. Med.
343:1594-1602)。
抗體、抗體片段及細胞激素可藉由連續灌輸或藉由間隔劑量(例如,1天、1週或每週1-7次)來提供。可靜脈內、皮下、局部、經口、經鼻、直腸、肌肉內、腦內、脊髓內或藉由吸入來提供劑量。較佳的劑量方案為包括避免明顯不良副作用之最大劑量或劑量頻率的方案。每週總劑量一般為至少0.05 μg/kg體重,更一般為至少0.2 μg/kg,最一般為至少0.5 μg/kg,典型為至少1 μg/kg,更典型為至少10 μg/kg,最典型為至少100 μg/kg,較佳為至少0.2 mg/kg,更佳為至少1.0 mg/kg,最佳為至少2.0 mg/kg,較理想為至少10 mg/kg,更理想為至少25 mg/kg,且最理想為至少50 mg/kg(例如,參見Yang等人(2003)New Engl. J. Med.
349:427-434;Herold等人(2002)New Engl. J. Med.
346:1692-1698;Liu等人(1999)J. Neurol. Neurosurg. Psych.
67:451-456;Portielji等人(2003)Cancer Immunol. Immunother.
52:133-144)。諸如類肽物、天然產品或有機化學品之小分子治療劑的所要劑量約與抗體或多肽相同,其以莫耳/公斤為基礎。
特殊患者之有效劑量可視多個因素而變化,例如正在治療之症狀、患者的整體健康狀況、投藥方法路徑與劑量及副作用之嚴重程度(例如,參見Maynard等人(1996)A Handbook of SOPs for Good Clinical Practice
,Interpharm Press,Boca Raton,FL;Dent(2001)Good Laboratory and Good Clinical Practice
,Urch Publ.,London,UK)。
典型牲畜、實驗或研究對象包括猴子、狗、貓、大鼠、小鼠、兔子、天竺鼠(guinea pig)、馬及人類。
適當劑量係藉由臨床醫師(例如)利用此項技術中已知或懷疑會影響治療或預測會影響治療之參數或因素來決定。一般而言,劑量以稍微少於理想劑量的量來開始,且其後增加小增量直至達成相對於任何消極副作用之所要或理想效果。重要的診斷量測包括(例如)發炎之徵兆的量測或所產生的炎性細胞激素之量的量測。即將使用之生物劑較佳源於與治療目標動物相同之物種,藉此最小化對試劑之體液回應。
用於藉由第二治療劑(例如,細胞激素、類固醇、化學治療劑、抗生素或輻射)來共同投藥或治療之方法在此項技術中已為吾人所熟知(例如,參見Hardman等人(eds.)(2001)Goodman及Gilman's The Pharmacological Basis of Therapeutics
,第10版,McGraw-Hill,New York,NY;Poole及Peterson(eds.)(2001)Pharmacotherapeutics for Advanced Practice: A Practical Approach
,Lippincott,Williams & Wilkins,Phila.,PA;Chabner及Longo(eds.)(2001)Cancer Chemotherapy and Biotherapy
,Lippincott,Williams & Wilkins,Phila.,PA)。治療劑之有效劑量會使徵兆降低:典型為至少10%,通常為至少20%,較佳為至少30%,更佳為至少40%,且最佳為至少50%。
本發明提供在一診斷套組中之IL-23蛋白質及其片段、核酸及其片段。本發明亦提供用於偵測IL-23與IL-23受體及其代謝物與分解產物之結合組合物,包括抗體或抗體片段。該套組一般具有一隔室,該隔室含有p19多肽或其抗原片段、其結合組合物、或核酸(例如,核酸探針或底塗劑)。核酸探針或底塗劑在緊急情況下會特定地雜交至編碼p19或IL-23R之核酸。
該套組可包含(例如)試劑及隔室,試劑及使用說明,或具有隔室之試劑與使用說明。試劑可包含p19、p19與p40之錯合物、IL-23R、IL-23R與IL-12Rβ1之錯合物、或其抗原片段、結合組合物或核酸。用於測定測試化合物(例如,自生物樣本或化學實驗室取得)之結合的套組可包含對照化合物、標記化合物及用於將無標記化合物與經結合之標記化合物分離之方法。
可藉由諸如活細胞、細胞提取物、細胞溶離物、固定細胞、細胞培養物、體液或法醫樣本之生物母質來使用診斷檢定。可用於診斷或套組之目的之共軛抗體包括偶合至染料、同位素、酶及金屬之抗體(例如,參見Le Doussal等人(1991)New Engl. J. Med.
146:169-175;Gibellini等人(1998)J. Immunol.
160:3891-3898;Hsing及Bishop(1999)New Engl. J. Med.
162:2804-2811;Everts等人(2002)New Engl. J. Med.
168:883-889)。存在各種檢定形式,例如放射性免疫檢定(RIA)、ELISA及在碎片上實驗(美國專利第6,176,962號及第6,517,234號)。
本發明提供在一診斷套組中之IL-23及IL-23R之多肽及核酸、及其片段,例如用於增生性症狀、癌症、腫瘤及癌症前期病症(例如發育異常)之診斷。
本發明亦提供用於偵測p19、p19與p40之錯合物、IL-23R、IL-23R與IL-23Rβ1之錯合物、及其代謝物與分解產物之結合組合物,包括抗體或抗體片段。該套組一般具有一隔室,該隔室含有IL-23或IL-23R多肽、或其抗原片段、其結合組合物、或核酸(例如,核酸探針、底塗劑,或分子信標)(例如,參見Rajendran等人(2003)Nucleic Acids Res
. 31:5700-5713;Cockerill(2003)Arch. Pathol. Lab. Med
. 127:1112-1120;Zammatteo等人(2002)Biotech. Annu. Rev
. 8:85-101;Klein(2002)Trends Mol. Med
. 8:257-260)。
診斷方法可包含使來自受測者(例如,測試受測者)之樣本與一結合組合物接觸,其中該結合組合物特定結合至p19、p19與p40之錯合物、IL-23R、及IL-23R與IL-12Rβ1之錯合物的多肽或核酸。該方法可進一步包含使來自對照受測者、正常受測者之樣本或來自測試受測者之正常組織或流體與該結合組合物接觸。此外,該方法可額外包含:將該組合物同測試受測者之特定結合與該組合物同正常受測者、對照受測者或來自測試受測者之正常組織或流體之特定結合進行比較。測試樣本或測試受測者之表現或活性可與來自對照樣本或對照受測者之表現或活性進行比較。對照樣本可包含(例如)罹患免疫病症之患者的非感染性或非發炎性組織之樣本。所提供之來自對照受測者或對照樣本之表現或活性可作為一預定值,例如自統計學上適當的組群之對照受測者取得的值。
本發明提供使用IL-23激動劑及拮抗劑之方法,其係藉由調控免疫反應以治療及診斷發炎性病症及症狀,其中發炎性病症及症狀為(例如)腫瘤性疾病、癌症、腫瘤、血管生成、諸如發育異常之癌症前期症狀、厭食症、惡病質及癌症惡病質。
本發明提供之方法係用以治療或診斷增生性症狀或病症,例如子宮癌、子宮頸癌、乳腺癌、前列腺癌、睾丸癌、陰莖癌、胃腸道癌(例如,食道、口咽、胃、小腸或大腸、結腸或直腸)、腎、腎細胞、膀胱、骨、骨髓、皮膚、頭或頸、皮膚、肝臟、膽囊、心臟、肺、胰腺、唾腺、腎上腺、甲狀腺、腦、神經中樞、中樞神經系統(CNS)及週邊神經系統(PNS)、及免疫系統(例如,脾與胸腺)。本發明提供用於治療以下症狀或病症之方法:例如免疫原腫瘤、非免疫原腫瘤、休眠腫瘤、病毒誘發之癌症,例如上皮細胞癌、內皮細胞癌、鱗狀細胞惡瘤、乳頭狀瘤病毒、腺癌、淋巴瘤、惡瘤、黑素瘤、白血病、骨髓瘤、肉瘤、畸胎瘤、化學誘發之癌症、轉移性病竈及血管生成。本發明亦期望(例如)藉由對調控T細胞(Treg)之活性的調節來降低腫瘤細胞或癌細胞抗原之耐受性(例如,參見Ramirez-Montagut等人(2003)Oncogene
22:3180-3187;Sawaya等人(2003)New Engl. J. Med.
349:1501-1509;Farrar等人(1999)J. Immunol.
162:2842-2849;Le等人(2001)J. Immunol
167:6765-6772;Cannistra及Niloff(1996)New Engl. J. Med.
334:1030-1038;Osborne(1998)New Engl. J. Med.
339:1609-1618;Lynch及Chapelle(2003)New Engl J. Med.
348:919-932;Enzinger及Mayer(2003)New Engl J. Med.
349:2241-2252;Forastiere等人(2001)New Engl. J. Med.
345:1890-1900;Izbicki等人(1997)New Engl. J. Med.
337:1188-1194;Holland等人(eds.)(1996)Cancer Medicine Encyclopedia of Cancer.
第4版,Academic Press,San Diego,CA)。
本發明提供用於藉由IL-23激動劑或拮抗劑及至少一額外治療劑或診斷劑來治療增生性症狀、癌症、腫瘤或諸如發育異常之癌症前期症狀之方法。該至少一額外治療劑或診斷劑可為(例如)細胞激素或細胞激素拮抗劑(例如,IL-12、干擾素-α或抗外皮生長因子受體)、阿黴素(doxorubicin)、表柔比星(epirubicin)、抗葉酸物(例如氨甲喋呤(methotrexate)或氟尿嘧啶(fluoruracil))、伊立替康(irinotecan)、環磷醯胺(cyclophosphamide)、放射線療法、激素或抗激素治療(例如雄性激素、雌性激素、抗雌性激素、氟他米特(flutamide)或已烯雌酚(diethylstibestrol))、外科手術、他莫西芬(tamoxifen)、異環磷醯胺(ifosfamide)、二溴衛矛醇(mitolactol)、烴化劑(例如,米爾法蘭(melphalan)或順鉑(cis-platin))、足葉乙甙(etoposide)、溫諾平(vinorelbine)、長春鹼(vinblastine)、去乙醯長春醯胺(vindesine)、腎上腺糖皮質激素、組胺受體拮抗劑、血管生成抑制劑、輻射、輻射敏化劑、小紅莓(anthracycline)、長春花屬生物鹼、紫杉烷(taxane)(例如,太平洋紫杉醇(paclitaxel)及歐洲紫杉醇(docetaxel)),細胞循環抑制劑(例如,週期素依賴性激酶抑制劑(cyclin-dependent kinase inhibitor))、單株抗體、單株抗體與毒素之錯合物、T細胞輔助劑、骨髓移植、或抗原遞呈細胞(例如,樹突狀細胞治療)。可提供疫苗作為(例如)可溶性蛋白質或編碼蛋白質之核酸(例如,參見Le等人supra
;Greco及Zellefsky(eds.)(2000)Radiotherapy of Prostate Cancer
,Harwood Academic,Amsterdam;Shapiro及Recht(2001)New Engl. J. Med.
344:1997-2008;Hortobagyi(1998)New Engl. J. Med.
339:974-984;Catalona(1994)New Engl. J. Med.
331:996-1004;Naylor及Hadden(2003)Int. Immunopharmacol.
3:1205-1215;The Int. Adjuvant Lung Cancer Trial Collaborative Group(2004)New Engl. J. Med.
350:351-360;Slamon等人(2001)New Engl. J. Med.
344:783-792;Kudelka等人(1998)New Engl. J. Med.
338:991-992;van Netten等人(1996)New Engl. J. Med.
334:920-921)。
本發明提供用於治療及診斷厭食症及惡病質(包括癌症惡病質)之方法。惡病質係一種消耗性綜合症,其發生在大量疾病中,包括癌症,例如肺癌及上胃腸道癌。所有癌症患者中約有一半出現惡病質。惡病質之診斷係根據大量體重減輕、胃口減少及深度虛弱(以上係針對先期疾病而言)及肌肉消耗(瘦體重(lean body mass)損耗)之病史。已將細胞激素,例如IL-6、IL-1、TNF-α及IFN-γ,與惡病質相聯繫(例如,參見MacDOnald等人,supra
;Rubin,supra
;Tisdale,supra
;Lelli等人,supra
;Argiles等人,supra
)。
本發明亦提供治療癌症之髓外造血(EMH)之方法。EMH已有描述(例如,參見Rao等人(2003)Leuk. Lymphoma
44:715-718;Lane等人(2002)J Cutan. Pathol
. 29:608-612)。
胃腸道包含(例如)嘴唇、口腔、食道、胃、小腸、闌尾、大腸、結腸、肛門及直腸。呼吸道包含(例如)氣管、細支氣管、支氣管、肺、肺泡。生殖系統包括(例如)睾丸、陰莖、卵巢、子宮、輸卵管。內分泌系統包括(例如)垂體、視丘下部、松果腺、甲狀腺、副甲狀腺、內分泌胰腺、胰島、生殖腺及腎上腺。
參考以下實例可最好地理解本發明之廣闊範圍,該等實例並無意將本發明限制為具體實施例。
本文所有引證均以引用的方式併入本文,該引用的程度就如同以特定地及個別地將各個公開案或專利申請案之揭示內容以引用的方式併入一般。
本發明之許多修正及變體可在未脫離其精髓及範疇的情況下作出,此對於熟悉此項技術者而言將顯而易見。本文所描述之具體實施例僅作為實例呈現,且本發明受限於隨附申請專利範圍之條款及授權給該等申請專利範圍之等效物的全部範疇;且本發明不限於本文中作為實例展現之具體實施例。
分子生物學之標準方法已有描述(Maniatis等人(1982)Molecular Cloning,A Laboratory Manual
,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Sambrook及Russell(2001)Molecular Cloning
,第三版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Wu(1993)Recombinant DNA
,Vol. 217,Academic Press,San Diego,CA)。標準方法亦發表在Ausbel等人(2001)Current Protocols in Molecular Biology
,Vols.1-4,John Wiley及Sons,Inc. New York,NY,其描述了細菌細胞之克隆技術(cloning)及DNA之突變誘發(Vol.1),哺乳動物細胞及酵母之克隆技術(Vol.2),結合糖(glycoconjugate)及蛋白質表現(Vol.3),及生物資訊學(Vol.4)。
蛋白質純化方法已有描述,包括免疫沈澱反應(immunoprecipitation)、層析法(chromatography)、電泳法、離心法及結晶法(Coligan等人(2000)Current Protocols in Protein Science,Vol. 1
,John Wiley and Sons,Inc.,New York)。化學分析、化學修飾、轉移後修飾、融合蛋白質之產生、蛋白質之糖基化已有描述(例如,參見Coligan等人(2000)Current Protocols in Protein Science,Vol.
2.John Wiley and Sons,Inc.,New York;Ausubel等人(2001)Current Protocols in Molecular Biology
,Vol. 3
,John Wiley and Sons,Inc.,NY,NY,pp. 16.0.5-16.22.17;Sigma-Aldrich,Co.(2001)Products for Life Science Research
,St. Louis,MO;pp.45-89;Amersham Pharmacia Biotech(2001)BioDirectory
,Piscataway,N.J.,pp.384-391)。多株及單株抗體之產生、純化及分裂已有描述(Coligan等人(2001)Current Protcols in Immunology,Vol. 1
,John Wiley and Sons,Inc.,New York;Harlow及Lane(1999)Using Antibodies
,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Harlow及Lane,supra
)。可以獲得用於表徵配位子/受體相互作用之標準技術(例如,參見Coligan等人(2001)Current Protcols in Immunology,Vol. 4
,John Wiley,Inc.,New York)。
可以獲得流式細胞量測方法,包括螢光活化細胞分類法(FACS)(例如,參見Owens等人(1994)Flow Cytometry Principles for Clinical Laboratory Practice
,John Wiley及Sons,Hoboken,NJ;Givan(2001)Flow Cytometry
,第二版,Wiley-Liss,Hoboken,NJ;Shapiro(2003)Practical Flow Cytometry
,John Wiley and Sons,Hoboken,NJ)。可以獲得適於修飾核酸(包括核酸底塗劑及探針)、多肽及抗體之螢光試劑以用作(例如)診斷試劑(Molecular Probes(2003)Catalogue
,Molecular Probes,Inc.,Eugene,OR;Sigma-Aldrich(2003)Catalogue
,St. Louis,MO)。
免疫系統組織學之標準方法已有描述(例如,參見Muller-Harmelink(ed.)(1986)Human Thymus: Histopathology及Pathology
,Springer Verlag,New York,NY;Hiatt等人(2000)Color Atlas of Histology
,Lippincott,Williams,and Wilkins,Phila,PA;Louis等人(2002)Basic Histology: Text and Atlas
,McGraw-Hill,New York,NY)。
用於治療及診斷癌症之方法已有描述(例如,參見Alison(ed.)(2001)The Cancer Handbook
,Grove's Dictionaries,Inc.,St. Louis,MO;Oldham(ed.)(1998)Principles of Cancer Biotherapy
,第三版,Kluwer Academic Publ.,Hingham,MA;Thompson等人(eds.)(2001)Textbook of Melanoma
,Martin Dunitz,Ltd.,London,UK;Devita等人(eds.)(2001)Cancer: Principles and Practice of Oncology
,第六版,Lippincott,Phila,PA;Holland等人(eds.)(2000)Holland
-Frei Cancer Medicine
,BC Decker,Phila.,PA;Garrett及Sell(eds.)(1995)Cellular Cancer Markers
,Humana Press,Totowa,NJ;MacKie(1996)Skin Cancer
,第二版,Mosby,St. Louis;Moertel(1994)New Engl. J. Med
. 330:1136-1142;Engleman(2003)Semin. Oncol
. 30(3 Suppl. 8):23-29;Mohr等人(2003)Onkologie
26:227-233)。
可以獲得用於測定(例如)抗原片段、前導序列、蛋白質褶皺、功能域、糖基化點及序列排列之軟體包及資料庫(例如,參見GenBank,Vector NTISuite(Informax,Inc,Bethesda,MD);GCG Wisconsin Package(Accelrys,Inc.,San Diego,CA): DeCypher(TimeLogic Corp.,Crystal Bay,Nevada);Menne等人(2000)Bioinformatics
16:741-742;Menne等人(2000)Bioinformatics Applications Note
16:741-742;Wren等人(2002)Comput. Methods Programs Biomed
. 68:177-181;von Heijne(1983)Eur. J. Biochem
. 133:17-21;von Heijne(1986)Nucleic Acids Res
. 14:4683-4690)。
如Cua等人在supra
中所述地產生缺乏IL-23 p19之小鼠。特別缺乏IL-23之小鼠(p19KO小鼠,p19剔除小鼠,p19-/-
小鼠)、p19+/-
小鼠及p19+/+
野生類對照小鼠具有B6/129 F2背景。
以化學方法誘發野生類小鼠(wt)或缺乏IL-23之小鼠(p19KO小鼠)之皮膚瘤。使用50微克7,12二甲基苯并蒽(DMBA)引發腫瘤,隨後進行由兩次處理組成之促進步驟,其中每一處理各為每週30微克TPA處理(例如,參見Oft等人(2002)Nat. Cell. Biol
. 4:487-494)。
就對Ep2X1B1-nu/nu小鼠所作的腫瘤研究而言,腫瘤轉移,同時並未出現惡病質。小鼠死於(例如)髓外造血(EMH))。就對Ep2XB1-Balb/c小鼠所作的腫瘤研究而言,未出現腫瘤轉移,此顯然是因為該等小鼠之完整的免疫系統。
IL-23之p19子單元及IL-23受體之IL-23R子單元的表現在大量癌症、腫瘤及細胞系中提高,例如胃腸道癌、生殖道癌、皮膚癌及乳腺癌(表1)。
使用RNeasy管柱(Qiagen,Valencia)萃取來自組織或細胞顆粒物(pellet)之RNA,並以Dnase I(Promega,Madison,WI)對其進行處理。製備cDNA,且將其用作供定量實時PCR用之模板。使用GeneAmp5700序列偵測系統(Applied Biosystems,Foster City,CA)來分析cDNA(25 ng)之一定範圍之基因的表現。將對來自正常及腫瘤結腸及卵巢組織之cDNA樣本的分析標準化為管家基因(housekeeping gene)泛激素之表現。
(例如)藉由以抗p19之抗體進行治療或藉由p19子單元(p19KO)之基因切除,根除或減輕了以IL-23拮抗劑治療之小鼠中由所注射之腫瘤細胞或由化學致癌作用所誘發之腫瘤。p19僅為IL-23之子單元,而p40同為IL-23及IL-12之子單元。相比之下,在某些情況下,以IL-12進行治療會使腫瘤惡化,意即導致腫瘤體積相對於對照小鼠而增加。
小鼠中之腫瘤導致癌症、癌症惡病質、髓外造血及死亡。以抗p19抗體治療攜帶腫瘤之Balb/c小鼠會導致停止增加腫瘤體積,而以抗p40抗體進行治療會激起動物體重增加(此可能是惡病質之逆轉),但腫瘤體積增加(表2)。
誘發小鼠中之癌症致死及癌症惡病質,其中藉由抗p40抗體來防止死亡及體重減輕。對小鼠注射1×106
EpXT腫瘤細胞(s.c.)。攜帶腫瘤之裸小鼠(Ep2XBl nu/nu)死於致命性肺部轉移性病竈,其中死亡發生於注射後22-42天。攜帶腫瘤之Exp2XBl Balb/c小鼠死於注射後22-49天,該等死亡的BalbC/c小鼠並無肺部轉移性病竈。惡病質係藉由體重出現下降(死亡前)來預示。體重逐漸減輕在約第16天開始發生。第1天的初始體重為22-23克,而死亡時的體重在16-18克範圍內。
以C17.8大鼠抗p40抗體(1毫克/週)進行抗體治療。藉由抗體治療,Ep2XBl-Balb/C小鼠(免疫活性小鼠)存活至約第64天,之後直至第85天才死亡。抗p40抗體治療亦導致一半的小鼠體重保持不變(大約17克),其餘小鼠在實驗期間內體重逐漸增加至22-23克的最大值。因此,根據存活時間及體重恢復,抗p40抗體會導致健康改善,但抗p40抗體亦可導致健康下降,如腫瘤大小增加所示(表2)。
藉由每週以DMBA(50微克)及2×30微克十四烷醯佛波醇-13-乙酸酯(tetradecanoylphorbol-13-acetate)(TPA)處理來化學誘發癌症(Gschwendt等人(1991)Trends Biochem Sci
. 16:167-169)。將化學致癌治療施用於B6/129野生類小鼠及p19KO小鼠。野生類小鼠較易發展腫瘤,但p19KO小鼠並不會得腫瘤(表3)。
獨立研究證實:p19KO防止腫瘤形成,而p35KO加劇腫瘤形成(表4)。
在致癌物處理後測定IL-23之子單元及IL-12之子單元的組織及細胞表現。單獨的DMBA、單獨的TPA、及DMBA與TPA誘發IL-23之p19子單元的表現,將該等化學物質施加至小鼠後背。舉例而言,以DMBA處理2天後,導致p19表現自1.5(未處理)增加至6.3(第2天)。P40表現增加,但在該時間間隔內相對較低(未處理時為0.1,第2天為0.4)。以TPA處理5小時後,導致p19表現增加(對照值為2.5,以TPA處理值為15.5),但p40表現相對變化較小(對照值為2.0,以TPA處理值為3.5)。以DMBA加TPA處理5小時後,導致p19表現有較大增加(對照值為6.0,DMBA+TPA值為32.0),但p40表現僅有中等程度的增加(對照值為2.0,DMBA+TPA值為4.0)。
亦測定人體角化細胞對(例如)DMBA、TPA及脂多糖(LPS)之回應(表5)。TPA具體誘發p19,且極少或沒有誘發p40(其為IL-23及IL-12之共同子單元)。LPS誘發p19,此表示先天回應中IL-23中之作用。結合LPS之類鍾受體(toll-like receptor)出現在角化細胞上(例如,參見Song等人(2002)J. Invest. Dermatol
. 119:424-432)。足葉乙甙係抑制局部異構酶(topoisomerase)II及誘發細胞凋亡之抗癌劑(例如,參見Robertson等人(2000)J. Biol. Chem
. 275:32438-32443;Karpinich等人(2000)J. Biol. Chem
. 277:16547-16552)。
測試抗p19抗體對4T1小鼠乳腺癌細胞模型之影響。以對照mIgG1(27F11)抗體或以抗p19抗體(29A2)處理小鼠。在第1、3、4、5、6、7、8、9、10及11天監控腫瘤生長。在第2、5、8及10天投予抗體(1毫克/劑)。在第4天,以對照抗體治療之小鼠的腫瘤大小為約175 mm3
,而以抗p19抗體治療之小鼠的腫瘤大小為約135 mm3
。因此,抗p19抗體可有效地治療乳腺癌模型。4天後,兩組腫瘤以大約相同的速率生長,此表示在以後的時期內抗體劑量不足以及時抵消腫瘤所表現的IL-23。
Ep2小鼠之乳腺癌模型的組織學證實了IL-23R與NK細胞之共定位,如藉由將存在於結合至IL-23R位置的p19著色及藉由將CD49B(其為NK細胞之標記)著色所測定。該共定位發生在腫瘤之中心部位,意即在壞死區域。Ep2小鼠之乳腺癌組織學亦證實了p19及T細胞之共定位。T細胞位置係藉由將CD3著色來測定。該共定位發生在腫瘤之外周部位。
序列標識號:1係人體IL-23 p19核酸序列;序列標識號:2係人體IL-23 p19胺基酸序列;序列標識號:3係小鼠IL-23 p19核酸序列;序列標識號:4係小鼠IL-23 p19胺基酸序列;序列標識號:5係人體IL-23受體核酸序列;序列標識號:6係人體IL-23受體胺基酸序列;序列標識號:7係人體IL-12Rβ1胺基酸序列;序列標識號:8係人體IL-12 p40胺基酸序列;序列標識號:9係小鼠IL-12 p40胺基酸序列;序列標識號:10係小鼠IL-23超細胞素;序列標識號:11係人體IL-23超細胞素。
本文所有引證均以引用的方式併入本文,該引用的程度就如同以特定地及個別地將各個公開案或專利申請案之揭示內容以引用的方式併入一般。
本發明之許多修正及變體可在未脫離其精髓及範疇的情況下作出,此對於熟悉此項技術者而言將顯而易見。本文所描述之具體實施例僅作為實例呈現,且本發明受限於隨附申請專利範圍之條款及授權給該等申請專利範圍之等效物的全部範疇;且本發明不限於本文中作為實例展現之具體實施例。
<110> Schering Corporation
<120> IL-23激動劑及拮抗劑之用途及相關試劑
<130> DX06022WO01
<140> 093106213
<141> 2004-03-09
<150> U.S. 60/453,672
<151> 2003-03-10
<160> 11
<170> PatentIn version 3.1
<210> 1
<211> 570
<212> DNA
<213> 人類
<220>
<221> CDS
<222> (1)..(567)
<223>
<220>
<221> mat_peptide
<222> (64)..(567)
<223>
<400> 1
<210> 2
<211> 189
<212> PRT
<213> 人類
<400> 2
<210> 3
<211> 1203
<212> DNA
<213> 小家鼠
<220>
<221> CDS
<222> (113)..(700)
<223>
<220>
<221> mat_peptide
<222> (176)..(700)
<223>
<400> 3
<210> 4
<211> 196
<212> PRT
<213> 小家鼠
<400> 4
<210> 5
<211> 2859
<212> DNA
<213> 人類
<220>
<221> CDS
<222> (119)..(2005)
<223>
<220>
<221> mat_peptide
<222> (188)..(2005)
<223>
<400> 5
<210> 6
<211> 629
<212> PRT
<213> 人類
<220>
<221> misc_feature
<222> (-21)..(-21)
<223> -21位置處的'Xaa'代表Gln或His。
<220>
<221> misc_feature
<222> (126)..(126)
<223> 126位置處的'Xaa'代表Gly或Arg。
<400> 6
<210> 7
<211> 862
<212> PRT
<213> 人類
<400> 7
<210> 8
<211> 328
<212> PRT
<213> 人類
<400> 8
<210> 9
<211> 335
<212> PRT
<213> 小家鼠
<400> 9
<210> 10
<211> 531
<212> PRT
<213> 小家鼠
<400> 10
<210> 11,
<211> 521
<212> PRT
<213> 人類
<400> 11
Claims (7)
- 一種與人類IL-23 R(SEQ ID NO:6)專一性鍵結之抗體或其抗原鍵結片段用於製造治療腫瘤或癌症之藥劑之用途。
- 如申請專利範圍第1項之用途,其中該抗體或其片段可抑制或防止腫瘤生長。
- 如申請專利範圍第1項之用途,其中該腫瘤表現IL-23。
- 如申請專利範圍第1項之用途,其中該抗體或其片段包含:a)多株抗體;b)單株抗體;c)人源化抗體,或其片段;或d)Fab、Fv或F(ab')2 片段。
- 如申請專利範圍第1項之用途,其中該腫瘤為:a)結腸腫瘤;b)卵巢腫瘤;c)乳腺腫瘤;或d)黑素瘤。
- 如申請專利範圍第1項之用途,其中該抗體或其片段可抑制:a)該癌症或腫瘤之生長;b)惡病質;c)厭食症;或d)血管生成。
- 如申請專利範圍第1項之用途,其中該癌症或腫瘤係下列之癌症或腫瘤:a)胃腸道;b)呼吸道;c)生殖系統;或d)內分泌系統。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US45367203P | 2003-03-10 | 2003-03-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201141521A TW201141521A (en) | 2011-12-01 |
TWI439285B true TWI439285B (zh) | 2014-06-01 |
Family
ID=32990805
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW100126443A TWI439285B (zh) | 2003-03-10 | 2004-03-09 | Il-23激動劑及拮抗劑之用途及相關試劑 |
TW093106213A TWI357336B (en) | 2003-03-10 | 2004-03-09 | Uses of il-23 agonists and antagonists; related re |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW093106213A TWI357336B (en) | 2003-03-10 | 2004-03-09 | Uses of il-23 agonists and antagonists; related re |
Country Status (23)
Country | Link |
---|---|
US (4) | US7282204B2 (zh) |
EP (2) | EP2108658B1 (zh) |
JP (4) | JP4605798B2 (zh) |
CN (1) | CN1759123B (zh) |
AT (1) | ATE440864T1 (zh) |
AU (2) | AU2004219625B9 (zh) |
BR (1) | BRPI0408247A (zh) |
CA (1) | CA2518262C (zh) |
CL (1) | CL2004000467A1 (zh) |
CY (1) | CY1109468T1 (zh) |
DE (1) | DE602004022781D1 (zh) |
DK (1) | DK1601694T3 (zh) |
ES (1) | ES2330220T3 (zh) |
HK (1) | HK1076477A1 (zh) |
MX (1) | MXPA05009717A (zh) |
NO (1) | NO20054630L (zh) |
NZ (2) | NZ567860A (zh) |
PL (1) | PL1601694T3 (zh) |
PT (1) | PT1601694E (zh) |
SI (1) | SI1601694T1 (zh) |
TW (2) | TWI439285B (zh) |
WO (1) | WO2004081190A2 (zh) |
ZA (1) | ZA200506879B (zh) |
Families Citing this family (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020137890A1 (en) * | 1997-03-31 | 2002-09-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP1576011B1 (en) * | 2002-10-30 | 2009-08-12 | Genentech, Inc. | Inhibition of il-17 production |
US7282204B2 (en) * | 2003-03-10 | 2007-10-16 | Schering Corporation | Uses of IL-23 agonists and antagonists; related reagents |
WO2004101750A2 (en) * | 2003-05-09 | 2004-11-25 | Centocor, Inc. | IL-23p40 SPECIFIC IMMUNOGLOBULIN DERIVED PROTEINS, COMPOSITIONS, METHODS AND USES |
WO2005079837A1 (en) * | 2004-02-17 | 2005-09-01 | Schering Corporation | Methods of modulating il-23 activity; related reagents |
US20060193821A1 (en) * | 2004-03-05 | 2006-08-31 | Diener John L | Aptamers to the human IL-12 cytokine family and their use as autoimmune disease therapeutics |
JP2007527246A (ja) * | 2004-03-05 | 2007-09-27 | アーケミックス コーポレイション | ヒトil−12サイトカインファミリーに対するアプタマーおよび自己免疫疾患の治療剤としてのそれらの使用 |
AR051444A1 (es) * | 2004-09-24 | 2007-01-17 | Centocor Inc | Proteinas derivadas de inmunoglobulina especifica de il-23p40, composiciones, epitopos, metodos y usos |
EP2292758A3 (en) * | 2004-12-20 | 2013-12-25 | Merck Sharp & Dohme Corp. | Uses of mammalian cytokine; related reagents |
PL1896073T3 (pl) * | 2005-06-30 | 2013-08-30 | Janssen Biotech Inc | Przeciwciała anty-IL-23, kompozycje, sposoby i zastosowania |
AU2012258409B2 (en) * | 2005-06-30 | 2016-01-07 | Centocor, Inc. | Anti-IL-23 antibodies, compositions, methods and uses |
AU2006265898A1 (en) * | 2005-06-30 | 2007-01-11 | Archemix Corp. | Polynucleotides and polypeptides of the IL-12 family of cytokines |
PL1937721T3 (pl) * | 2005-08-25 | 2010-12-31 | Lilly Co Eli | Przeciwciała anty-IL23 |
SG10201402712QA (en) | 2005-08-31 | 2014-08-28 | Merck Sharp & Dohme | Engineered anti-il-23 antibodies |
EP1933869B1 (en) | 2005-09-01 | 2009-10-14 | Schering Corporation | Use of il-23 and il-17 antagonists to treat autoimmune ocular inflammatory disease |
RS53685B1 (en) * | 2005-12-29 | 2015-04-30 | Janssen Biotech Inc. | HUMAN ANTI-IL-23 ANTIBODIES, COMPOSITIONS, METHODS AND APPLICATIONS |
US7910703B2 (en) | 2006-03-10 | 2011-03-22 | Zymogenetics, Inc. | Antagonists to IL-17A, IL-17F, and IL-23P19 and methods of use |
WO2007147019A2 (en) | 2006-06-13 | 2007-12-21 | Zymogenetics, Inc. | Il-17 and il-23 antagonists and methods of using the same |
EP1882699A1 (en) * | 2006-07-27 | 2008-01-30 | Heinfried Radeke | Regulation of interleukin-23 |
TWI426918B (zh) * | 2007-02-12 | 2014-02-21 | Merck Sharp & Dohme | Il-23拮抗劑於治療感染之用途 |
JP2010518858A (ja) | 2007-02-23 | 2010-06-03 | シェーリング コーポレイション | 操作された抗−il−23p19抗体 |
EP2059534B1 (en) | 2007-02-23 | 2012-04-25 | Schering Corporation | Engineered anti-il-23p19 antibodies |
CN101675076B (zh) | 2007-02-28 | 2013-09-18 | 默沙东公司 | 工程化的抗il-23r抗体 |
NZ579297A (en) | 2007-02-28 | 2012-03-30 | Schering Corp | Combination therapy comprising an il-23 antagonist and a cytokine antagonist for treatment of immune disorders |
US20100190710A1 (en) * | 2007-07-06 | 2010-07-29 | Valorisation Hsj, Societe En Commandite | Il-23 receptor antagonists and uses thereof |
AR068723A1 (es) * | 2007-10-05 | 2009-12-02 | Glaxo Group Ltd | Proteina que se une a antigenos que se une a il-23 humana y sus usos |
WO2009054454A1 (ja) | 2007-10-24 | 2009-04-30 | National University Corporation Tokyo Medical And Dental University | カテプシン阻害剤を有効成分として含有するToll様受容体のシグナル伝達の調整剤 |
BRPI0908312A2 (pt) * | 2008-05-05 | 2015-08-18 | Novimmune Sa | '' anticorpo monoclonal totalmente humano isolado, composição farmacêutica, método de alívio de um sintoma de uma indicação clínica e método de alívio de um sintoma de uma doença autoimune, distúrbio inflamatório ou distúrbio da proliferação celular'' |
US20110158992A1 (en) * | 2008-08-27 | 2011-06-30 | Schering Corporation | Engineered Anti-IL-23R Antibodies |
US20110183859A1 (en) * | 2008-09-25 | 2011-07-28 | The United States Of America, As Represented By The Secretary, | Inflammatory genes and microrna-21 as biomarkers for colon cancer prognosis |
PL2350316T3 (pl) * | 2008-10-20 | 2014-10-31 | Valipharma | Sposoby i zastosowania obejmujące aberracje genetyczne NAV3 i nieprawidłową ekspresję wielu genów |
CA2757237A1 (en) * | 2009-04-01 | 2010-10-14 | Jane Elizabeth Clarkson | Anti-il-23 immunoglobulins |
KR101811886B1 (ko) | 2009-05-05 | 2017-12-22 | 노비뮨 에스 에이 | 항―il―17f 항체 및 이의 사용 방법 |
EP2456787A4 (en) * | 2009-07-24 | 2013-01-30 | Univ Leland Stanford Junior | CYTOKINE COMPOSITIONS AND METHODS OF USE |
US20110086806A1 (en) * | 2009-10-09 | 2011-04-14 | Anaphore, Inc. | Polypeptides that Bind IL-23R |
JO3244B1 (ar) | 2009-10-26 | 2018-03-08 | Amgen Inc | بروتينات ربط مستضادات il – 23 البشرية |
US20110311527A1 (en) | 2010-06-16 | 2011-12-22 | Allergan, Inc. | IL23p19 ANTIBODY INHIBITOR FOR TREATING OCULAR AND OTHER CONDITIONS |
LT2635601T (lt) | 2010-11-04 | 2016-10-10 | Boehringer Ingelheim International Gmbh | Antikūnai prieš il-23 |
USRE49026E1 (en) | 2011-06-14 | 2022-04-12 | Medical Diagnostic Laboratories, Llc | Polypeptides that bound to IL-23 receptor and inhibit binding of IL-23 and cell signaling thereof |
US8946150B2 (en) | 2011-06-14 | 2015-02-03 | Medical Diagnostic Laboratories, LLC. | Polypeptides that bound to IL-23 receptor and inhibit binding of IL-23 and cell signaling thereof |
JP6293120B2 (ja) | 2012-05-03 | 2018-03-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 抗IL−23p19抗体 |
US9803010B2 (en) | 2012-06-27 | 2017-10-31 | Merck Sharp & Dohme Corp. | Crystalline anti-human IL-23p19 antibodies |
UA117466C2 (uk) | 2012-12-13 | 2018-08-10 | Мерк Шарп Енд Доме Корп. | СТАБІЛЬНИЙ СКЛАД У ВИГЛЯДІ РОЗЧИНУ АНТИТІЛА ДО IL-23p19 |
AR094877A1 (es) | 2013-03-08 | 2015-09-02 | Lilly Co Eli | Anticuerpos que se unen a il-23 |
JP2017524359A (ja) | 2014-07-24 | 2017-08-31 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Il−23a関連疾患の処置に有用なバイオマーカー |
MY192824A (en) | 2014-09-03 | 2022-09-12 | Boehringer Ingelheim Int | Compound targeting il-23a and tnf-alpha and uses thereof |
AR102417A1 (es) | 2014-11-05 | 2017-03-01 | Lilly Co Eli | Anticuerpos biespecíficos anti-tnf- / anti-il-23 |
US11279754B2 (en) | 2015-03-11 | 2022-03-22 | Rush University Medical Center | Compositions and methods for treating cancer |
MX2019013072A (es) | 2017-05-02 | 2019-12-16 | Merck Sharp & Dohme | Formulaciones de anticuerpos anti-lag3 y coformulaciones de anticuerpos anti-lag3 y anticuerpos anti-pd-1. |
JOP20190260A1 (ar) | 2017-05-02 | 2019-10-31 | Merck Sharp & Dohme | صيغ ثابتة لأجسام مضادة لمستقبل الموت المبرمج 1 (pd-1) وطرق استخدامها |
US11548941B2 (en) | 2018-11-20 | 2023-01-10 | Janssen Biotech, Inc. | Safe and effective method of treating psoriasis with anti-IL-23 specific antibody |
US11780911B2 (en) | 2019-05-23 | 2023-10-10 | Janssen Biotech, Inc. | Method of treating inflammatory bowel disease with a combination therapy of antibodies to IL-23 and TNF alpha |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6176962B1 (en) | 1990-02-28 | 2001-01-23 | Aclara Biosciences, Inc. | Methods for fabricating enclosed microchannel structures |
US5783415A (en) | 1991-03-29 | 1998-07-21 | Genentech, Inc. | Method of producing an IL-8 receptor polypeptide |
US6132764A (en) | 1994-08-05 | 2000-10-17 | Targesome, Inc. | Targeted polymerized liposome diagnostic and treatment agents |
WO1997003715A1 (en) | 1995-07-21 | 1997-02-06 | The General Hospital Corporation | Method and apparatus of enhancing the delivery of a pharmaceutical formulation |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
US6060284A (en) * | 1997-07-25 | 2000-05-09 | Schering Corporation | DNA encoding interleukin-B30 |
US5842787A (en) | 1997-10-09 | 1998-12-01 | Caliper Technologies Corporation | Microfluidic systems incorporating varied channel dimensions |
US6326482B1 (en) | 1999-04-23 | 2001-12-04 | Genentech, Inc. | SH2 domain-containing peptides |
AU764211C (en) | 1998-12-01 | 2006-03-30 | Abbvie Biotherapeutics Inc. | Humanized antibodies to gamma-interferon |
IL148300A0 (en) | 1999-09-09 | 2002-09-12 | Schering Corp | Mammalian cytokines; related reagents and methods |
MXPA02011081A (es) * | 2000-05-10 | 2003-03-10 | Schering Corp | Proteinas de subunidad de receptor de citocina de mamifero, reactivos y metodos relacionados. |
AU2002223182B2 (en) | 2000-10-06 | 2007-08-30 | Immunex Corporation | Hematopoietin receptors HPR1 and HPR2 |
US20030157105A1 (en) * | 2001-05-30 | 2003-08-21 | Carton Jill M. | Anti-p40 immunglobulin derived proteins, compositions, methods and uses |
US7282204B2 (en) * | 2003-03-10 | 2007-10-16 | Schering Corporation | Uses of IL-23 agonists and antagonists; related reagents |
-
2004
- 2004-03-09 US US10/797,157 patent/US7282204B2/en active Active
- 2004-03-09 CL CL200400467A patent/CL2004000467A1/es unknown
- 2004-03-09 CN CN2004800067148A patent/CN1759123B/zh not_active Expired - Fee Related
- 2004-03-09 WO PCT/US2004/007198 patent/WO2004081190A2/en active Application Filing
- 2004-03-09 DE DE602004022781T patent/DE602004022781D1/de not_active Expired - Lifetime
- 2004-03-09 JP JP2006507006A patent/JP4605798B2/ja not_active Expired - Fee Related
- 2004-03-09 AT AT04718824T patent/ATE440864T1/de active
- 2004-03-09 EP EP09163834.6A patent/EP2108658B1/en not_active Expired - Lifetime
- 2004-03-09 TW TW100126443A patent/TWI439285B/zh not_active IP Right Cessation
- 2004-03-09 SI SI200431281T patent/SI1601694T1/sl unknown
- 2004-03-09 BR BRPI0408247-8A patent/BRPI0408247A/pt not_active IP Right Cessation
- 2004-03-09 NZ NZ567860A patent/NZ567860A/en not_active IP Right Cessation
- 2004-03-09 EP EP04718824A patent/EP1601694B1/en not_active Expired - Lifetime
- 2004-03-09 NZ NZ541898A patent/NZ541898A/en not_active IP Right Cessation
- 2004-03-09 MX MXPA05009717A patent/MXPA05009717A/es active IP Right Grant
- 2004-03-09 TW TW093106213A patent/TWI357336B/zh not_active IP Right Cessation
- 2004-03-09 PT PT04718824T patent/PT1601694E/pt unknown
- 2004-03-09 DK DK04718824T patent/DK1601694T3/da active
- 2004-03-09 PL PL04718824T patent/PL1601694T3/pl unknown
- 2004-03-09 AU AU2004219625A patent/AU2004219625B9/en not_active Ceased
- 2004-03-09 CA CA2518262A patent/CA2518262C/en not_active Expired - Fee Related
- 2004-03-09 ES ES04718824T patent/ES2330220T3/es not_active Expired - Lifetime
-
2005
- 2005-08-26 ZA ZA200506879A patent/ZA200506879B/en unknown
- 2005-10-07 NO NO20054630A patent/NO20054630L/no not_active Application Discontinuation
- 2005-12-07 HK HK05111191.9A patent/HK1076477A1/xx not_active IP Right Cessation
-
2007
- 2007-02-26 JP JP2007046287A patent/JP2007197453A/ja active Pending
- 2007-08-31 US US11/848,462 patent/US20080057058A1/en not_active Abandoned
-
2009
- 2009-08-24 US US12/546,230 patent/US8034341B2/en not_active Expired - Lifetime
- 2009-10-06 CY CY20091101030T patent/CY1109468T1/el unknown
-
2010
- 2010-08-16 AU AU2010212372A patent/AU2010212372B2/en not_active Ceased
- 2010-09-07 JP JP2010200382A patent/JP2011032275A/ja not_active Withdrawn
-
2011
- 2011-10-10 US US13/270,077 patent/US20120034219A1/en not_active Abandoned
-
2013
- 2013-08-15 JP JP2013168870A patent/JP2014005286A/ja active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI439285B (zh) | Il-23激動劑及拮抗劑之用途及相關試劑 | |
TWI363091B (en) | Uses of mammalian cytokine; related reagents | |
US20060140950A1 (en) | Uses of mammalian cytokine; related reagents | |
US20050214296A1 (en) | Methods of modulating cytokine activity; related reagents | |
EP1725261A2 (en) | Use for interleukin-33 (il-33) and the il-33 receptor complex |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |