JP2012502113A - 病原性単球の標的化 - Google Patents
病原性単球の標的化 Download PDFInfo
- Publication number
- JP2012502113A JP2012502113A JP2011527020A JP2011527020A JP2012502113A JP 2012502113 A JP2012502113 A JP 2012502113A JP 2011527020 A JP2011527020 A JP 2011527020A JP 2011527020 A JP2011527020 A JP 2011527020A JP 2012502113 A JP2012502113 A JP 2012502113A
- Authority
- JP
- Japan
- Prior art keywords
- monocytes
- agent
- 1alpha
- cells
- subject
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 210000001616 monocyte Anatomy 0.000 title claims abstract description 85
- 230000008685 targeting Effects 0.000 title abstract description 10
- 230000001717 pathogenic effect Effects 0.000 title abstract description 4
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 claims abstract description 68
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 claims abstract description 68
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 claims abstract description 64
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 claims abstract description 64
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 claims abstract description 63
- 108010082786 Interleukin-1alpha Proteins 0.000 claims abstract description 45
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 43
- 210000000265 leukocyte Anatomy 0.000 claims abstract description 29
- 102000004125 Interleukin-1alpha Human genes 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims description 56
- 230000014509 gene expression Effects 0.000 claims description 40
- 238000009739 binding Methods 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 108020003175 receptors Proteins 0.000 claims description 14
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 10
- 210000000601 blood cell Anatomy 0.000 claims description 8
- 230000001575 pathological effect Effects 0.000 claims description 8
- 230000007170 pathology Effects 0.000 claims description 7
- 210000005259 peripheral blood Anatomy 0.000 claims description 6
- 239000011886 peripheral blood Substances 0.000 claims description 6
- 230000002159 abnormal effect Effects 0.000 claims description 3
- 230000001363 autoimmune Effects 0.000 claims description 3
- 230000004968 inflammatory condition Effects 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 abstract description 73
- 230000000770 proinflammatory effect Effects 0.000 abstract description 6
- 239000003550 marker Substances 0.000 abstract description 4
- 102100020881 Interleukin-1 alpha Human genes 0.000 description 37
- 108090000623 proteins and genes Proteins 0.000 description 36
- 230000006870 function Effects 0.000 description 35
- 102000004169 proteins and genes Human genes 0.000 description 32
- 108020004707 nucleic acids Proteins 0.000 description 17
- 102000039446 nucleic acids Human genes 0.000 description 17
- 150000007523 nucleic acids Chemical class 0.000 description 17
- 102000005962 receptors Human genes 0.000 description 13
- 210000002889 endothelial cell Anatomy 0.000 description 10
- 108020004999 messenger RNA Proteins 0.000 description 10
- 102100023471 E-selectin Human genes 0.000 description 8
- 230000000692 anti-sense effect Effects 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 231100000599 cytotoxic agent Toxicity 0.000 description 8
- 238000000684 flow cytometry Methods 0.000 description 8
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 7
- 210000002540 macrophage Anatomy 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 238000013519 translation Methods 0.000 description 7
- 239000002619 cytotoxin Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 229960005486 vaccine Drugs 0.000 description 6
- 108060003951 Immunoglobulin Proteins 0.000 description 5
- 230000006303 immediate early viral mRNA transcription Effects 0.000 description 5
- 102000018358 immunoglobulin Human genes 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 230000005012 migration Effects 0.000 description 5
- 238000013508 migration Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 239000002356 single layer Substances 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 108091023037 Aptamer Proteins 0.000 description 4
- 108010024212 E-Selectin Proteins 0.000 description 4
- 101000622123 Homo sapiens E-selectin Proteins 0.000 description 4
- 101001002634 Homo sapiens Interleukin-1 alpha Proteins 0.000 description 4
- 102000003777 Interleukin-1 beta Human genes 0.000 description 4
- 108090000193 Interleukin-1 beta Proteins 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 238000001261 affinity purification Methods 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 230000002163 immunogen Effects 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 210000000440 neutrophil Anatomy 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 210000003606 umbilical vein Anatomy 0.000 description 4
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 3
- 102000053642 Catalytic RNA Human genes 0.000 description 3
- 108090000994 Catalytic RNA Proteins 0.000 description 3
- 102000000018 Chemokine CCL2 Human genes 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 3
- 101000599048 Homo sapiens Interleukin-6 receptor subunit alpha Proteins 0.000 description 3
- 206010062016 Immunosuppression Diseases 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 102100022297 Integrin alpha-X Human genes 0.000 description 3
- 102100025390 Integrin beta-2 Human genes 0.000 description 3
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 3
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 3
- 201000001779 Leukocyte adhesion deficiency Diseases 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000004417 polycarbonate Substances 0.000 description 3
- 229920000515 polycarbonate Polymers 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 108091092562 ribozyme Proteins 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- 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 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 101710112752 Cytotoxin Proteins 0.000 description 2
- 102000016607 Diphtheria Toxin Human genes 0.000 description 2
- 108010053187 Diphtheria Toxin Proteins 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 206010015866 Extravasation Diseases 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 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 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 2
- 101000762949 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) Exotoxin A Proteins 0.000 description 2
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000000074 antisense oligonucleotide Substances 0.000 description 2
- 238000012230 antisense oligonucleotides Methods 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 208000037976 chronic inflammation Diseases 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000036251 extravasation Effects 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 230000005714 functional activity Effects 0.000 description 2
- 230000009368 gene silencing by RNA Effects 0.000 description 2
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 210000002074 inflammatory monocyte Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 238000010232 migration assay Methods 0.000 description 2
- 238000001823 molecular biology technique Methods 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 239000002751 oligonucleotide probe Substances 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 210000004976 peripheral blood cell Anatomy 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 108010066676 Abrin Proteins 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 102000010970 Connexin Human genes 0.000 description 1
- 108050001175 Connexin Proteins 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 108060002716 Exonuclease Proteins 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000622304 Homo sapiens Vascular cell adhesion protein 1 Proteins 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- -1 JM-216 Chemical compound 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001529936 Murinae Species 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
- 101710163270 Nuclease Proteins 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 235000009074 Phytolacca americana Nutrition 0.000 description 1
- 241001275115 Phytolacca bogotensis Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 108010084592 Saporins Proteins 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 102100023543 Vascular cell adhesion protein 1 Human genes 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
- 241000700605 Viruses Species 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Chemical class Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 101150087698 alpha gene Proteins 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940044684 anti-microtubule agent Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000012832 cell culture technique Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229960000284 efalizumab Drugs 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000008497 endothelial barrier function Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000006862 enzymatic digestion Effects 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 102000013165 exonuclease Human genes 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000003348 filter assay Methods 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 210000000497 foam cell Anatomy 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000003976 gap junction Anatomy 0.000 description 1
- 102000054767 gene variant Human genes 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 229940045109 genistein Drugs 0.000 description 1
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 1
- 235000006539 genistein Nutrition 0.000 description 1
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000003701 histiocyte Anatomy 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000004073 interleukin-2 production Effects 0.000 description 1
- 230000007154 intracellular accumulation Effects 0.000 description 1
- 230000003780 keratinization Effects 0.000 description 1
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 1
- 210000001821 langerhans cell Anatomy 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical group 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000012423 maintenance 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
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical class CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000000955 neuroendocrine Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000002135 phase contrast microscopy Methods 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical group 0.000 description 1
- 208000024335 physical disease Diseases 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000007114 proinflammatory cascade Effects 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 210000002437 synoviocyte Anatomy 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 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
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide 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](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 210000004026 tunica intima Anatomy 0.000 description 1
- 210000001692 type a synoviocyte Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 239000013598 vector Substances 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
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 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]
- C07K16/245—IL-1
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
-
- 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
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
【選択図】なし
Description
本出願は、2008年9月12日に出願された米国特許仮出願第61/096,563号の優先権を請求するものである。
該当しない。
本発明は、一般的に、免疫学、白血球生物学、炎症、癌、血管障害、及び医学の分野に関する。より詳しくは、本発明は、著しい病的状態又は全身性免疫抑制を引き起こさずに、治療選択を決定する方法、治療効能を評価する方法、及び疾患関連白血球を標的とする方法に関する。
従来の免疫学的技術及び分子生物学的技術が関与する方法が、本明細書に記述されている。免疫学的方法(例えば、抗原−Ab複合体を検出及び所在確認するためのアッセイ、免疫沈降、及び免疫ブロット等)は、当技術分野で一般的に知られており、Current Protocols in Immunology,Coligan et al.,ed.,John Wiley&Sons,New York等の方法論文書に記述されている。分子生物学的技術は、Molecular Cloning:A Laboratory Manual,2nd ed.,vol.1−3,Sambrook et al.,ed.,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,2001;及びCurrent Protocols in Molecular Biology,Ausubel et al.,ed.,Greene Publishing and Wiley−Interscience,New York等の文書で詳細に記述されている。Ab法は、Handbook of Therapeutic Antibodies,Dubel,S.,ed.,Wiley−VCH,2007に記述されている。血球分析法は、Flow Cytometry,David Keren,American Society for Clinical Pathology;4th edition,2007及びLichtman et al.,Williams Hematology,McGraw−Hill Professional;7th edition,2005に記述されている。
本発明の種々の方法は、IL−1アルファの機能又は発現を調節する作用剤を、ヒト対象体に投与するステップを特色とする。IL−1アルファの機能又は発現を調節する任意の好適な作用剤を使用することができる。例えば、作用剤は、IL−1アルファ受容体に対するIL−1アルファの結合を妨害する作用剤、又はIL−1アルファをコードする核酸の転写又は翻訳のレベルを調節する作用剤であってもよい。多数のそのような作用剤は、公知であるか、又は当業者であれば、本明細書の教示若しくは当技術分野の知識を使用して製作することができる。これらには、IL−1アルファ又はIL−1アルファ受容体と特異的に結合する抗体(そのためIL−1アルファに対する結合が遮断される)、対象体においてそのような抗体の濃度を増加させるワクチン、IL−1アルファ受容体等のIL−1アルファ結合タンパク質及びそれらの変異体(例えば、断片又はアミノ酸置換突然変異体)、IL−1アルファに結合する核酸(例えば、アプタマー)、IL−1アルファと特異的に結合する有機低分子、IL−1アルファ発現を低減又は調節する核酸、及び前述したものの2つ以上(例えば、2、3、4、又は5つ以上)の組合せが含まれる。
本発明の方法に有用な抗体には、対象体に投与した際に、対象体のCD14+CD16+単球の量又は機能を調節する(例えば、低減する)抗体が含まれる。CD14+CD16+単球はIL−1アルファも発現するため、IL−1アルファ又はIL−1アルファ受容体と特異的に結合するAbを、そのような単球の機能又は量を調節するために使用することができる。抗IL−1アルファ又は抗IL−1アルファ受容体Abは、ポリクローナルであってもよく又はモノクローナルであってもよい。望ましくない反応を防止するために、本発明の方法で使用されるAbは、好ましくはヒト化されているか、又はより好ましくはヒトである。
また、本方法では、IL−1アルファの機能又は発現を調節(例えば、阻害)する作用剤は、対象体のIL−1アルファと特異的に結合する抗体の濃度を増加させるワクチンであってもよい。好適なワクチンは、薬学的に許容される担体中に免疫原性形態のIL−1アルファを含むことができる。アルミニウム塩等のアジュバントが、同様に含まれていてもよい。免疫原性形態のIL−1アルファは、完全なタンパク質又はそのようなタンパク質のペプチド断片を含んでいてもよい。免疫応答を増強するために、免疫原性形態のIL−1アルファは、キーホールリンペットヘモシニアン又はシュードモナス菌体外毒素等の担体タンパク質と結合されていてもよい。ワクチン投与の結果として産生されるAbは、上述のように収集及び使用することができる。
直接標的化によりIL−1アルファの発現及び/又は機能を調節するタンパク質の例には、IL−1RI、IL−1RII、及びそのIL−1アルファ結合変異体(例えば、組換え形態、断片、模倣体、突然変異体、及びそれらの結合体)等のIL−I受容体(IL−1R)が含まれる。可溶性形態のIL−1Rは、投与が容易であるため好ましい。IL−1アルファの発現及び/又は機能を間接的に調節することができるタンパク質の例には、IL−1R等のリガンド結合を単球関連IL−1アルファと競合することができるタンパク質(例えば、活性化シグナルを伝達しないタンパク質)が含まれる。これらには、修飾された非活性化IL−1アルファ(前駆IL−1アルファ、膜結合型IL−1アルファ、及び組換えIL−1アルファを含む)、修飾された非活性化IL−1ベータ(前駆IL−1ベータ及び成熟IL−1ベータを含む)、IL−I受容体拮抗剤(IL−1Ra;可溶性IL−1Ra、icIL−1RaI、及びicIL−1RaIIを含む)、及びそれらの変異体が含まれていてもよい。
また、IL−1アルファの発現/活性を調節する作用剤は、核酸であってもよい。例えば、核酸は、IL−1アルファタンパク質をコードするセンス核酸であってもよい(例えば、細胞に導入することにより、細胞のIL−1アルファ活性を増加させることができる)。また、核酸は、IL−1アルファをコードするmRNAにハイブリダイズして、翻訳を阻害し、タンパク質の発現を減少させるアンチセンス核酸であってもよい。本発明で使用するためのアンチセンス核酸分子は、例えば転写及び/又は翻訳を阻害することによりIL−1アルファタンパク質の発現を阻害するように、IL−1アルファタンパク質をコードする細胞性mRNA及び/又はゲノムDNAと、細胞性条件下で特異的にハイブリダイズする(例えば、結合する)アンチセンス核酸分子である。結合は、従来の塩基対相補性によるものであってもよく、又は例えばDNA二本鎖に結合する場合は、二重らせんの主溝における特異的相互作用によるものであってもよい。
一連の選択(例えば、SELEXによる;指数関数的な濃縮によるリガンドの系統的進化)を繰り返すことによりIL−1アルファに結合するように遺伝子操作されたアプタマー又は核酸種を、IL−1アルファの機能を調節するために、本発明で使用することもできる。特定のマーカーに対するアプタマーを製作及び使用する方法は、例えば、米国特許第5,670,637号;第6,331,398号;及び第5,270,163号;第5,567,588号に記述されている。
低分子(一般的には有機)も、IL−1アルファの発現又は機能を調節することができる。コルチコステロイド、シクロオキシゲナーゼ阻害剤、リノミド(ロキニメックス)、サリドマイド、ペントキシフィリン、及びゲニステイン等の、抗炎症作用を有する公知の低分子を使用することができる。低分子のライブラリーをスクリーニングして、単球中でIL−1アルファの発現を調節する(上方制御又は下方制御する)分子を特定することにより、他の分子を特定することができる。
本発明の1つの方法は、IL−1アルファの発現及び/又は機能を調節する作用剤の投与が、対象体のCD14+CD16+単球の量を調節するかどうかを決定するステップが、投与前後の対象体のCD14+CD16+単球の量(例えば、数、全血球百分率数での白血球のパーセント、濃度、CD14++単球等の他の血球に対する比率)を決定することを含むことができることを特色とする。投与前後の対象体のCD14+CD16+単球の量を決定することは、任意の好適な方法により実施することができる。例えば、末梢血単核細胞(PBMC)をヒト対象体から単離し、その後CD14及びCD16に特異的な抗体を使用して、フローサイトメトリーにかけることができる。末梢血細胞を遠心分離して細胞を濃縮し、免疫組織化学的技術を使用してCD14+CD16+集団を特定及び定量化することもできる。
本発明の1つの方法は、IL−1アルファを標的とする作用剤の投与が対象体のCD14+CD16+単球の機能を調節するかどうかを決定するステップが、投与前後の対象体のCD14+CD16+単球の機能を評価することを含むことができることを特色とする。投与前後の対象体のCD14+CD16+単球の機能を決定することは、任意の好適な方法により実施することができる。例えば、CD14+CD16+単球は、ヒト対象体から収集された末梢血単核細胞から単離することができる。その後、単離された単球を、人工膜基材に接着したヒト臍帯静脈内皮細胞を使用するin vitro結合及び経内皮遊走アッセイにかけることができる。例えば、Etingin et al.(1991)Proc.Nat’l.Acad.Sci.USA,88:7200−7203を参照されたい。
本発明の方法は、任意の好適なヒト対象体に対して実施することができる。しかしながら、好ましくは、対象体は、CD14+CD16+単球のレベル異常又は機能異常に関連する状態を罹患している対象体だろう。そのような対象体の例には、炎症状態、自己免疫状態、癌(例えば、乳癌、結腸直腸癌、前立腺癌、卵巣癌、白血病、肺癌、子宮内膜癌、又は肝臓癌)、アテローム性動脈硬化、関節炎(例えば、骨関節炎又は関節リウマチ)、炎症性腸疾患(例えば、潰瘍性大腸炎又はクローン病)、末梢血管疾患、脳血管発作(脳卒中)、慢性炎症が存在する病態、単球/マクロファージ浸潤を示す病変を特徴とする病態、アミロイド斑が脳に存在する病態(例えば、アルツハイマー病)、骨粗しょう症、筋萎縮性側索硬化症、又は多発性硬化症等の、CD14+CD16+単球の機能異常又はレベル異常に関連する病態を示す対象体が含まれる。
方法:健常ドナーから全血を無菌条件下で収集した。2.5mlの全血を、溶解緩衝液(150mM酢酸アンモニウム 0.1mM EDTA)で10倍に希釈した。細胞を、氷上で10分間緩衝液中で維持し、その後1000Gで5分間遠心沈降した。細胞を、氷冷FACS緩衝液(1%粉乳で補完されたPBS、0.2μmフィルターでろ過されている)に再懸濁した。細胞を、FACS緩衝液で2回洗浄した。ペレット化した細胞を、2.8mlのFACS緩衝液に再懸濁し、血球計を使用して計数し、以下のスキームに従って蛍光性標識抗体を薄明りの下で添加した:
1)PerCP−Cy5.5結合抗CD14(eBioscience(商標)親和性精製、マウス抗ヒトIgG、カッパ、45−109番)
2)PE結合抗CD16(eBioscience(商標)親和性精製、マウス抗ヒトIgG1、12−0168番)
3)FITC結合抗IL−1a(eBioscience(商標)親和性精製、マウスIgG1、抗ヒトIL−1a、11−718番)
4)FITC結合抗KLH(eBioscience(商標)親和性精製、マウスIgG1、カッパ、11−4714番)
5)抗CD14、抗CD16
6)抗CD14、抗CD16、抗IL−1a
7)抗CD14、抗CD16、抗IL−1a、抗KLH
MABp1は、内皮細胞の表面における細胞接着分子の発現誘導を阻害することができる。2つの重要な接着分子CD54(ICAM−1)及びCD62E(E−セレクチン)のMABP1媒介性阻害を、ヒト臍帯静脈内皮細胞(HUVEC)をモデル系として使用して観察した。MABp1効果は、HUVECが、可溶性組換えヒトIL1アルファによってではなく、遺伝子操作されたDG44 CHO細胞(GPI−IL1A細胞)の表面にグリコシル−ホスファチジルイノシトール(GPI)により係留された膜性IL1アルファによって刺激される場合に、最も著しい。代表的な実験では、6ウエルプレート中のHUVEC細胞のコンフルエント培養を、M−200培地中で5×106個のGPI−IL1A DG44細胞と共に、単独で、10μg/mL MABP1の存在下で、又は10μg/mL D5ヒトIgG1アイソタイプ対照抗体の存在下で、終夜共培養した。17〜20時間後、HUVEC単層を、ダルベッコPBSでよく洗浄し、その後CellStripper試薬(Cellgro Mediatech社製)を用いた20分間の非酵素処理により取り上げた。標準的フローサイトメトリープロトコールを使用して、CD62E(E−セレクチン)発現について、細胞を直ちに分析した。染色緩衝液は、2%加熱不活性化ウシ胎仔血清で補完されたダルベッコPBSを含んでいた。PE結合マウス抗ヒトCD62Eモノクローナル抗体(eBioscience社製、クローンP2H3)又はPE結合マウスIgG1kアイソタイプ対照(eBioscience社製、クローンP3)を、製造業者の説明書に従って使用して、室温、暗所で20分間100マイクロリットルの染色容積中でHUVEC細胞を染色した。その後、染色緩衝液で2回の洗浄を実施し、次にFACSCaliburフローサイトメーター(BD Biosciences社製)で試料を取得した。n=3の実験で、膜性GPI−IL1Aにより誘導されたHUVEC細胞表面上にあるE−セレクチンの上方制御は、MABP1により、未刺激HUVEC細胞が示すような基線レベルに中和された。
本発明は、その詳細な説明と共に記述されているが、前述の説明は例示を目的としており、添付の特許請求の範囲により定義される本発明の範囲を限定しないことが理解されるべきである。他の態様、利点、及び改変は、添付の請求項の範囲内にある。
Claims (16)
- (a)IL−1アルファの機能又は発現を調節する作用剤を、ヒト対象体に投与するステップと、
(b)そのような作用剤の投与が、前記対象体のCD14+CD16+単球の量又は機能を調節するかどうかを決定するステップとを含む方法。 - 前記IL−1アルファの機能又は発現を調節する作用剤が、IL−1アルファ受容体に対するIL−1アルファの結合を妨害する作用剤である、請求項1に記載の方法。
- 前記作用剤が、IL−1アルファと特異的に結合する抗体である、請求項1に記載の方法。
- 前記抗体が、IL−1アルファと特異的に結合するモノクローナル抗体である、請求項3に記載の方法。
- 前記モノクローナル抗体がヒト抗体である、請求項4に記載の方法。
- 前記ヒト抗体がIgG1である、請求項5に記載の方法。
- 前記ヒト抗体が、配列番号3のアミノ酸配列を含む重鎖と、配列番号4のアミノ酸配列を含む軽鎖とを有する、請求項6に記載の方法。
- 前記ヒト対象体が、CD14+CD16+単球の機能異常又はレベル異常に関連する病態を示す、請求項1に記載の方法。
- 前記病態が炎症状態である、請求項8に記載の方法。
- 前記病態が自己免疫状態である、請求項8に記載の方法。
- 前記作用剤の投与前には、前記ヒト対象体の末梢血白血球の少なくとも1.5%がCD14+CD16+単球であり、前記作用剤の投与後には、前記ヒト対象体の末梢血白血球細胞の1.5%未満がCD14+CD16+単球である、請求項1に記載の方法。
- 前記作用剤の投与が、その結果として、全血球百分率数で少なくとも10%のCD14+CD16+単球パーセントの低減をもたらす、請求項1に記載の方法。
- そのような投与が前記対象体のCD14+CD16+単球の量又は機能を調節するかどうかを決定するステップが、前記作用剤の投与前後の前記対象体のCD14+CD16+単球の機能を評価することを含む、請求項1に記載の方法。
- 前記作用剤の投与が、その結果として、少なくとも10%のCD14+CD16+単球機能の低減をもたらす、請求項13に記載の方法。
- (a)疾患又は病理学的障害を有するヒト対象体が、前記疾患又は病理学的障害に寄与するCD14+/CD16+単球を有することを決定するステップと、
(b)IL−1アルファの機能又は発現を調節する作用剤を、前記ヒト対象体に投与するステップと、
(c)そのような作用剤の投与が、前記対象体のCD14+CD16+単球の量を調節するかどうかを決定するステップとを含む方法。 - 対象体のCD14+CD16+単球の量又は機能を調節する薬剤を調製するための、IL−1アルファと特異的に結合する抗体の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9656308P | 2008-09-12 | 2008-09-12 | |
US61/096,563 | 2008-09-12 | ||
PCT/US2009/056809 WO2010030979A2 (en) | 2008-09-12 | 2009-09-14 | Targeting pathogenic monocytes |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2012502113A true JP2012502113A (ja) | 2012-01-26 |
JP2012502113A5 JP2012502113A5 (ja) | 2012-10-11 |
JP5976319B2 JP5976319B2 (ja) | 2016-08-23 |
Family
ID=42005801
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2011527020A Active JP5976319B2 (ja) | 2008-09-12 | 2009-09-14 | 病原性単球の標的化 |
Country Status (7)
Country | Link |
---|---|
US (2) | US8242074B2 (ja) |
EP (1) | EP2326347A4 (ja) |
JP (1) | JP5976319B2 (ja) |
CN (1) | CN102209557A (ja) |
AU (1) | AU2009291536B2 (ja) |
CA (1) | CA2737056C (ja) |
WO (1) | WO2010030979A2 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018197250A (ja) * | 2012-08-31 | 2018-12-13 | ファイブ プライム セラピューティックス インコーポレイテッド | コロニー刺激因子1受容体(csf1r)を結合する抗体によって状態を治療する方法 |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2006274698B2 (en) | 2005-08-02 | 2011-06-09 | Xbiotech, Inc. | Diagnosis, treatment, and prevention of vascular disorders using IL-1a autoantibodies |
WO2007132338A2 (en) * | 2006-05-15 | 2007-11-22 | Xbiotech Inc. | IL-1α IMMUNIZATION INDUCES AUTOANTIBODIES PROTECTIVE AGAINST ATHEROSCLEROSIS |
US20110008282A1 (en) * | 2006-05-15 | 2011-01-13 | Xbiotech, Inc. | IL-1alpha immunization induces autoantibodies protective against atherosclerosis |
SI2109623T1 (sl) * | 2006-05-22 | 2012-05-31 | Xbiotech Inc | Zdravljenje raka z anti il protitelesi |
PL3085773T3 (pl) * | 2008-05-30 | 2021-01-11 | Xbiotech, Inc | Zastosowanie przeciwciał il-1 alfa |
US20130231257A1 (en) | 2010-05-12 | 2013-09-05 | The University Of Birmingham | Biomarker |
TWI615405B (zh) | 2010-05-14 | 2018-02-21 | 艾伯維有限公司 | Il-1結合蛋白 |
KR102167261B1 (ko) * | 2010-06-18 | 2020-10-20 | 엑스바이오테크, 인크. | 관절염 치료 |
AU2015203524B2 (en) * | 2010-06-18 | 2016-10-20 | Xbiotech Inc. | Arthritis treatment |
AU2011293554B9 (en) | 2010-08-23 | 2015-03-19 | Xbiotech Inc. | Treatment for neoplastic diseases |
AU2015271978B2 (en) * | 2010-08-23 | 2017-10-26 | Xbiotech Inc. | Treatment for neoplastic diseases |
PT2694107T (pt) * | 2011-04-01 | 2018-11-27 | Xbiotech Inc | Tratamento para patologias dermatológicas |
US9724409B2 (en) | 2011-04-01 | 2017-08-08 | Xbiotech, Inc. | Treatment of inflammatory skin disease |
US10813630B2 (en) | 2011-08-09 | 2020-10-27 | Corquest Medical, Inc. | Closure system for atrial wall |
US10307167B2 (en) | 2012-12-14 | 2019-06-04 | Corquest Medical, Inc. | Assembly and method for left atrial appendage occlusion |
US10314594B2 (en) | 2012-12-14 | 2019-06-11 | Corquest Medical, Inc. | Assembly and method for left atrial appendage occlusion |
MX356808B (es) | 2011-09-23 | 2018-06-14 | Xbiotech Inc | Uso de una composición farmacéutica que comprende un anticuerpo anti-il-1a para el tratamiento de la caquexia. |
EP2638896A1 (en) | 2012-03-14 | 2013-09-18 | Bioneer A/S | Cationic liposomal drug delivery system for specific targeting of human cd14+ monocytes in whole blood |
US9545441B2 (en) | 2012-09-18 | 2017-01-17 | Xbiotech, Inc. | Treatment of diabetes |
US20140142689A1 (en) | 2012-11-21 | 2014-05-22 | Didier De Canniere | Device and method of treating heart valve malfunction |
US9566443B2 (en) | 2013-11-26 | 2017-02-14 | Corquest Medical, Inc. | System for treating heart valve malfunction including mitral regurgitation |
US10842626B2 (en) | 2014-12-09 | 2020-11-24 | Didier De Canniere | Intracardiac device to correct mitral regurgitation |
WO2018150265A1 (en) | 2017-02-16 | 2018-08-23 | Xbiotech, Inc. | Treatment of hidradenitis suppurativa |
US10975146B2 (en) | 2018-06-29 | 2021-04-13 | Cedars-Sinai Medical Center | Interleukin-1 inhibition for combination treatment of pancreatic cancer |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6040858A (ja) * | 1983-08-15 | 1985-03-04 | Nissan Motor Co Ltd | 自動変速機の油圧制御装置 |
JPH03505279A (ja) * | 1988-05-27 | 1991-11-21 | シナージェン,インコーポレーテッド | インターロイキン―1インヒビター |
WO2003015128A2 (en) * | 2001-08-07 | 2003-02-20 | Corporation For National Research Initiatives | An electromechanical switch and method of fabrication |
JP2004502428A (ja) * | 2000-06-29 | 2004-01-29 | アボット・ラボラトリーズ | 二重特異性抗体ならびに作製方法および使用方法 |
WO2007132338A2 (en) * | 2006-05-15 | 2007-11-22 | Xbiotech Inc. | IL-1α IMMUNIZATION INDUCES AUTOANTIBODIES PROTECTIVE AGAINST ATHEROSCLEROSIS |
JP2011524740A (ja) * | 2008-05-30 | 2011-09-08 | エックスバイオテク,インコーポレイテッド | インターロイキン1α抗体及び有用な方法 |
Family Cites Families (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH652145A5 (de) | 1982-01-22 | 1985-10-31 | Sandoz Ag | Verfahren zur in vitro-herstellung von hybridomen welche humane monoklonale antikoerper erzeugen. |
US5672347A (en) | 1984-07-05 | 1997-09-30 | Genentech, Inc. | Tumor necrosis factor antagonists and their use |
US5168062A (en) | 1985-01-30 | 1992-12-01 | University Of Iowa Research Foundation | Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence |
US4965198A (en) | 1985-12-24 | 1990-10-23 | Konica Corporation | Monoclonal antibody and method of manufacturing hybridoma producing the same |
DE3631229A1 (de) | 1986-09-13 | 1988-03-24 | Basf Ag | Monoklonale antikoerper gegen humanen tumornekrosefaktor (tnf) und deren verwendung |
DK590387A (da) | 1986-11-13 | 1988-05-14 | Otsuka Pharma Co Ltd | Antistoffer mod interleukin-1 |
US5034316A (en) | 1987-03-30 | 1991-07-23 | The Regents Of The University Of California | In vitro human monoclonal IgG rheumatoid factor autoantibody |
FR2640146B1 (fr) | 1988-12-08 | 1993-12-24 | Commissariat A Energie Atomique | Anticorps monoclonaux anti-interleukines 1(alpha) et 1(beta), leur procede de production et applications desdits anticorps a la detection des interleukines 1(alpha) et 1(beta) et en therapeutique |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
GB9122820D0 (en) | 1991-10-28 | 1991-12-11 | Wellcome Found | Stabilised antibodies |
AU5355094A (en) | 1992-10-14 | 1994-05-09 | Sterling Winthrop Inc. | Therapeutic and diagnostic imaging compositions and methods |
DE69427928T3 (de) | 1993-03-05 | 2012-05-10 | Bayer Healthcare Llc | Humane monoklonale anti-TNF alpha Antikörper |
US5959085A (en) | 1993-11-23 | 1999-09-28 | Schering Corporation | Human monoclonal antibodies against human cytokines and methods of making and using such antibodies |
EP0659766A1 (en) * | 1993-11-23 | 1995-06-28 | Schering-Plough | Human monoclonal antibodies against human cytokines and methods of making and using such antibodies |
GB9509620D0 (en) | 1995-05-12 | 1995-07-05 | Nat Blood Authority | Transepithelial transport of molecular species |
US6140470A (en) | 1995-06-30 | 2000-10-31 | Yale University | Human monoclonal anti-tumor antibodies |
US6090382A (en) | 1996-02-09 | 2000-07-18 | Basf Aktiengesellschaft | Human antibodies that bind human TNFα |
SE9802402D0 (sv) | 1998-07-03 | 1998-07-03 | Karolinska Innovations Ab | Method of diagnosing cardiovascular disease and early atherosclerosis |
US20030040617A9 (en) | 1999-03-12 | 2003-02-27 | Rosen Craig A. | Nucleic acids, proteins and antibodies |
US20030232054A1 (en) | 2000-01-25 | 2003-12-18 | Tang Y. Tom | Novel nucleic acids and polypeptides |
US20020131954A1 (en) | 2000-05-02 | 2002-09-19 | Tobinick Edward L. | Interleukin antagonists for the treatment of neurological, retinal and muscular disorders |
US20030026806A1 (en) | 2000-10-27 | 2003-02-06 | Amgen Inc. | Antibodies and other selective IL-1 binding agents that allow binding to IL-1 receptor but not activation thereof |
US7030126B2 (en) * | 2001-11-16 | 2006-04-18 | Als Therapy Development Foundation, Inc. | Use of polyamine analogs for amyotrophic lateral sclerosis |
CA2497884C (en) * | 2002-09-06 | 2013-10-22 | Brian Varnum | Therapeutic human anti-il-1r1 monoclonal antibody |
US20040224893A1 (en) | 2003-05-06 | 2004-11-11 | Li-Hsien Wang | Methods of using IL-1 antagonists to treat neointimal hyperplasia |
HN2004000285A (es) | 2003-08-04 | 2006-04-27 | Pfizer Prod Inc | ANTICUERPOS DIRIGIDOS A c-MET |
US7799327B2 (en) | 2003-12-24 | 2010-09-21 | Henry John Smith | Autoantibodies utilized as carrier agents for pharmaceutical compounds used in cancer treatment |
US7105183B2 (en) * | 2004-02-03 | 2006-09-12 | The Regents Of The University Of California | Chlorite in the treatment of neurodegenerative disease |
US20050276807A1 (en) | 2004-06-15 | 2005-12-15 | Advanced Biotherapy, Inc. | Treatment of acne |
US7718674B2 (en) | 2004-09-27 | 2010-05-18 | Bridge Pharma, Inc. | Methods of relieving neuropathic pain with the S-isomer of 2-{2[N-(2-indanyl)-N-phenylamino]ethyl}piperidine |
PT1819359E (pt) | 2004-12-09 | 2015-05-28 | Janssen Biotech Inc | Imunoconjugados anti-integrina, métodos para a sua produção e sua utilização |
AU2006274698B2 (en) | 2005-08-02 | 2011-06-09 | Xbiotech, Inc. | Diagnosis, treatment, and prevention of vascular disorders using IL-1a autoantibodies |
US7612181B2 (en) | 2005-08-19 | 2009-11-03 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
AU2006298767B2 (en) | 2005-09-28 | 2013-01-10 | Cytos Biotechnology Ag | Interleukin-1 conjugates and uses thereof |
SI2109623T1 (sl) | 2006-05-22 | 2012-05-31 | Xbiotech Inc | Zdravljenje raka z anti il protitelesi |
EP2446904B1 (en) | 2006-05-30 | 2015-04-29 | Genentech, Inc. | Anti-CD22 antibodies, their immunoconjugates and uses thereof |
US8324350B2 (en) | 2006-12-29 | 2012-12-04 | Abbott Laboratories | Dual-specific IL-1α/IL-1β antibodies |
WO2009128934A1 (en) | 2008-04-15 | 2009-10-22 | Sarcode Corporation | Topical lfa-1 antagonists for use in localized treatment of immune related disorders |
SG172855A1 (en) | 2009-01-29 | 2011-08-29 | Abbott Lab | Il-1 binding proteins |
-
2009
- 2009-09-14 JP JP2011527020A patent/JP5976319B2/ja active Active
- 2009-09-14 CA CA2737056A patent/CA2737056C/en active Active
- 2009-09-14 WO PCT/US2009/056809 patent/WO2010030979A2/en active Application Filing
- 2009-09-14 EP EP09813742A patent/EP2326347A4/en active Pending
- 2009-09-14 AU AU2009291536A patent/AU2009291536B2/en active Active
- 2009-09-14 US US12/559,019 patent/US8242074B2/en active Active
- 2009-09-14 CN CN2009801446182A patent/CN102209557A/zh active Pending
-
2012
- 2012-07-10 US US13/545,166 patent/US8546331B2/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6040858A (ja) * | 1983-08-15 | 1985-03-04 | Nissan Motor Co Ltd | 自動変速機の油圧制御装置 |
JPH03505279A (ja) * | 1988-05-27 | 1991-11-21 | シナージェン,インコーポレーテッド | インターロイキン―1インヒビター |
JP2004502428A (ja) * | 2000-06-29 | 2004-01-29 | アボット・ラボラトリーズ | 二重特異性抗体ならびに作製方法および使用方法 |
WO2003015128A2 (en) * | 2001-08-07 | 2003-02-20 | Corporation For National Research Initiatives | An electromechanical switch and method of fabrication |
WO2007132338A2 (en) * | 2006-05-15 | 2007-11-22 | Xbiotech Inc. | IL-1α IMMUNIZATION INDUCES AUTOANTIBODIES PROTECTIVE AGAINST ATHEROSCLEROSIS |
JP2011524740A (ja) * | 2008-05-30 | 2011-09-08 | エックスバイオテク,インコーポレイテッド | インターロイキン1α抗体及び有用な方法 |
Non-Patent Citations (4)
Title |
---|
JPN6013056801; JOOSTEN,L.A.B. et al.: Agents and Actions Vol.41, No.2 supplement, 1994, p.C174-6 * |
JPN6013056803; DINARELLO,C. et al.: The New England Journal of Medicine Vol.328, No.2, 1993, p.106-13 * |
JPN6013056812; HEYDERMAN,R.S. et al.: Inflammation Research Vol.44, 1995, p.275-80 * |
JPN6013056814; GARRONE,P. et al.: Molecular Immunology Vol.33, 1996, p.649-58 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018197250A (ja) * | 2012-08-31 | 2018-12-13 | ファイブ プライム セラピューティックス インコーポレイテッド | コロニー刺激因子1受容体(csf1r)を結合する抗体によって状態を治療する方法 |
US10822421B2 (en) | 2012-08-31 | 2020-11-03 | Five Prime Therapeutics, Inc. | Methods of treating conditions with antibodies that bind colony stimulating factor 1 receptor (CSF1R) |
JP7106386B2 (ja) | 2012-08-31 | 2022-07-26 | ファイブ プライム セラピューティックス インコーポレイテッド | コロニー刺激因子1受容体(csf1r)を結合する抗体によって状態を治療する方法 |
Also Published As
Publication number | Publication date |
---|---|
JP5976319B2 (ja) | 2016-08-23 |
AU2009291536B2 (en) | 2012-08-16 |
CN102209557A (zh) | 2011-10-05 |
WO2010030979A3 (en) | 2011-04-14 |
EP2326347A2 (en) | 2011-06-01 |
US20100068212A1 (en) | 2010-03-18 |
US20120276110A1 (en) | 2012-11-01 |
WO2010030979A2 (en) | 2010-03-18 |
EP2326347A4 (en) | 2013-03-06 |
CA2737056A1 (en) | 2010-03-18 |
US8242074B2 (en) | 2012-08-14 |
AU2009291536A1 (en) | 2010-03-18 |
CA2737056C (en) | 2018-10-30 |
US8546331B2 (en) | 2013-10-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5976319B2 (ja) | 病原性単球の標的化 | |
RU2369636C2 (ru) | Лиганд gitr и связанные с лигандом gitr молекулы и антитела и варианты их применения | |
JP5419067B2 (ja) | 増殖性障害を処置するための組成物および方法 | |
RU2613422C2 (ru) | Антитело к blys | |
KR20070107703A (ko) | 인터루킨-17f 항체 및 기타 il-17f 신호전달안타고니스트 및 그의 용도 | |
ES2399503T3 (es) | Uso de reactivos relacionados con citocinas de mamíferos | |
US10611839B2 (en) | Anti CD84 antibodies, compositions comprising same and uses thereof | |
US20110171290A1 (en) | Inhibition of angiogenesis and tumor metastasis | |
Zhu et al. | Cardiac ectopic lymphoid follicle formation in viral myocarditis involving the regulation of podoplanin in Th17 cell differentiation | |
ZA200509143B (en) | GITR ligand and GITR ligand-related molecules and antibodies and uses thereof | |
EP3777889A1 (en) | Use of probdnf regulator in b cell-related diseases | |
WO2006013923A1 (ja) | 自己免疫疾患を伴う関節炎の治療剤 | |
US8246959B1 (en) | Dendritic cell-associated lectin-like molecules, compositions and methods of use | |
Becker | T cell homing in inflammatory bowel diseases and single cell exposure-efficacy characteristics of the anti-α4β7 antibody vedolizumab | |
JP2023549473A (ja) | 活性化された免疫細胞の細胞表面抗原およびその多様な用途 | |
EP4172213A1 (en) | Methods and compositions for the reduction of chimeric antigen receptor tonic signaling | |
Lécuyer | ALCAM: cell adhesion molecule or tight junction? The characterization of its role in the context of neuroinflammation | |
Wojkowska et al. | Th17 Cells Interactions with the Brain Endothelium in Vitro | |
Jamin et al. | A8. 27 Control of the humoral response by regulatory B cells | |
Forde | Cytokine Expression and Regulation of Experimental Autoimmune Encephalomyelitis; a Murine Model of Multiple Sclerosis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120822 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20120822 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20131119 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20140219 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20140319 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140324 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20140415 Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20140314 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140421 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20140930 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150130 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20150130 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150326 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20150403 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20150326 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20150529 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20160506 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160523 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20160720 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5976319 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |