JP6845802B2 - トランスフォーミング増殖因子β1に高親和性、アビディティおよび特異性で結合するscFv−Fc二量体 - Google Patents
トランスフォーミング増殖因子β1に高親和性、アビディティおよび特異性で結合するscFv−Fc二量体 Download PDFInfo
- Publication number
- JP6845802B2 JP6845802B2 JP2017546178A JP2017546178A JP6845802B2 JP 6845802 B2 JP6845802 B2 JP 6845802B2 JP 2017546178 A JP2017546178 A JP 2017546178A JP 2017546178 A JP2017546178 A JP 2017546178A JP 6845802 B2 JP6845802 B2 JP 6845802B2
- Authority
- JP
- Japan
- Prior art keywords
- seq
- scfv
- binding protein
- amino acid
- human
- 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.)
- Active
Links
- 239000000539 dimer Substances 0.000 title claims description 111
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 title description 4
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 title description 4
- 229940099456 transforming growth factor beta 1 Drugs 0.000 title description 2
- 210000004027 cell Anatomy 0.000 claims description 67
- 150000001413 amino acids Chemical group 0.000 claims description 57
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 42
- 108091008324 binding proteins Proteins 0.000 claims description 36
- 201000010099 disease Diseases 0.000 claims description 34
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 29
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 23
- 229920001184 polypeptide Polymers 0.000 claims description 22
- 238000006467 substitution reaction Methods 0.000 claims description 22
- 239000013598 vector Substances 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 101500025614 Homo sapiens Transforming growth factor beta-1 Proteins 0.000 claims description 13
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 108090000623 proteins and genes Proteins 0.000 claims description 11
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 230000001404 mediated effect Effects 0.000 claims description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 238000004166 bioassay Methods 0.000 claims description 8
- 102000004169 proteins and genes Human genes 0.000 claims description 8
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 7
- 208000017169 kidney disease Diseases 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 108091033319 polynucleotide Proteins 0.000 claims description 7
- 102000040430 polynucleotide Human genes 0.000 claims description 7
- 239000002157 polynucleotide Substances 0.000 claims description 7
- 201000003066 Diffuse Scleroderma Diseases 0.000 claims description 6
- 101500025624 Homo sapiens Transforming growth factor beta-2 Proteins 0.000 claims description 6
- 101500026551 Homo sapiens Transforming growth factor beta-3 Proteins 0.000 claims description 6
- 210000004962 mammalian cell Anatomy 0.000 claims description 6
- 210000003734 kidney Anatomy 0.000 claims description 4
- 241000699802 Cricetulus griseus Species 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 3
- 208000024883 bone remodeling disease Diseases 0.000 claims description 3
- 238000012258 culturing Methods 0.000 claims description 3
- 210000001672 ovary Anatomy 0.000 claims description 3
- 102000014914 Carrier Proteins Human genes 0.000 claims 19
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims 1
- 230000001605 fetal effect Effects 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 235000001014 amino acid Nutrition 0.000 description 50
- 230000027455 binding Effects 0.000 description 42
- 125000003275 alpha amino acid group Chemical group 0.000 description 26
- 230000004048 modification Effects 0.000 description 26
- 238000012986 modification Methods 0.000 description 26
- 108020004707 nucleic acids Proteins 0.000 description 24
- 102000039446 nucleic acids Human genes 0.000 description 24
- 150000007523 nucleic acids Chemical class 0.000 description 24
- 238000011282 treatment Methods 0.000 description 18
- 239000000427 antigen Substances 0.000 description 17
- 108091007433 antigens Proteins 0.000 description 17
- 102000036639 antigens Human genes 0.000 description 17
- 102000023732 binding proteins Human genes 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 16
- 210000004602 germ cell Anatomy 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 12
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 12
- 230000006870 function Effects 0.000 description 9
- 239000000178 monomer Substances 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 238000010494 dissociation reaction Methods 0.000 description 7
- 230000005593 dissociations Effects 0.000 description 7
- 239000013604 expression vector Substances 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 231100000241 scar Toxicity 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 6
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 6
- 108010029485 Protein Isoforms Proteins 0.000 description 6
- 102000001708 Protein Isoforms Human genes 0.000 description 6
- 230000002776 aggregation Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 208000032544 Cicatrix Diseases 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 210000002889 endothelial cell Anatomy 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 210000001236 prokaryotic cell Anatomy 0.000 description 5
- 230000037387 scars Effects 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 108091026890 Coding region Proteins 0.000 description 4
- 206010016654 Fibrosis Diseases 0.000 description 4
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 4
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 4
- 108060003951 Immunoglobulin Proteins 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- 102100024952 Protein CBFA2T1 Human genes 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 210000003527 eukaryotic cell Anatomy 0.000 description 4
- 230000004761 fibrosis Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 108010044804 gamma-glutamyl-seryl-glycine Proteins 0.000 description 4
- 102000018358 immunoglobulin Human genes 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 229950005555 metelimumab Drugs 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 230000003472 neutralizing effect Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 208000005069 pulmonary fibrosis Diseases 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- JARGNLJYKBUKSJ-KGZKBUQUSA-N (2r)-2-amino-5-[[(2r)-1-(carboxymethylamino)-3-hydroxy-1-oxopropan-2-yl]amino]-5-oxopentanoic acid;hydrobromide Chemical compound Br.OC(=O)[C@H](N)CCC(=O)N[C@H](CO)C(=O)NCC(O)=O JARGNLJYKBUKSJ-KGZKBUQUSA-N 0.000 description 3
- 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 3
- 241000196324 Embryophyta Species 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 3
- 206010062016 Immunosuppression Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000007107 Stomach Ulcer Diseases 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 210000002744 extracellular matrix Anatomy 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 201000005917 gastric ulcer Diseases 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- 108090001008 Avidin Proteins 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 102100029193 Low affinity immunoglobulin gamma Fc region receptor III-A Human genes 0.000 description 2
- 101710099301 Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 2
- 230000004988 N-glycosylation Effects 0.000 description 2
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 206010057249 Phagocytosis Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108020005067 RNA Splice Sites Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 108091005735 TGF-beta receptors Proteins 0.000 description 2
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 206010000891 acute myocardial infarction Diseases 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- -1 antibiotic Substances 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000012875 competitive assay Methods 0.000 description 2
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 201000005206 focal segmental glomerulosclerosis Diseases 0.000 description 2
- 231100000854 focal segmental glomerulosclerosis Toxicity 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000019736 interleukin-11 production Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 230000006715 negative regulation of smooth muscle cell proliferation Effects 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 208000008494 pericarditis Diseases 0.000 description 2
- 230000008782 phagocytosis Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 2
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 208000002267 Anti-neutrophil cytoplasmic antibody-associated vasculitis Diseases 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000001187 Collagen Type III Human genes 0.000 description 1
- 108010069502 Collagen Type III Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 208000028006 Corneal injury Diseases 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 208000026292 Cystic Kidney disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 206010011985 Decubitus ulcer Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- 208000024134 Diffuse cutaneous systemic sclerosis Diseases 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- 108010021468 Fc gamma receptor IIA Proteins 0.000 description 1
- 108010021472 Fc gamma receptor IIB Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000007522 Fused Kidney Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 108700007698 Genetic Terminator Regions Proteins 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000003815 Interleukin-11 Human genes 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 208000035901 Ischaemic ulcer Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 125000000998 L-alanino group Chemical group [H]N([*])[C@](C([H])([H])[H])([H])C(=O)O[H] 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
- 241000713666 Lentivirus Species 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100025297 Mannose-P-dolichol utilization defect 1 protein Human genes 0.000 description 1
- 101710089919 Mannose-P-dolichol utilization defect 1 protein Proteins 0.000 description 1
- 208000001826 Marfan syndrome Diseases 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- 208000001738 Nervous System Trauma Diseases 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 206010030201 Oesophageal ulcer Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 208000004362 Penile Induration Diseases 0.000 description 1
- 208000020758 Peyronie disease Diseases 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 206010060932 Postoperative adhesion Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000032056 Radiation Fibrosis Syndrome Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010068033 Renal fusion anomaly Diseases 0.000 description 1
- 206010038470 Renal infarct Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical class O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 102100033663 Transforming growth factor beta receptor type 3 Human genes 0.000 description 1
- 101710132313 Transforming growth factor beta receptor type 3 Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 206010048302 Tubulointerstitial nephritis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000000558 Varicose Ulcer Diseases 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
- SXEHKFHPFVVDIR-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=C(NN)C=C1 SXEHKFHPFVVDIR-UHFFFAOYSA-N 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000003872 anastomosis Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000005888 antibody-dependent cellular phagocytosis Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 230000008984 colonic lesion Effects 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 108020001096 dihydrofolate reductase Proteins 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000005274 electronic transitions Effects 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000008556 epithelial cell proliferation Effects 0.000 description 1
- 208000028299 esophageal disease Diseases 0.000 description 1
- 208000019064 esophageal ulcer Diseases 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000004299 exfoliation Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 230000033581 fucosylation Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 230000000774 hypoallergenic effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 229940027941 immunoglobulin g Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 201000006334 interstitial nephritis Diseases 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000005291 magnetic effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000010172 mouse model Methods 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
- 206010028537 myelofibrosis Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000000651 myofibroblast Anatomy 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 201000009925 nephrosclerosis Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 208000028412 nervous system injury Diseases 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 201000002674 obstructive nephropathy Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 206010038534 renal tuberculosis Diseases 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 102220080600 rs797046116 Human genes 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000013605 shuttle vector Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 230000008477 smooth muscle tissue growth Effects 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
-
- 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
-
- 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
- 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
-
- 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
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/35—Valency
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/626—Diabody or triabody
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/72—Increased effector function due to an Fc-modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/20—Fusion polypeptide containing a tag with affinity for a non-protein ligand
- C07K2319/23—Fusion polypeptide containing a tag with affinity for a non-protein ligand containing a GST-tag
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/73—Fusion polypeptide containing domain for protein-protein interaction containing coiled-coiled motif (leucine zippers)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- Zoology (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Endocrinology (AREA)
- Pulmonology (AREA)
- Gastroenterology & Hepatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Peptides Or Proteins (AREA)
Description
本特許出願は、参照によって本明細書にその全体を組み入れる2015年3月4日に出願された米国仮特許出願第62/128,133号の利益を主張する。
(VD1)−(リンカー1)n−(VD2)−(リンカー2)m−(ヒンジ)p−(Fc領域)
を有し、
式中、VD1は、TGFβ1に結合することができる抗体から単離されたVLドメインおよびTGFβ1に結合することができる抗体から単離されたVHドメインからなる群から選択される第1の可変ドメインを含み、VD2は、TGFβ1に結合することができる抗体から単離されたVLドメインおよびTGFβ1に結合することができる抗体から単離されたVHドメインからなる群から選択される第2の可変ドメインを含み;nは0または1であり、mは0または1であり、pは0または1である、結合タンパク質を対象とする。
(VHドメイン)−(リンカー1)n−(VLドメイン)−(リンカー2)m−(ヒンジ)p−(Fc領域)
を有し、式中、pは0または1でありえ、nは0または1でありえ、mは0または1でありうるポリペプチド鎖を含みうる。
一実施形態では、本発明のscFv−Fc二量体の可変ドメインは、参照により本明細書に組み入れる米国特許第6,492,497号に開示のCDR(例えば、米国特許第6,492,497号の配列番号11〜19)に由来する相補性決定領域(CDR)を含む。CDR領域を下記に列挙する。
HCDR1 SYMGH 配列番号22
HCDR2 VISYDGSIKYYADSVKG 配列番号23
HCDR3 TGEYSGYDTSGVEL 配列番号24
TGEYSGYDTDPQYS 配列番号25
TGFYSGYDTPASPD 配列番号26
LCDR1 RASQGIGDDLG 配列番号27
LCDR2 GTSTLQS 配列番号28
LCDR3 LQDSNYPLT 配列番号29
HCDR3 TGX1YSGYDTX2X3X4X5X6 配列番号30
ここで、
X1は、任意のアミノ酸(好ましくは、EもしくはF)でありうるか、または存在せず、X2は、任意のアミノ酸(好ましくは、S、DもしくはP)でありうるか、または存在せず、
X3は、任意のアミノ酸(好ましくは、G、PもしくはA)でありうるか、または存在せず、
X4は、任意のアミノ酸(好ましくは、V、QもしくはS)でありうるか、または存在せず、
X5は、任意のアミノ酸(好ましくは、E、YもしくはP)でありうるか、または存在せず、
X6は、任意のアミノ酸(好ましくは、L、SもしくはD)でありうるか、または存在しない。
Sci. USA、85:5879−5883を参照。連結は、例えば、コード核酸をインフレームで融合して、融合タンパク質を適切な宿主細胞で発現することにより、達成することができる。適切なリンカーは、[G4S]3型のリンカーを含む。[G4S]3型リンカーは、グリシンおよびセリン残基の繰り返し単位で構成される。そのようなリンカーは、例えば、SGGGSGGGGSGGGGS(配列番号3)またはGGGGSGGGGSGGGGS(配列番号4)の配列、または4個までのアミノ酸の修飾を有するそれらのバリアントを有しうる。修飾としては、リンカーの長さを変化させる欠失もしくは挿入、またはアミノ酸の置換、好ましくはGlyからSerへもしくはその逆のアミノ酸置換が挙げられる。[G4S]3型リンカーは、scFv構造の可変ドメインを連結させるために広く使用されているが、その理由は、リンカーが低アレルギー性であり、可変ドメインに対してコンフォメーション的に最小の歪みしか生じさせないためである。例えば、Hustonら、(1988)、Proc. Natl. Acad. Sci. USA、85:5879−83を参照。
本発明のさらなる態様は、scFv−Fc二量体をコードする核酸を提供する。単離された核酸は、例えば、合成DNA、非天然mRNA、またはcDNAでありうる。例としては、米国特許第6,492,497号の配列番号3、5、7および9に示されるVHおよびVLドメインをコードする核酸が挙げられる。さらなる核酸としては、配列番号14に示されるダイアボディ5aaをコードする本発明の配列番号13で示される配列、ならびに、配列番号16に示されるアミノ酸配列を有するロイシンジッパーペプチド由来二量体をコードする配列番号15に示される配列が挙げられる。さらなる核酸としては、配列番号9に示されるアミノ酸配列を有するCAT191(scFv−Fc)をコードする配列番号17に示される配列が挙げられる。核酸は、プラスミド、ベクター、または転写もしくは発現カセットに挿入しうる。scFv−Fc二量体をコードする核酸は、当該分野で周知の従来技術、例えばBorsiら、(2002)Int. J. Cancer、102:75−85に開示の技術を使用して、作製され、発現される抗体は試験される。
scFv−Fc二量体は、ヒトまたは動物体の処置または診断方法において使用することができ、例えば、患者を処置するために有効量を投与することを含む、ヒト患者における疾患または障害の処置(予防的処置を含みうる)方法において使用することができる。処置可能な状態としては、TGFβ1が作用している任意の状態、例えば、線維性疾患、がん、免疫媒介性疾患および創傷治癒、例えば、びまん性全身性硬化症(diffuse systemic sclerosis)、骨リモデリング疾患、腎臓疾患および/またはそれらの組み合わせが挙げられる。
に示されている。
CAT192(IgG4)(メテリムマブ)は、TGF−β1を選択的に中和するヒトIgG4モノクローナル抗体である。TGFβ1(20−600RU)を、NHS/EDC化学を使用して、BiacoreのCM5チップに固定化した。様々な量のCAT192(IgG4)を表面に注射し、表面プラズモン共鳴により決定されるTGFβ1に対する結合を観察した。データを、1:1結合モデルを用いて解析し、結合定数を決定した。CAT192(IgG4)は、図2に示すように、親のCAT191scFvによる結合と比較して、表面プラズモン共鳴により決定される相対的に低い親和性で、TGFβ1に結合することが分かった。CAT192(IgG4)は、さらに、A549細胞ベースの効力アッセイにおいて、TGFβ1刺激IL−11産生の阻害により測定される相対的に低い効能(IC50=約10nM)を示した。A549アッセイの代表的な結果を図3に示す。A549アッセイは、Rapozaら、(2006)、「Development of an in vitro potency assay for therapeutic TGFβ antagonists: the A549 cell bioassay」、J. Immunol. Methods、316:18−26に開示されている手法にしたがって実施した。約10nMの見かけの解離定数によりTGFβ1に対する特異的な結合が示されたが、CAT192(IgG4)の治療適用は、相対的に高い効力から利益を得ていた。
CAT192(IgG4)の親和性は、ある特定の変性条件により、わずかに増強され、scFvがIgG4に変換される間に、抗体フォールディングにより親和性の喪失が引き起こされたことが示唆された。IgG4フォールディングは特有であることが提唱されてきた(Aalberse and Schuurman、「IgG4 breaking the rules」、Immunology、105:9−19)。IgG4におけるFabアーム交換ならびにFabsのFc CH2ドメインとの相互作用は、CAT192(IgG4)による親和性の喪失を説明しうる可能性があった。それゆえ、CAT192を、IgG4 Fc(CH1、CH2およびCH3ドメイン)のコンセンサスIgG1配列への置き換えにより再構築し、IgG1型を作製した。CAT192(IgG1)をコードするDNAを、GeneArtから合成し、発現ベクターpCEP4(−E+I)Destにサブクローニングした。
CAT191(scFv)(配列番号12)は、表面プラズモン共鳴により、高親和性でTGFβ1に結合することが分かったが、CAT191(scFv)は、TGFβ1の効果的な中和のために必要となるアビディティを欠いていた。したがって、様々な他のフォーマットを、scFv成分を基本構築単位として使用して、試験した。試験したフォーマットを含む、抗体断片の全体的なフォーマットを図1に示す。
CAT191(scFv−Fc)を、より大きいスケールでCHO細胞においてクローニングおよび製造した。CAT191scFv−Fcコード配列を、遺伝子特異的フォワードおよびリバースプライマーセットを使用して、pCEP4系発現ベクターからPCR増幅した。PCR増幅の一部として、以下の変化を、CAT191scFv−Fcコード配列に導入した:1)5’および3’端でのエンドヌクレアーゼ部位の付加、2)開始コドンの直ぐ上流へのKozakコンセンサス配列の付加、3)「TAG」終止コドンの「TAA」への変更、ならびに4)停止コドン上流の4つのチミジンヌクレオチドから1つのグアノシンへの変異による内在性スプライスドナー部位の除去。スプライスドナー部位の変異は、アミノ酸変化をもたらさなかった。
CAT191(scFv−Fc)の循環半減期を、表3に示す試験設計を使用してマウスモデルで試験した。
−80℃で保存したCAT191(scFv−Fc)の安定性を、SEC−HPLC、Biacore TGFβ1結合、およびA549効力アッセイにより1年間観察した。試験期間の間に、凝集、親和性または効力の変化は観察されなかった。4℃で保存した材料は、1年間で、わずかだが、安定した凝集の増加を示した。小さい大きさ、高選択性、TGFβ1に対する効力、および長いin vivo半減期の特有の組み合わせにより、CAT191(scFv−Fc)は、治療適用のための理想的な候補であった。
配列番号1:ヒトIgG1 VHドメインクローンSL15(SQN4 US6492497)
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSS
配列番号2:ヒトIgG1 VHドメインクローンJT182(SQN10 US6492497)
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTPASPDWGQGTTVTVSS
配列番号3:合成リンカー
SGGGSGGGGSGGGGS
配列番号4:合成リンカー
GGGGSGGGGSGGGGS
配列番号5:ヒトIgG1 VκドメインクローンSL15A:(SQN6 US6492497)
EIVLTQSPSSLSASVGDRVTITCRASQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIK
配列番号6:ヒトIgG1 VκドメインクローンSL15S:(SQN8 US6492497)
EIVLTQSPSSLSASVGDRVTITCRSSQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIK
配列番号7:ヒトIgG1ヒンジ領域
PKSCDKTHTCPPCPAPELLGGP
配列番号8:ヒトIgG1 Fc領域
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
配列番号9:CAT191(scFv−Fc)
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSSSGGGSGGGGSGGGGSEIVLTQSPSSLSASVGDRVTITCRSSQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIKGGSGPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK配列番号10:CAT192(IgG4)軽鎖
EWLTQSPSSLSASVGDRVTITCRASQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号11:CAT192(IgG4)重鎖
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
配列番号12:CAT191(scFv)
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSSSGGGSGGGGSGGGGSEIVLTQSPSSLSASVGDRVTITCRSSQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIK
配列番号13:ダイアボディ5aaをコードする核酸
atgaccatgattacgccaagctttggagccttttttttggagattttcaacgtgaaaaaattattattcgcaattcctttagttgttcctttctatgcggcccagccggccatggccgaggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctctggattcaccttcagtagctatggcatgcactgggtccgccaggctccaggcaaggagctggagtgggtggcagttatatcatatgatggaagtattaaatactatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgagagctgaggacacggctgtgtattactgtgcgcgaactggtgaatatagtggctacgatacggacccccagtactcctgggggcaagggaccacggtcaccgtctcctcaggttcctctggcggtgaaattgtgctgactcagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccggtcaagtcagggcattggagatgatttgggctggtatcagcagaagccagggaaagcccctatcctcctgatctatggtacatccactttacaaagtggggtcccgtcaaggttcagcggcagtggatctggcacagatttcactctcaccatcaacagcctgcagcctgaagattttgcaacttattactgtctacaagattccaattacccgctcactttcggcggagggacacgactggagattaaacgtgcggccgcacatcatcatcaccatcacggggccgcagaacaaaaactcatctcagaagaggatctgaatggggccgcatagtagctcgagatcaaacgggctagccagccagaactcgccccggaagaccccgaggatgtcgagcaccaccaccaccac
配列番号14:ダイアボディ5aa
EVQLVESGGGVVQPGRSLRLSCAASGFTESSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSSGSSGGEIVLTQSPSSLSASVGDRVTITCRSSQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIKRAAAHHHHHHGAAEQKLISEEDLNGAA
配列番号15:ロイシンジッパーペプチド由来二量体をコードする核酸
gaggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctctggattcaccttcagtagctatggcatgcactgggtccgccaggctccaggcaaggagctggagtgggtggcagttatatcatatgatggaagtattaaatactatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgagagctgaggacacggctgtgtattactgtgcgcgaactggtgaatatagtggctacgatacggacccccagtactcctgggggcaagggaccacggtcaccgtctcctcaagtggaggcggttcaggcggaggtggcagcggcggtggcggatcggaaattgtgctgactcagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccggtcaagtcagggcattggagatgatttgggctggtatcagcagaagccagggaaagcccctatcctcctgatctatggtacatccactttacaaagtggggtcccgtcaaggttcagcggcagtggatctggcacagatttcactctcaccatcaacagcctgcagcctgaagattttgcaacttattactgtctacaagattccaattacccgctcactttcggcggagggacacgactggagattaaacgtgcggccgcacatcatcatcaccatcacggggccgcagaacaaaaactcatctcagaagaggatctgaatggggccgcacccaagcccagtacccccccaggttcttcaggcgaactggaagaactgctgaaacatctgaaagaactgctgaaaggcccgcgtaaaggcgaactggaagaactgctgaaacatctgaaagaactgctgaaaggcggtgcgccgggcggtcatcatcatcaccatcat
配列番号16:ロイシンジッパーペプチド由来二量体
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSSSGGGSGGGGSGGGGSEIVLTQSPSSLSASVGDRVTITCRSSQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIKRAAAHHHHHHGAAEQKLISEEDLNGAAPKPSTPPGSSGELEELLKHLKELLKGPRKGELEELLKHLKELLKGGAPGGHHHHHH
配列番号17:CAT191(scFv−Fc)をコードする核酸
gaggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctctggattcaccttcagtagctatggcatgcactgggtccgccaggctccaggcaaggagctggagtgggtggcagttatatcatatgatggaagtattaaatactatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgagagctgaggacacggctgtgtattactgtgcgcgaactggtgaatatagtggctacgatacggacccccagtactcctgggggcaagggaccacggtcaccgtctcctcaagtggaggcggttcaggcggaggtggcagcggcggtggcggatcggaaattgtgctgactcagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccggtcaagtcagggcattggagatgatttgggctggtatcagcagaagccagggaaagcccctatcctcctgatctatggtacatccactttacaaagtggggtcccgtcaaggttcagcggcagtggatctggcacagatttcactctcaccatcaacagcctgcagcctgaagattttgcaacttattactgtctacaagattccaattacccgctcactttcggcggagggacacgactggagattaaaggtggcagcggacctaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacgtgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcagatggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaatagtag
配列番号18:ヒトTGFβ1
ALDTNYCFSSTEKNCCVRQLYIDFRKDLGWKWIHEPKGYHANFCLGPCPYIWSLDTQYSKVLALYNQHNPGASAAPCCVPQALEPLPIVYYVGRKPKVEQLSNMIVRSCKCS
配列番号19
GSSGG
配列番号20
GGSG
配列番号21
CPPCP
配列番号22
SYGMH
配列番号23
VISYDGSIKYYADSVKG
配列番号24
TGEYSGYDTSGVEL
配列番号25
TGEYSGYDTDPQYS
配列番号26
TGFYSGYDTPASPD
配列番号27
RASQGIGDDLG
配列番号28
GTSTLQS
配列番号29
LQDSNYPLT
配列番号30
TGX1YSGYDTX2X3X4X5X6
Claims (20)
- TGFβ1に結合する単離された結合タンパク質であって、該単離された結合タンパク質は、N末端からC末端へ、式:
(VHドメイン)−(リンカー1)−(VLドメイン)−(リンカー2)−(ヒンジ)−(Fc領域)
を有するポリペプチド鎖から形成される二量体である、
ここで、
VHドメインは、
配列番号22のアミノ酸配列を有する重鎖相補性決定領域(HCDR)1;配列番号23のアミノ酸配列を有するHCDR2;および配列番号25のアミノ酸配列を有するHCDR3を含み;
VLドメインは、
配列番号27のアミノ酸配列またはA2S置換した配列番号27のアミノ酸配列を有する軽鎖相補性決定領域(LCDR)1、配列番号28のアミノ酸配列を有するLCDR2、および配列番号29のアミノ酸配列を有するLCDR3を含み;
リンカー1は、[G4S]3型のリンカーであり;
リンカー2は、配列番号20あるいはそのバリアントであり、ここで、当該バリアントは、配列番号20とは、1〜4個のアミノ酸によって長さが異なっていて、あるいは、配列番号20とは、グリシンからセリンへのないしはセリンからグリシンへの2個までのアミノ酸の置換を有することで異なっていて;そして、
ヒンジは、ヒトIgG1またはIgG4ヒンジ領域由来のアミノ酸配列、または配列番号7または配列番号21のアミノ酸配列を含む、
前記単離された結合タンパク質。 - VHドメインは、配列番号1に示されるヒトVHドメイン配列を含み;
VLドメインは、配列番号5もしくは6に示されるヒトVκドメイン配列を含む;
請求項1に記載の単離された結合タンパク質。 - VHドメインおよびVLドメインは、それぞれ、配列番号1および5に示されるアミノ酸配列を含む、請求項2に記載の単離された結合タンパク質。
- ポリペプチド鎖は、配列番号9に示されるアミノ酸配列を含む、請求項1に記載の単離された結合タンパク質。
- 単離された結合タンパク質は、以下の特徴:
a)選択的にTGFβ1に結合する;
b)A549バイオアッセイにおけるヒトTGFβ1に対するIC50が1nM未満である;
c)表面プラズモン共鳴により測定されるヒトTGFβ2に対するKdよりも少なくとも約50%低いKdをヒトTGFβ1に対して示す;および
d)表面プラズモン共鳴により測定されるヒトTGFβ3に対するKdよりも少なくとも約50%低いKdをヒトTGFβ1に対して示す;
の少なくとも1つを有する、
請求項1〜4のいずれか1項に記載の単離された結合タンパク質。 - リンカー1は
アミノ酸配列SGGGSGGGGSGGGGS(配列番号3)、または、アミノ酸配列GGGGSGGGGSGGGGS(配列番号4)を含む、
請求項1に記載の単離された結合タンパク質。 - リンカー2は、配列番号20である、請求項1に記載の単離された結合タンパク質。
- Fc領域は、ヒトIgG1、ヒトIgG4、または10個までのアミノ酸が修飾されているヒトIgG1もしくはIgG4のバリアントから誘導される、請求項1〜7のいずれか1項に記載の単離された結合タンパク質。
- 請求項1〜8のいずれか1項に記載の単離された結合タンパク質および薬学的に許容される賦形剤を含む、医薬組成物。
- 請求項1〜8のいずれか1項に記載の単離された結合タンパク質をコードする単離されたポリヌクレオチド。
- ポリヌクレオチドが配列番号17に示される配列を含む、請求項4に記載の単離された結合タンパク質をコードする単離されたポリヌクレオチド。
- 請求項10または11のいずれかに記載の単離されたポリヌクレオチドを含むベクター。
- 請求項12に記載のベクターを含む宿主細胞。
- 宿主細胞が哺乳動物細胞である、請求項13に記載の宿主細胞。
- 哺乳動物細胞がヒト胎児由来腎臓293(HEK293)細胞である、請求項14に記載の宿主細胞。
- 哺乳動物細胞がチャイニーズハムスター卵巣(CHO)細胞である、請求項14に記載の宿主細胞。
- 単離された結合タンパク質を作成する方法であって、
請求項14〜16のいずれか1項に記載の宿主細胞を結合タンパク質を生産するのに適
切な条件下で培養する工程を含む、前記方法。 - TGFβ1活性を阻害する必要のあるヒトにおける疾患を処置するための医薬品の製造に使用するための、請求項1〜8のいずれか1項に記載の単離された結合タンパク質あるいは請求項9に記載の医薬組成物。
- 疾患は、線維性疾患、がん、および免疫媒介性疾患からなる群から選択される、請求項18に記載の使用のための単離された結合タンパク質あるいは医薬組成物。
- 疾患は、びまん性全身性皮膚硬化症、骨リモデリング疾患、または腎臓疾患である、請求項18に記載の使用のための単離された結合タンパク質あるいは医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562128133P | 2015-03-04 | 2015-03-04 | |
US62/128,133 | 2015-03-04 | ||
PCT/US2016/020779 WO2016141244A1 (en) | 2015-03-04 | 2016-03-03 | scFv-Fc DIMERS THAT BIND TRASFORMING GROWTH FACTOR-β1 WITH HIGH AFFINITY, AVIDITY AND SPECIFICITY |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2018508218A JP2018508218A (ja) | 2018-03-29 |
JP2018508218A5 JP2018508218A5 (ja) | 2019-03-28 |
JP6845802B2 true JP6845802B2 (ja) | 2021-03-24 |
Family
ID=55538640
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017546178A Active JP6845802B2 (ja) | 2015-03-04 | 2016-03-03 | トランスフォーミング増殖因子β1に高親和性、アビディティおよび特異性で結合するscFv−Fc二量体 |
Country Status (15)
Country | Link |
---|---|
US (3) | US10508146B2 (ja) |
EP (1) | EP3265484A1 (ja) |
JP (1) | JP6845802B2 (ja) |
KR (2) | KR20230156798A (ja) |
CN (1) | CN107889491B (ja) |
AR (1) | AR103839A1 (ja) |
AU (1) | AU2016226097B2 (ja) |
BR (1) | BR112017018767A2 (ja) |
CA (1) | CA2978459A1 (ja) |
IL (1) | IL254238B (ja) |
MX (2) | MX2017011251A (ja) |
RU (1) | RU2733286C2 (ja) |
SG (2) | SG11201707105TA (ja) |
TW (1) | TWI726870B (ja) |
WO (1) | WO2016141244A1 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI733661B (zh) | 2015-03-04 | 2021-07-21 | 美商健臻公司 | 以高親合性、結合性及特異性結合轉化生長因子-β1的經修飾IgG抗體 |
TWI726870B (zh) | 2015-03-04 | 2021-05-11 | 美商健臻公司 | 具有高親和性、結合性及專一性之結合轉形生長因子-β1的scFv-Fc二聚體 |
WO2017189964A2 (en) | 2016-04-29 | 2017-11-02 | Voyager Therapeutics, Inc. | Compositions for the treatment of disease |
WO2017189959A1 (en) | 2016-04-29 | 2017-11-02 | Voyager Therapeutics, Inc. | Compositions for the treatment of disease |
CN112500491B (zh) * | 2020-12-18 | 2022-04-08 | 深圳市迈加瑞生物技术有限公司 | 一种特异性中和辅助性T细胞TGF-β信号的双特异性抗体、其药物组合及其用途 |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020099179A1 (en) | 1989-12-21 | 2002-07-25 | Linda K. Jolliffe | Cdr-grafted antibodies |
US5616561A (en) | 1995-03-31 | 1997-04-01 | Regents Of The University Of California | TGF-β antagonists as mitigators of radiation-induced tissue damage |
ES2146552B1 (es) * | 1998-11-24 | 2001-04-16 | Inst Cientifico Tecnol Navarra | Peptidos inhibidores de tgf/31 |
US6492497B1 (en) | 1999-04-30 | 2002-12-10 | Cambridge Antibody Technology Limited | Specific binding members for TGFbeta1 |
EP1486560A3 (en) | 1999-04-30 | 2005-02-09 | Cambridge Antibody Technology LTD | Specific antibodies and antibody fragments for TGFBETA1 |
WO2004098637A1 (en) | 2003-04-30 | 2004-11-18 | Genzyme Corporation | Tgf-beta antagonists combined with renin-angiotensin-aldosteron-system antagonists for treating renal insufficiency |
NZ550217A (en) | 2004-03-31 | 2009-11-27 | Genentech Inc | Humanized anti-TGF-beta antibodies |
WO2006036729A2 (en) | 2004-09-22 | 2006-04-06 | Genzyme Corporation | USE OF TGF-β ANTAGONISTS TO LIMIT NEPHROTOXICITY OF IMMUNOSUPPRESSIVE AGENTS |
US9284375B2 (en) * | 2005-04-15 | 2016-03-15 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
PL1874818T3 (pl) * | 2005-04-22 | 2011-09-30 | Lilly Co Eli | Przeciwciała swoiste wobec TGF-beta 1 |
CN101346394B (zh) * | 2005-12-23 | 2012-07-25 | 伊莱利利公司 | TGF-β结合组合物 |
BRPI0709598A8 (pt) | 2006-03-17 | 2019-01-08 | Biogen Idec Inc | composições de polipeptídeos estabilizados |
EP2006380A4 (en) | 2006-03-23 | 2010-08-11 | Kyowa Hakko Kirin Co Ltd | AGONIST ANTIBODY AGAINST THE HUMAN THROMBOPOIETINE RECEPTOR |
PL2083863T3 (pl) | 2006-10-03 | 2015-08-31 | Genzyme Corp | Przeciwciała przeciwko TGF-beta do stosowania w leczeniu niemowląt obarczonych ryzykiem rozwinięcia się dysplazji oskrzelowo-płucnej |
MX2011000071A (es) | 2008-07-02 | 2011-05-03 | Emergent Product Dev Seattle | Inmunoterapeuticos de interleucina-6 (il6). |
US9409950B2 (en) * | 2010-12-23 | 2016-08-09 | Biogen Ma Inc. | Linker peptides and polypeptides comprising same |
TWI803876B (zh) | 2011-03-28 | 2023-06-01 | 法商賽諾菲公司 | 具有交叉結合區定向之雙重可變區類抗體結合蛋白 |
EP2714735B1 (en) | 2011-06-03 | 2021-07-21 | XOMA Technology Ltd. | Antibodies specific for tgf-beta |
US20140072581A1 (en) | 2012-07-23 | 2014-03-13 | Zymeworks Inc. | Immunoglobulin Constructs Comprising Selective Pairing of the Light and Heavy Chains |
MX365385B (es) | 2013-03-11 | 2019-05-31 | Genzyme Corp | Anticuerpos anti-tgf-beta modificados genéticamente y fragmentos de unión a antígeno. |
TWI733661B (zh) | 2015-03-04 | 2021-07-21 | 美商健臻公司 | 以高親合性、結合性及特異性結合轉化生長因子-β1的經修飾IgG抗體 |
TWI726870B (zh) | 2015-03-04 | 2021-05-11 | 美商健臻公司 | 具有高親和性、結合性及專一性之結合轉形生長因子-β1的scFv-Fc二聚體 |
-
2016
- 2016-03-02 TW TW105106243A patent/TWI726870B/zh active
- 2016-03-03 KR KR1020237037758A patent/KR20230156798A/ko not_active Application Discontinuation
- 2016-03-03 US US15/555,499 patent/US10508146B2/en active Active
- 2016-03-03 RU RU2017134042A patent/RU2733286C2/ru active
- 2016-03-03 BR BR112017018767A patent/BR112017018767A2/pt not_active IP Right Cessation
- 2016-03-03 AU AU2016226097A patent/AU2016226097B2/en not_active Ceased
- 2016-03-03 CA CA2978459A patent/CA2978459A1/en active Pending
- 2016-03-03 WO PCT/US2016/020779 patent/WO2016141244A1/en active Application Filing
- 2016-03-03 SG SG11201707105TA patent/SG11201707105TA/en unknown
- 2016-03-03 EP EP16710059.3A patent/EP3265484A1/en active Pending
- 2016-03-03 SG SG10201912449UA patent/SG10201912449UA/en unknown
- 2016-03-03 AR ARP160100559A patent/AR103839A1/es unknown
- 2016-03-03 JP JP2017546178A patent/JP6845802B2/ja active Active
- 2016-03-03 MX MX2017011251A patent/MX2017011251A/es unknown
- 2016-03-03 KR KR1020177027371A patent/KR102598790B1/ko active IP Right Grant
- 2016-03-03 CN CN201680025665.5A patent/CN107889491B/zh active Active
-
2017
- 2017-08-31 MX MX2022007456A patent/MX2022007456A/es unknown
- 2017-08-31 IL IL254238A patent/IL254238B/en unknown
-
2019
- 2019-10-30 US US16/669,211 patent/US11325971B2/en active Active
-
2022
- 2022-04-04 US US17/713,087 patent/US11976112B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
AU2016226097A1 (en) | 2017-10-26 |
RU2017134042A (ru) | 2019-04-05 |
MX2022007456A (es) | 2022-06-27 |
KR20230156798A (ko) | 2023-11-14 |
WO2016141244A1 (en) | 2016-09-09 |
IL254238A0 (en) | 2017-10-31 |
EP3265484A1 (en) | 2018-01-10 |
CN107889491A (zh) | 2018-04-06 |
RU2733286C2 (ru) | 2020-10-01 |
JP2018508218A (ja) | 2018-03-29 |
US20200131258A1 (en) | 2020-04-30 |
SG10201912449UA (en) | 2020-02-27 |
US20220363740A1 (en) | 2022-11-17 |
US11976112B2 (en) | 2024-05-07 |
AU2016226097B2 (en) | 2022-01-13 |
US10508146B2 (en) | 2019-12-17 |
AU2016226097A8 (en) | 2017-11-09 |
CA2978459A1 (en) | 2016-09-09 |
BR112017018767A2 (pt) | 2018-04-17 |
KR20170120173A (ko) | 2017-10-30 |
RU2017134042A3 (ja) | 2019-10-08 |
US11325971B2 (en) | 2022-05-10 |
US20180222970A1 (en) | 2018-08-09 |
MX2017011251A (es) | 2018-02-19 |
TW201706303A (zh) | 2017-02-16 |
CN107889491B (zh) | 2022-01-07 |
KR102598790B1 (ko) | 2023-11-07 |
IL254238B (en) | 2022-01-01 |
TWI726870B (zh) | 2021-05-11 |
WO2016141244A8 (en) | 2016-10-20 |
SG11201707105TA (en) | 2017-09-28 |
AR103839A1 (es) | 2017-06-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6495884B2 (ja) | 改変抗tgfベータ抗体および抗原結合フラグメント | |
US11834495B2 (en) | Modified-IgG antibodies that bind transforming growth factor-BETA1 with high affinity, avidity and specificity | |
US11976112B2 (en) | scFv-Fc dimers that bind transforming growth factor-β1 with high affinity, avidity and specificity | |
US20220411520A1 (en) | Gipr antibody and fusion protein between same and glp-1, and pharmaceutical composition and application thereof | |
US20210061904A1 (en) | Gipr antibody and glp-1 fusion protein thereof, and pharmaceutical composition and application thereof | |
KR102668864B1 (ko) | 전환 성장 인자-베타1에 높은 친화성, 결합력 및 특이성으로 결합하는 변형된-igg 항체 | |
KR20240076851A (ko) | 전환 성장 인자-베타1에 높은 친화성, 결합력 및 특이성으로 결합하는 변형된-igg 항체 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190218 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190218 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191203 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20191129 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200228 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200602 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20200901 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201020 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20210202 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210226 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6845802 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |