JP2000511407A - 不活性化耐性第▲viii▼因子 - Google Patents
不活性化耐性第▲viii▼因子Info
- Publication number
- JP2000511407A JP2000511407A JP09538216A JP53821697A JP2000511407A JP 2000511407 A JP2000511407 A JP 2000511407A JP 09538216 A JP09538216 A JP 09538216A JP 53821697 A JP53821697 A JP 53821697A JP 2000511407 A JP2000511407 A JP 2000511407A
- Authority
- JP
- Japan
- Prior art keywords
- protein
- fviii
- nucleic acid
- acid molecule
- apc
- 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
- 102000001690 Factor VIII Human genes 0.000 title claims description 14
- 108010054218 Factor VIII Proteins 0.000 title claims description 14
- 229960000301 factor viii Drugs 0.000 title claims description 10
- 230000002779 inactivation Effects 0.000 title description 56
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 131
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 127
- 108090000190 Thrombin Proteins 0.000 claims abstract description 58
- 229960004072 thrombin Drugs 0.000 claims abstract description 56
- 150000007523 nucleic acids Chemical group 0.000 claims abstract description 50
- 108010047303 von Willebrand Factor Proteins 0.000 claims abstract description 42
- 102100036537 von Willebrand factor Human genes 0.000 claims abstract description 41
- 229960001134 von willebrand factor Drugs 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 35
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims abstract description 24
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 24
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 24
- 108091028043 Nucleic acid sequence Proteins 0.000 claims abstract description 19
- 102000057593 human F8 Human genes 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 102100026735 Coagulation factor VIII Human genes 0.000 claims abstract description 8
- 230000004913 activation Effects 0.000 claims description 35
- 230000035772 mutation Effects 0.000 claims description 35
- 150000001413 amino acids Chemical class 0.000 claims description 34
- 239000012634 fragment Substances 0.000 claims description 26
- 230000001965 increasing effect Effects 0.000 claims description 25
- 230000014509 gene expression Effects 0.000 claims description 22
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 19
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 17
- 229920001184 polypeptide Polymers 0.000 claims description 16
- 210000004369 blood Anatomy 0.000 claims description 14
- 239000008280 blood Substances 0.000 claims description 14
- 238000012217 deletion Methods 0.000 claims description 13
- 230000037430 deletion Effects 0.000 claims description 13
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 12
- 239000004473 Threonine Substances 0.000 claims description 12
- 239000013604 expression vector Substances 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000000833 heterodimer Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 239000002773 nucleotide Substances 0.000 claims description 10
- 125000003729 nucleotide group Chemical group 0.000 claims description 10
- 230000002947 procoagulating effect Effects 0.000 claims description 8
- 239000003805 procoagulant Substances 0.000 claims description 7
- 230000004048 modification Effects 0.000 claims description 6
- 238000012986 modification Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 4
- 239000004971 Cross linker Substances 0.000 claims description 3
- 230000015271 coagulation Effects 0.000 claims description 3
- 238000005345 coagulation Methods 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 2
- 238000012258 culturing Methods 0.000 claims 4
- 238000003776 cleavage reaction Methods 0.000 abstract description 69
- 230000007017 scission Effects 0.000 abstract description 68
- 208000009292 Hemophilia A Diseases 0.000 abstract description 11
- 208000031220 Hemophilia Diseases 0.000 abstract description 9
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 3
- 235000018102 proteins Nutrition 0.000 description 90
- 230000000694 effects Effects 0.000 description 69
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 60
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 58
- 210000004027 cell Anatomy 0.000 description 49
- 102200052247 rs199469640 Human genes 0.000 description 30
- 230000028327 secretion Effects 0.000 description 26
- 229940024606 amino acid Drugs 0.000 description 21
- 235000001014 amino acid Nutrition 0.000 description 21
- 108020004414 DNA Proteins 0.000 description 19
- 238000003556 assay Methods 0.000 description 18
- 239000003636 conditioned culture medium Substances 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 17
- 102000014914 Carrier Proteins Human genes 0.000 description 16
- 108091008324 binding proteins Proteins 0.000 description 16
- 238000011534 incubation Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 206010056867 Activated protein C resistance Diseases 0.000 description 13
- 239000000872 buffer Substances 0.000 description 13
- 230000035602 clotting Effects 0.000 description 12
- 230000000875 corresponding effect Effects 0.000 description 11
- 238000001890 transfection Methods 0.000 description 11
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- 239000013598 vector Substances 0.000 description 10
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- 230000002950 deficient Effects 0.000 description 9
- 238000001415 gene therapy Methods 0.000 description 9
- 238000003752 polymerase chain reaction Methods 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 206010053567 Coagulopathies Diseases 0.000 description 8
- 101100007328 Cocos nucifera COS-1 gene Proteins 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- 238000002703 mutagenesis Methods 0.000 description 8
- 231100000350 mutagenesis Toxicity 0.000 description 8
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 7
- 125000000539 amino acid group Chemical group 0.000 description 7
- 238000003149 assay kit Methods 0.000 description 7
- 239000002299 complementary DNA Substances 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 241000894007 species Species 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 102220364037 c.2219G>A Human genes 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 5
- 239000006180 TBST buffer Substances 0.000 description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000014616 translation Effects 0.000 description 5
- 108010039627 Aprotinin Proteins 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 108091034117 Oligonucleotide Proteins 0.000 description 4
- 229920002684 Sepharose Polymers 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 229960004405 aprotinin Drugs 0.000 description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
- 230000000717 retained effect Effects 0.000 description 4
- 238000002741 site-directed mutagenesis Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 238000013519 translation Methods 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- 101000583086 Bunodosoma granuliferum Delta-actitoxin-Bgr2b Proteins 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 238000000376 autoradiography Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000036039 immunity Effects 0.000 description 3
- 238000001114 immunoprecipitation Methods 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229960000310 isoleucine Drugs 0.000 description 3
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 210000004962 mammalian cell Anatomy 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 229920002401 polyacrylamide Polymers 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000009256 replacement therapy Methods 0.000 description 3
- 125000006850 spacer group Chemical group 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 2
- 208000002109 Argyria Diseases 0.000 description 2
- 102000002110 C2 domains Human genes 0.000 description 2
- 108050009459 C2 domains Proteins 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 201000003542 Factor VIII deficiency Diseases 0.000 description 2
- 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 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 208000032843 Hemorrhage 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
- 241000124008 Mammalia Species 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 239000008156 Ringer's lactate solution Substances 0.000 description 2
- 108091058545 Secretory proteins Proteins 0.000 description 2
- 102000040739 Secretory proteins Human genes 0.000 description 2
- 238000012300 Sequence Analysis Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229940122618 Trypsin inhibitor Drugs 0.000 description 2
- 101710162629 Trypsin inhibitor Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 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 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 102000055691 human APC Human genes 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 230000006337 proteolytic cleavage Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 239000002753 trypsin inhibitor Substances 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- YMXHPSHLTSZXKH-RVBZMBCESA-N (2,5-dioxopyrrolidin-1-yl) 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoate Chemical compound C([C@H]1[C@H]2NC(=O)N[C@H]2CS1)CCCC(=O)ON1C(=O)CCC1=O YMXHPSHLTSZXKH-RVBZMBCESA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- RGEMJCLUPGZKTQ-WAUHAFJUSA-N (3s,8r,9s,10r,13s,14s)-3-[2-(dimethylamino)ethoxy]-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one Chemical compound C([C@@H]12)C[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OCCN(C)C)C1 RGEMJCLUPGZKTQ-WAUHAFJUSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 101000588924 Anthopleura elegantissima Delta-actitoxin-Ael1a Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 108010075016 Ceruloplasmin Proteins 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- 108020004638 Circular DNA Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 102100031780 Endonuclease Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 108700041152 Endoplasmic Reticulum Chaperone BiP Proteins 0.000 description 1
- 102100021451 Endoplasmic reticulum chaperone BiP Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010048049 Factor IXa Proteins 0.000 description 1
- 108010014172 Factor V Proteins 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 101150112743 HSPA5 gene Proteins 0.000 description 1
- 108091027305 Heteroduplex Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000012741 Laemmli sample buffer Substances 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 239000012124 Opti-MEM Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 102100026827 Protein associated with UVRAG as autophagy enhancer Human genes 0.000 description 1
- 101710102978 Protein associated with UVRAG as autophagy enhancer Proteins 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 101100111629 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) KAR2 gene Proteins 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 210000001766 X chromosome Anatomy 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- RIIWUGSYXOBDMC-UHFFFAOYSA-N benzene-1,2-diamine;hydron;dichloride Chemical compound Cl.Cl.NC1=CC=CC=C1N RIIWUGSYXOBDMC-UHFFFAOYSA-N 0.000 description 1
- 238000013357 binding ELISA Methods 0.000 description 1
- 229960000182 blood factors Drugs 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 102220346075 c.1079G>A Human genes 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000000749 co-immunoprecipitation Methods 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 210000001840 diploid cell Anatomy 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 101150028578 grp78 gene Proteins 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 125000005842 heteroatom Chemical class 0.000 description 1
- 229960000900 human factor viii Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 238000010324 immunological assay Methods 0.000 description 1
- 239000012133 immunoprecipitate Substances 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000012933 kinetic analysis Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 238000001466 metabolic labeling Methods 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000007758 minimum essential medium Substances 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000009465 prokaryotic expression Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 102220064236 rs367619172 Human genes 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000036301 sexual development Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 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
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical group CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- KUUVQVSHGLHAKZ-UHFFFAOYSA-N thionine Chemical compound C=1C=CC=CSC=CC=1 KUUVQVSHGLHAKZ-UHFFFAOYSA-N 0.000 description 1
- 229960003766 thrombin (human) Drugs 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 238000003151 transfection method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000014599 transmission of virus Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 108020005087 unfolded proteins Proteins 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Toxicology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.Phe309での変異を含む修飾をされているヒトFVIIIポリペプチドを含む、 凝/血促進活性FVIIIタンパク質。 2.変異が置換である、請求項1記載のタンパク質。 3.変異が欠失である、請求項1記載のタンパク質。 4.変異がPheのSerへの置換を含む、請求項2記載のタンパク質。 5.請求項1記載のタンパク質をコードするヌクレオチド配列を含む、核酸分 子。 6.請求項5記載の核酸分子を含む、発現ベクター。 7.請求項5記載の核酸分子で形質転換またはトランスフェクトされた宿主細 胞。 8.非経口に許容される媒体または賦形剤との混合物である有効量の請求項1 記載のタンパク質を含む、医薬組成物。 9.a)請求項5記載の核酸分子で形質転換またはトランスフェクトした宿主 細胞を培養して生育させる;そして b)上記宿主細胞から、核酸分子の発現のポリペプチド生産物を単離する: 段階を含む、凝血促進活性タンパク質の製造法。 10.336位のArg残基のIleへの置換および562位のArg残基のLysへの置 換を含む修飾をされているヒトFVIIIポリペプチドを含む、凝血促進活性FVIIIタ ンパク質。 11.修飾が更にPhe309での変異を含む、請求項10記載のタンパク質。 12.請求項10記載のタンパク質をコードするヌクレオチド配列を含む核酸 分子。 13.非経口に許容される媒体または賦形剤との混合物である有効量の請求項 10記載のタンパク質を含む、医薬組成物。 14.請求項12記載の核酸分子を含む発現ベクター。 15.請求項12記載の核酸分子で形質転換またはトランスフェクトされた宿 主細胞。 16.a)請求項12記載の核酸分子で形質転換またはトランスフェクトした 宿主細胞を培養して生育させる;そして b)上記宿主細胞から、核酸分子の発現のポリペプチド生産物を単離する: 段階を含む、凝血促進活性タンパク質の製造法。 17.Bドメインの欠失、フォン ウィルブラント因子結合部位の欠失、Arg7 40での変異およびA2−とA3−ドメインの間のアミノ酸配列スペーサーの付加 を含む修飾をされているヒトFVIIIポリペプチドを含む、凝血促進活性FVIIIタン パク質。 18.修飾が更に336位のArg残基のIleへの置換および562位のArg残基 のLysへの置換を含む、請求項17記載のタンパク質。 19.修飾が更にPhe309での変異を含む、請求項10記載のタンパク質。 20.変異が740位のArgのAlaへの置換を含む、請求項17記載のタンパク 質。 21.アミノ酸配列スペーサーが54残基の長さである、請求項17記載のタ ンパク質。 22.アミノ酸配列スペーサーが、794くらいの残基がスレオニンおよびロ イシンからなる群から選択されたものである、野生型FVIIIの残基741から7 94を含む、請求項21記載のタンパク質。 23.794位の残基がスレオニンである、請求項22記載のタンパク質。 24.請求項17記載のタンパク質をコードするヌクレオチド配列を含む核酸 分子。 25.請求項24記載の核酸分子を含む発現ベクター。 26.請求項24記載の核酸分子で形質転換またはトランスフェクトされた宿 主細胞。 27.非経口に許容される媒体または賦形剤との混合物である有効量の請求項 17記載のタンパク質を含む、医薬組成物。 28.a)請求項24記載の核酸分子で形質転換またはトランスフェクトした 宿主細胞を培養して生育させる;そして b)上記宿主細胞から、核酸分子の発現のポリペプチド生産物を単離する: 段階を含む、凝血促進活性タンパク質の製造法。 29.タンパク質およびフォン ウィルブラント因子を含む血漿に、フォンウ ィルブラント因子へのタンパク質の結合親和性を増加させる抗体または架橋剤を 挿入する段階を含む、血漿中のフォン ウィルブラント因子への請求項17記載 のタンパク質の結合を増加させる方法。 30.抗体がタンパク質のアミノ酸2248から2285のエピトープを認識 する、請求項29記載の方法。 31.抗体がESH8である、請求項30記載の方法。 32.トロンビン活性化により、タンパク質がA1−ドメインフラグメントと A2−A3−C1−C2鎖を含むヘテロダイマーになることを特徴とする、ヒト 第VIII因子のA1−、A2−、A3−、C1−およびC2−を含む凝血促進活性 FVIIIタンパク質。 33.請求項32記載のタンパク質をコードするヌクレオチド配列を含む核酸 分子。 34.請求項33記載の核酸分子を含む発現ベクター。 35.請求項33記載の核酸分子で形質転換またはトランスフェクトされた宿 主細胞。 36.非経口に許容される媒体または賦形剤との混合物である有効量の請求項 32記載のタンパク質を含む、医薬組成物。 37.a)請求項33記載の核酸分子で形質転換またはトランスフェクトした 宿主細胞を培養して生育させる;そして b)上記宿主細胞から、核酸分子の発現のポリペプチド生産物を単離する: 段階を含む、凝血促進活性タンパク質の製造法。 38.タンパク質およびフォン ウィルブラント因子を含む血漿に、フォンウ ィルブラント因子へのタンパク質の結合親和性を増加させる抗体または架橋剤を 挿入する段階を含む、血漿中のフォン ウィルブラント因子への請求項32記載 のタンパク質の結合を増加させる方法。 39.抗体がタンパク質のアミノ酸2248から2285のエピトープを認識 する、請求項38記載の方法。 40.抗体がESH8である、請求項39記載の方法。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1611796P | 1996-04-24 | 1996-04-24 | |
US1778596P | 1996-05-15 | 1996-05-15 | |
US60/017,785 | 1996-05-15 | ||
US60/016,117 | 1996-05-15 | ||
PCT/US1997/006563 WO1997040145A1 (en) | 1996-04-24 | 1997-04-24 | Inactivation resistant factor viii |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007101700A Division JP4250661B2 (ja) | 1996-04-24 | 2007-04-09 | 不活性化耐性第viii因子 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2000511407A true JP2000511407A (ja) | 2000-09-05 |
JP2000511407A5 JP2000511407A5 (ja) | 2004-12-02 |
JP3987114B2 JP3987114B2 (ja) | 2007-10-03 |
Family
ID=26688196
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP53821697A Expired - Fee Related JP3987114B2 (ja) | 1996-04-24 | 1997-04-24 | 不活性化耐性第▲8▼因子 |
JP2007101700A Expired - Fee Related JP4250661B2 (ja) | 1996-04-24 | 2007-04-09 | 不活性化耐性第viii因子 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007101700A Expired - Fee Related JP4250661B2 (ja) | 1996-04-24 | 2007-04-09 | 不活性化耐性第viii因子 |
Country Status (10)
Country | Link |
---|---|
US (2) | US6838437B2 (ja) |
EP (3) | EP2202242A1 (ja) |
JP (2) | JP3987114B2 (ja) |
AT (2) | ATE319817T1 (ja) |
AU (1) | AU3202797A (ja) |
CA (1) | CA2252896C (ja) |
DE (2) | DE69740154D1 (ja) |
DK (1) | DK1754718T3 (ja) |
PT (1) | PT1754718E (ja) |
WO (1) | WO1997040145A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013100300A (ja) * | 2004-12-23 | 2013-05-23 | Novo Nordisk Health Care Ag | 関心のあるビタミンk依存性タンパク質を含んでなる組成物中におけるタンパク質混入物の量の減少 |
JP2016513697A (ja) * | 2013-03-15 | 2016-05-16 | バイエル・ヘルスケア・エルエルシーBayer HealthCare LLC | 変異体第viii因子ポリペプチドならびにそれらの製造方法および使用方法 |
Families Citing this family (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0833848T3 (da) * | 1995-06-12 | 2001-11-05 | Sanquin Bloedvoorziening | Faktor IX-bindende peptider afledt af faktor VIII og anvendelse heraf som inhibitorer af blodkoagulation |
DE69740154D1 (de) | 1996-04-24 | 2011-05-05 | Univ Michigan | Gegen Inaktivierung resistenter Faktor VIII |
US20040092442A1 (en) * | 1996-04-24 | 2004-05-13 | University Of Michigan | Inactivation resistant factor VIII |
US8183344B2 (en) | 1996-04-24 | 2012-05-22 | University Of Michigan | Inactivation resistant factor VIII |
WO1999041385A1 (en) * | 1998-02-13 | 1999-08-19 | Cadus Pharmaceutical Corporation | Mekk1 proteins and fragments thereof for use in regulating apoptosis |
WO2002060951A2 (en) * | 2001-01-12 | 2002-08-08 | The American National Red Cross | Methods and compositions for reducing heparan sulfate proteoglycan-mediated clearance of factor viii |
AU2003241599A1 (en) * | 2002-05-22 | 2003-12-12 | The Children's Hospital Of Philadelphia | Compositions and methods for the treatment of hemophilia a |
US7041635B2 (en) * | 2003-01-28 | 2006-05-09 | In2Gen Co., Ltd. | Factor VIII polypeptide |
EP1502921A1 (en) * | 2003-07-29 | 2005-02-02 | ZLB Behring GmbH | Recombinant mutated human factor VIII (FVIII) with improved stability |
WO2006108590A1 (en) * | 2005-04-14 | 2006-10-19 | Csl Behring Gmbh | Modified coagulation factor viii with enhanced stability and its derivates |
EP1816201A1 (en) | 2006-02-06 | 2007-08-08 | CSL Behring GmbH | Modified coagulation factor VIIa with extended half-life |
US20090203077A1 (en) * | 2006-06-30 | 2009-08-13 | The Regents Of The University Of Michigan | Method of producing factor viii proteins by recombinant methods |
CA2656558A1 (en) * | 2006-06-30 | 2008-01-10 | The Regents Of The University Of Michigan | Method of producing factor viii proteins by recombinant methods |
AU2007338298B2 (en) | 2006-12-22 | 2013-02-07 | Csl Behring Gmbh | Modified coagulation factors with prolonged in vivo half-life |
ES2654336T3 (es) | 2008-06-24 | 2018-02-13 | Csl Behring Gmbh | Factor VIII, factor de von Willebrand o sus complejos con semivida in vivo prolongada |
SG190136A1 (en) * | 2010-11-05 | 2013-07-31 | Baxter Int | A new variant of antihemophilic factor viii having increased specific activity |
SI23610A (sl) | 2011-01-13 | 2012-07-31 | Diagen@d@o@o | Nove adicijske soli ziprasidona postopek za njihovo pripravo in njihova uporaba v terapiji |
KR20140084208A (ko) | 2011-10-18 | 2014-07-04 | 시에스엘 리미티드 | 정제된 인자 viii의 재구성 후의 안정성을 향상시키는 방법 |
AU2012318303B2 (en) | 2011-10-18 | 2015-09-03 | Csl Behring Gmbh | Combined use of a sulfated glycosaminoglycan and a hyaluronidase for improving the bioavailability of Factor VIII |
EP2768522B1 (en) | 2011-10-18 | 2016-07-27 | CSL Behring GmbH | Use of sulfated glycosaminoglycans for improving the bioavailability of factor viii |
US9458223B2 (en) | 2012-02-15 | 2016-10-04 | Csl Behring Gmbh | Von willebrand factor variants having improved factor VIII binding affinity |
IN2012CH03778A (ja) * | 2012-09-12 | 2015-04-24 | Ct For Bioseparation Technology Vit | |
SG11201503719WA (en) * | 2012-11-29 | 2015-06-29 | Bayer Healthcare Llc | MONOCLONAL ANTIBODIES AGAISNT ACTIVATED PROTEIN C (aPC) |
RU2015125343A (ru) | 2012-11-29 | 2017-01-11 | БАЙЕР ХелсКер ЛЛСи | Гуманизированные моноклональные антитела против активированного белка с и их применение |
EP2796145B1 (en) | 2013-04-22 | 2017-11-01 | CSL Ltd. | A covalent complex of von willebrand factor and faktor viii linked by a disulphide bridge |
EP3114138B1 (en) | 2014-03-05 | 2021-11-17 | Pfizer Inc. | Improved muteins of clotting factor viii |
KR20170026580A (ko) | 2014-07-02 | 2017-03-08 | 씨에스엘 리미티드 | 변형된 폰 빌레브란트 인자 |
SG11201706659WA (en) | 2015-03-06 | 2017-09-28 | Csl Behring Recombinant Facility Ag | Modified von willebrand factor having improved half-life |
KR20170125942A (ko) * | 2015-03-06 | 2017-11-15 | 체에스엘 베링 리컴비넌트 퍼실리티 아게 | 폰 빌레브란트 인자의 반감기 개선용 화합물 |
AU2016266627A1 (en) | 2015-05-22 | 2018-01-18 | CSL Behring Lengnau AG | Truncated von Willebrand Factor polypeptides for treating hemophilia |
RU2017145002A (ru) | 2015-05-22 | 2019-06-24 | Цсл Беринг Ленгнау Аг | Способы получения модифицированного фактора фон виллебранда |
US11077187B2 (en) | 2015-11-17 | 2021-08-03 | Oklahoma Medical Research Foundation | Epitope of optimized humanized monoclonal antibodies against activated protein C and uses thereof |
ES2881701T3 (es) | 2016-01-07 | 2021-11-30 | CSL Behring Lengnau AG | Factor de von Willebrand mutado |
RU2018128582A (ru) | 2016-01-07 | 2020-02-11 | Цсл Беринг Ленгнау Аг | Мутированный укороченный фактор фон виллебранда |
TW201828974A (zh) | 2016-11-11 | 2018-08-16 | 瑞士商Csl貝林重組技能公司 | 用於血管外施予以治療或預防凝血疾病之截短型類血友病因子(von Willebrand factor)多肽類 |
KR20190085021A (ko) | 2016-11-11 | 2019-07-17 | 체에스엘 베링 렝나우 아게 | 혈우병을 치료하기 위한 절단된 폰 빌레브란트 인자 폴리펩타이드 |
JP2022512787A (ja) * | 2018-10-23 | 2022-02-07 | ザ・チルドレンズ・ホスピタル・オブ・フィラデルフィア | 第viii因子機能を調節するための組成物および方法 |
US11471497B1 (en) | 2019-03-13 | 2022-10-18 | David Gordon Bermudes | Copper chelation therapeutics |
CA3159985A1 (en) * | 2019-12-06 | 2021-06-10 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating factor viii function |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5214033A (en) * | 1983-03-31 | 1993-05-25 | Scripps Clinic & Research Foundation | Factor VIII coagulant polypeptides |
US4757006A (en) | 1983-10-28 | 1988-07-12 | Genetics Institute, Inc. | Human factor VIII:C gene and recombinant methods for production |
US5045455A (en) * | 1984-01-12 | 1991-09-03 | Chiron Corporation | Factor VIII:C cDNA cloning and expression |
SE8501050D0 (sv) | 1985-03-05 | 1985-03-05 | Kabivitrum Ab | Biologically active fragments of human antihemophilic factor and method for preparation thereof |
US4868112A (en) * | 1985-04-12 | 1989-09-19 | Genetics Institute, Inc. | Novel procoagulant proteins |
US5250421A (en) | 1986-01-03 | 1993-10-05 | Genetics Institute, Inc. | Method for producing factor VIII:C-type proteins |
ATE87663T1 (de) | 1986-01-03 | 1993-04-15 | Genetics Inst | Verfahren zur herstellung von faktor-viii:c-typ- proteinen. |
AT388079B (de) | 1986-04-18 | 1989-04-25 | Helmut Ing Koenig | Backofen |
US5422260A (en) * | 1986-05-29 | 1995-06-06 | Genetics Institute, Inc. -Legal Affairs | Human factor VIII:c muteins |
US5451521A (en) * | 1986-05-29 | 1995-09-19 | Genetics Institute, Inc. | Procoagulant proteins |
US4912040A (en) | 1986-11-14 | 1990-03-27 | Genetics Institute, Inc. | Eucaryotic expression system |
CA1331157C (en) | 1987-04-06 | 1994-08-02 | Randal J. Kaufman | Method for producing factor viii:c-type proteins |
DE3720246A1 (de) | 1987-06-19 | 1988-12-29 | Behringwerke Ag | Faktor viii:c-aehnliches molekuel mit koagulationsaktivitaet |
US5004803A (en) | 1988-11-14 | 1991-04-02 | Genetics Institute, Inc. | Production of procoagulant proteins |
JP2865861B2 (ja) | 1989-11-17 | 1999-03-08 | ノボ ノルディスク アクティーゼルスカブ | 第▲viii▼:c因子活性を有するタンパク質複合体およびその製法 |
US5661008A (en) * | 1991-03-15 | 1997-08-26 | Kabi Pharmacia Ab | Recombinant human factor VIII derivatives |
US5563045A (en) * | 1992-11-13 | 1996-10-08 | Genetics Institute, Inc. | Chimeric procoagulant proteins |
AU6486196A (en) | 1995-07-11 | 1997-02-10 | Chiron Corporation | Novel factor viii:c polypeptide analogs with altered protease sites |
WO1997003194A1 (en) | 1995-07-11 | 1997-01-30 | Chiron Corporation | Lysine 1689 factor viii:c polypeptide analogs |
DE69740154D1 (de) | 1996-04-24 | 2011-05-05 | Univ Michigan | Gegen Inaktivierung resistenter Faktor VIII |
-
1997
- 1997-04-24 DE DE69740154T patent/DE69740154D1/de not_active Expired - Lifetime
- 1997-04-24 PT PT06004484T patent/PT1754718E/pt unknown
- 1997-04-24 AU AU32027/97A patent/AU3202797A/en not_active Abandoned
- 1997-04-24 CA CA002252896A patent/CA2252896C/en not_active Expired - Fee Related
- 1997-04-24 EP EP10157809A patent/EP2202242A1/en not_active Withdrawn
- 1997-04-24 DE DE69735421T patent/DE69735421T2/de not_active Expired - Lifetime
- 1997-04-24 EP EP97927596A patent/EP0910628B1/en not_active Expired - Lifetime
- 1997-04-24 JP JP53821697A patent/JP3987114B2/ja not_active Expired - Fee Related
- 1997-04-24 EP EP06004484A patent/EP1754718B1/en not_active Expired - Lifetime
- 1997-04-24 DK DK06004484.9T patent/DK1754718T3/da active
- 1997-04-24 AT AT97927596T patent/ATE319817T1/de not_active IP Right Cessation
- 1997-04-24 WO PCT/US1997/006563 patent/WO1997040145A1/en active IP Right Grant
- 1997-04-24 AT AT06004484T patent/ATE502958T1/de active
-
2001
- 2001-04-11 US US09/819,098 patent/US6838437B2/en not_active Expired - Fee Related
-
2004
- 2004-10-26 US US10/974,534 patent/US7459534B2/en not_active Expired - Fee Related
-
2007
- 2007-04-09 JP JP2007101700A patent/JP4250661B2/ja not_active Expired - Fee Related
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013100300A (ja) * | 2004-12-23 | 2013-05-23 | Novo Nordisk Health Care Ag | 関心のあるビタミンk依存性タンパク質を含んでなる組成物中におけるタンパク質混入物の量の減少 |
US9187549B2 (en) | 2004-12-23 | 2015-11-17 | Novo Nordisk Healthcare A/G | Reduction of the content of protein contaminants in compositions comprising a vitamin K-dependent protein of interest |
JP2016513697A (ja) * | 2013-03-15 | 2016-05-16 | バイエル・ヘルスケア・エルエルシーBayer HealthCare LLC | 変異体第viii因子ポリペプチドならびにそれらの製造方法および使用方法 |
Also Published As
Publication number | Publication date |
---|---|
PT1754718E (pt) | 2011-07-13 |
EP0910628A1 (en) | 1999-04-28 |
EP1754718B1 (en) | 2011-03-23 |
US20060014683A1 (en) | 2006-01-19 |
EP1754718A2 (en) | 2007-02-21 |
WO1997040145A1 (en) | 1997-10-30 |
ATE502958T1 (de) | 2011-04-15 |
US20020132306A1 (en) | 2002-09-19 |
EP2202242A1 (en) | 2010-06-30 |
DE69735421T2 (de) | 2006-10-19 |
CA2252896C (en) | 2009-03-10 |
DE69735421D1 (de) | 2006-05-04 |
JP3987114B2 (ja) | 2007-10-03 |
US7459534B2 (en) | 2008-12-02 |
DE69740154D1 (de) | 2011-05-05 |
EP1754718A3 (en) | 2007-05-16 |
US6838437B2 (en) | 2005-01-04 |
EP0910628A4 (en) | 2001-05-02 |
JP4250661B2 (ja) | 2009-04-08 |
CA2252896A1 (en) | 1997-10-30 |
ATE319817T1 (de) | 2006-03-15 |
JP2007228973A (ja) | 2007-09-13 |
DK1754718T3 (da) | 2011-07-18 |
AU3202797A (en) | 1997-11-12 |
EP0910628B1 (en) | 2006-03-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4250661B2 (ja) | 不活性化耐性第viii因子 | |
WO1997040145A9 (en) | Inactivation resistant factor viii | |
AU693837B2 (en) | Hybrid human/animal factor VIII | |
US8183344B2 (en) | Inactivation resistant factor VIII | |
AU2007269233B2 (en) | Method of producing Factor VIII proteins by recombinant methods | |
US20040197875A1 (en) | Modified cDNA factor VIII and its derivatives | |
US20040092442A1 (en) | Inactivation resistant factor VIII | |
AU747644B2 (en) | Modified factor VIII | |
JP2000513934A (ja) | 改変された第▲viii▼因子 | |
US20020182670A1 (en) | Modified factor VIII | |
JP2008537680A (ja) | 安定性の増大された改変型凝固第viii因子およびその誘導体 | |
US20040249134A1 (en) | Factor viii c2 domain variants | |
Donath et al. | Characterization of des-(741–1668)-factor VIII, a single-chain factor VIII variant with a fusion site susceptible to proteolysis by thrombin and factor Xa | |
US20030148953A1 (en) | Inactivation resistant factor VIII | |
US20090203077A1 (en) | Method of producing factor viii proteins by recombinant methods | |
ES2363873T3 (es) | Factor viii resistente a la inactivación. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20040316 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20040316 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20070109 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20070409 |
|
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: 20070612 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20070712 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20100720 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110720 Year of fee payment: 4 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110720 Year of fee payment: 4 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120720 Year of fee payment: 5 |
|
LAPS | Cancellation because of no payment of annual fees |