JP2005511038A - 第ｖｉｉｉ因子ｃ２ドメインのバリアント - Google Patents
第ｖｉｉｉ因子ｃ２ドメインのバリアント Download PDFInfo
- Publication number
- JP2005511038A JP2005511038A JP2003548768A JP2003548768A JP2005511038A JP 2005511038 A JP2005511038 A JP 2005511038A JP 2003548768 A JP2003548768 A JP 2003548768A JP 2003548768 A JP2003548768 A JP 2003548768A JP 2005511038 A JP2005511038 A JP 2005511038A
- Authority
- JP
- Japan
- Prior art keywords
- factor viii
- amino acid
- modified
- human
- substitution
- 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.)
- Pending
Links
- 102000001690 Factor VIII Human genes 0.000 title claims abstract description 349
- 108010054218 Factor VIII Proteins 0.000 title claims abstract description 348
- 229960000301 factor viii Drugs 0.000 title claims abstract description 343
- 102000002110 C2 domains Human genes 0.000 title claims description 38
- 108050009459 C2 domains Proteins 0.000 title claims description 38
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract description 76
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims abstract description 69
- 102000057593 human F8 Human genes 0.000 claims abstract description 68
- 229960000900 human factor viii Drugs 0.000 claims abstract description 68
- 238000006467 substitution reaction Methods 0.000 claims abstract description 58
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 35
- 230000000694 effects Effects 0.000 claims abstract description 32
- 235000001014 amino acid Nutrition 0.000 claims description 71
- 238000000034 method Methods 0.000 claims description 55
- 230000035602 clotting Effects 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 26
- 150000001413 amino acids Chemical class 0.000 claims description 22
- 230000005847 immunogenicity Effects 0.000 claims description 15
- 230000002829 reductive effect Effects 0.000 claims description 15
- 235000004279 alanine Nutrition 0.000 claims description 13
- 150000007523 nucleic acids Chemical class 0.000 claims description 13
- 108020004707 nucleic acids Proteins 0.000 claims description 12
- 102000039446 nucleic acids Human genes 0.000 claims description 12
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 9
- 230000007423 decrease Effects 0.000 claims description 7
- 239000013604 expression vector Substances 0.000 claims description 5
- 102000003839 Human Proteins Human genes 0.000 claims description 4
- 108090000144 Human Proteins Proteins 0.000 claims description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical group C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 3
- 230000003247 decreasing effect Effects 0.000 claims description 3
- 230000009257 reactivity Effects 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical group OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical group CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 2
- 241000283984 Rodentia Species 0.000 claims description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Chemical group OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 5
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Chemical group NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 4
- 239000004472 Lysine Chemical group 0.000 claims 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 4
- 230000002947 procoagulating effect Effects 0.000 claims 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 claims 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims 1
- 208000009292 Hemophilia A Diseases 0.000 abstract description 35
- 208000031220 Hemophilia Diseases 0.000 abstract description 25
- 238000011282 treatment Methods 0.000 abstract description 14
- 210000002381 plasma Anatomy 0.000 description 38
- 108090000623 proteins and genes Proteins 0.000 description 38
- 238000003556 assay Methods 0.000 description 33
- 102000004169 proteins and genes Human genes 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 27
- 239000003112 inhibitor Substances 0.000 description 27
- 235000018102 proteins Nutrition 0.000 description 25
- 241001465754 Metazoa Species 0.000 description 24
- 108020004414 DNA Proteins 0.000 description 19
- 210000004369 blood Anatomy 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- 239000012634 fragment Substances 0.000 description 16
- 238000011084 recovery Methods 0.000 description 14
- 108010061932 Factor VIIIa Proteins 0.000 description 12
- 206010053567 Coagulopathies Diseases 0.000 description 11
- 239000002299 complementary DNA Substances 0.000 description 11
- 239000012528 membrane Substances 0.000 description 11
- 201000003542 Factor VIII deficiency Diseases 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 238000001802 infusion Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 239000013598 vector Substances 0.000 description 9
- 208000032843 Hemorrhage Diseases 0.000 description 7
- 108091028043 Nucleic acid sequence Proteins 0.000 description 7
- 108090000190 Thrombin Proteins 0.000 description 7
- 125000000539 amino acid group Chemical group 0.000 description 7
- 208000034158 bleeding Diseases 0.000 description 7
- 230000000740 bleeding effect Effects 0.000 description 7
- 150000003904 phospholipids Chemical class 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 230000023555 blood coagulation Effects 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 229960004072 thrombin Drugs 0.000 description 6
- 108010047303 von Willebrand Factor Proteins 0.000 description 6
- 102100036537 von Willebrand factor Human genes 0.000 description 6
- 229960001134 von willebrand factor Drugs 0.000 description 6
- 108010014173 Factor X Proteins 0.000 description 5
- 108010074860 Factor Xa Proteins 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 108010048049 Factor IXa Proteins 0.000 description 4
- 108010076504 Protein Sorting Signals Proteins 0.000 description 4
- 230000000890 antigenic effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 108091026890 Coding region Proteins 0.000 description 3
- 241000699800 Cricetinae Species 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108010014172 Factor V Proteins 0.000 description 3
- 108020004511 Recombinant DNA Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 241000282898 Sus scrofa Species 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 238000011109 contamination Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 238000003018 immunoassay Methods 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 210000003292 kidney cell Anatomy 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 238000002703 mutagenesis Methods 0.000 description 3
- 231100000350 mutagenesis Toxicity 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000001177 retroviral effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 241000699802 Cricetulus griseus Species 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 108010094028 Prothrombin Proteins 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000023597 hemostasis Effects 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 230000000951 immunodiffusion Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000014508 negative regulation of coagulation Effects 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000003805 procoagulant Substances 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 108010012557 prothrombin complex concentrates Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical group CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- 208000033316 Acquired hemophilia A Diseases 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108010075016 Ceruloplasmin Proteins 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 102000012410 DNA Ligases Human genes 0.000 description 1
- 108010061982 DNA Ligases Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 101710172064 Low-density lipoprotein receptor-related protein Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108010002747 Pfu DNA polymerase Proteins 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 108091036333 Rapid DNA Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 210000001766 X chromosome Anatomy 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000013633 acquired hemophilia Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 235000021120 animal protein Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001124 arachidoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 238000007820 coagulation assay 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
- 230000002860 competitive effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000005584 early death Effects 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- -1 linker amino acids Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 229940024790 prothrombin complex concentrate Drugs 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 239000006163 transport media Substances 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000008299 viral mechanism Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Images
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
- 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)
- Hematology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33456901P | 2001-11-30 | 2001-11-30 | |
| PCT/US2002/037884 WO2003047507A2 (en) | 2001-11-30 | 2002-11-27 | Factor viii c2 domain variants |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2005511038A true JP2005511038A (ja) | 2005-04-28 |
| JP2005511038A5 JP2005511038A5 (enExample) | 2005-12-22 |
Family
ID=23307813
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2003548768A Pending JP2005511038A (ja) | 2001-11-30 | 2002-11-27 | 第ｖｉｉｉ因子ｃ２ドメインのバリアント |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20040249134A1 (enExample) |
| EP (1) | EP1456235A4 (enExample) |
| JP (1) | JP2005511038A (enExample) |
| CN (1) | CN1630666A (enExample) |
| AU (1) | AU2002364509A1 (enExample) |
| CA (1) | CA2462966A1 (enExample) |
| MX (1) | MXPA04005079A (enExample) |
| WO (1) | WO2003047507A2 (enExample) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013541521A (ja) * | 2010-09-15 | 2013-11-14 | ノヴォ ノルディスク アー／エス | 細胞取込みが低下した第ｖｉｉｉ因子変異体 |
| WO2025164792A1 (ja) * | 2024-02-02 | 2025-08-07 | 学校法人自治医科大学 | 高比活性／高分泌発現型の第ｖｉｉｉ因子改変体、高発現型の第ｖｉｉｉ因子コード核酸及びそれらの用途 |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7560107B2 (en) | 1996-06-26 | 2009-07-14 | Emory University | Modified factor VIII |
| US6458563B1 (en) * | 1996-06-26 | 2002-10-01 | Emory University | Modified factor VIII |
| US7485291B2 (en) | 2003-06-03 | 2009-02-03 | Cell Genesys, Inc. | Compositions and methods for generating multiple polypeptides from a single vector using a virus derived peptide cleavage site, and uses thereof |
| WO2005017149A1 (en) | 2003-06-03 | 2005-02-24 | Cell Genesys, Inc. | Compositions and methods for enhanced expression of recombinant polypeptides from a single vector using a peptide cleavage site |
| US20050123997A1 (en) * | 2003-10-30 | 2005-06-09 | Lollar John S. | Modified fVIII having reduced immunogenicity through mutagenesis of A2 and C2 epitopes |
| PL1750733T3 (pl) * | 2004-05-03 | 2014-05-30 | Univ Emory | Sposób podawania świńskiego czynnika krzepnięcia VIII pozbawionego domeny B |
| MY185597A (en) * | 2005-09-20 | 2021-05-24 | Avantor Performance Mat Inc | Vegetarian protein a preparation and methods thereof |
| FR2913020B1 (fr) * | 2007-02-23 | 2012-11-23 | Biomethodes | Nouveaux facteurs viii pour le traitement des hemophiles de type a |
| IT1394522B1 (it) | 2009-01-09 | 2012-07-05 | Invatec Technology Ct Gmbh | Dispositivo medicale con rilascio di farmaco |
| CA2780763A1 (en) * | 2009-11-13 | 2011-05-19 | Puget Sound Blood Center | Factor viii b cell epitope variants having reduced immunogenicity |
| RU2579977C2 (ru) | 2009-11-13 | 2016-04-10 | Грифольс Терапьютикс Инк. | СОДЕРЖАЩИЕ ФАКТОР ФОН ВИЛЛЕБРАНДА (vWF) ПРЕПАРАТЫ И СПОСОБЫ, НАБОРЫ И ПРИМЕНЕНИЯ, СВЯЗАННЫЕ С НИМИ |
| BR112013011041B1 (pt) | 2010-11-05 | 2021-05-25 | Baxalta GmbH | variante de fator viii, método para produzir uma variante de fviii, uso da variante de fator viii, e, composição farmacêutica |
| EP3107561A4 (en) * | 2014-02-19 | 2017-12-20 | Bloodworks | Factor viii b cell epitope variants having reduced immunogenicity |
| EP3114138B1 (en) | 2014-03-05 | 2021-11-17 | Pfizer Inc. | Improved muteins of clotting factor viii |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4757006A (en) * | 1983-10-28 | 1988-07-12 | Genetics Institute, Inc. | Human factor VIII:C gene and recombinant methods for production |
| US4965199A (en) * | 1984-04-20 | 1990-10-23 | Genentech, Inc. | Preparation of functional human factor VIII in mammalian cells using methotrexate based selection |
| MX9203440A (es) * | 1985-04-12 | 1992-07-01 | Genetics Inst | Proteinas procoagulantes novedosas. |
| US5004803A (en) * | 1988-11-14 | 1991-04-02 | Genetics Institute, Inc. | Production of procoagulant proteins |
| US5663060A (en) * | 1992-04-07 | 1997-09-02 | Emory University | Hybrid human/animal factor VIII |
| US6180371B1 (en) * | 1996-06-26 | 2001-01-30 | Emory University | Modified factor VIII |
| US5888974A (en) * | 1992-04-07 | 1999-03-30 | Emory University | Hybrid human/animal factor VIII |
| US5364771A (en) * | 1992-04-07 | 1994-11-15 | Emory University | Hybrid human/porcine factor VIII |
| US5744446A (en) * | 1992-04-07 | 1998-04-28 | Emory University | Hybrid human/animal factor VIII |
| US6376463B1 (en) * | 1992-04-07 | 2002-04-23 | Emory University | Modified factor VIII |
| US5859204A (en) * | 1992-04-07 | 1999-01-12 | Emory University | Modified factor VIII |
| US6458563B1 (en) * | 1996-06-26 | 2002-10-01 | Emory University | Modified factor VIII |
| PL206105B1 (pl) * | 2000-09-19 | 2010-07-30 | Emory Universityemory University | Zmodyfikowany ludzki czynnik VIII oraz sposób modyfikacji ludzkiego czynnika VIII ze zmniejszeniem reaktywności na przeciwciało hamujące i zachowaniem aktywności prokoagulacyjnej |
-
2002
- 2002-11-27 US US10/491,464 patent/US20040249134A1/en not_active Abandoned
- 2002-11-27 WO PCT/US2002/037884 patent/WO2003047507A2/en not_active Ceased
- 2002-11-27 AU AU2002364509A patent/AU2002364509A1/en not_active Abandoned
- 2002-11-27 EP EP02799885A patent/EP1456235A4/en not_active Withdrawn
- 2002-11-27 CA CA002462966A patent/CA2462966A1/en not_active Abandoned
- 2002-11-27 MX MXPA04005079A patent/MXPA04005079A/es not_active Application Discontinuation
- 2002-11-27 JP JP2003548768A patent/JP2005511038A/ja active Pending
- 2002-11-27 CN CNA028238451A patent/CN1630666A/zh active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013541521A (ja) * | 2010-09-15 | 2013-11-14 | ノヴォ ノルディスク アー／エス | 細胞取込みが低下した第ｖｉｉｉ因子変異体 |
| JP2016180002A (ja) * | 2010-09-15 | 2016-10-13 | ノヴォ ノルディスク アー／エス | 細胞取込みが低下した第ｖｉｉｉ因子変異体 |
| WO2025164792A1 (ja) * | 2024-02-02 | 2025-08-07 | 学校法人自治医科大学 | 高比活性／高分泌発現型の第ｖｉｉｉ因子改変体、高発現型の第ｖｉｉｉ因子コード核酸及びそれらの用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA04005079A (es) | 2004-08-19 |
| AU2002364509A1 (en) | 2003-06-17 |
| CN1630666A (zh) | 2005-06-22 |
| WO2003047507A3 (en) | 2003-07-17 |
| WO2003047507A2 (en) | 2003-06-12 |
| CA2462966A1 (en) | 2003-06-12 |
| US20040249134A1 (en) | 2004-12-09 |
| EP1456235A4 (en) | 2005-08-17 |
| EP1456235A2 (en) | 2004-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6770744B2 (en) | Modified factor VIII | |
| JP4044337B2 (ja) | 修飾された第ｖｉｉｉ因子 | |
| EP0749444B1 (en) | Hybrid human/animal factor viii | |
| US5744446A (en) | Hybrid human/animal factor VIII | |
| US5859204A (en) | Modified factor VIII | |
| US6838437B2 (en) | Inactivation resistant factor VIII | |
| AU682147B2 (en) | Hybrid human/porcine factor VIII | |
| US20050123997A1 (en) | Modified fVIII having reduced immunogenicity through mutagenesis of A2 and C2 epitopes | |
| US20120190623A1 (en) | Inactivation Resistant Factor VIII | |
| JP2005500831A (ja) | 操作されたジスルフィド結合を有する安定化蛋白質 | |
| US20040092442A1 (en) | Inactivation resistant factor VIII | |
| WO1999046274A1 (en) | Modified factor viii | |
| WO2003047507A2 (en) | Factor viii c2 domain variants | |
| US5888974A (en) | Hybrid human/animal factor VIII | |
| US20030148953A1 (en) | Inactivation resistant factor VIII | |
| HK1078596A (en) | Modified factor viii |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20050907 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20080916 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20090310 |