RU2528855C2 - Модифицированный фактор виллебранда с удлиненным полупериодом существования in vivo, его применения и способы получения - Google Patents
Модифицированный фактор виллебранда с удлиненным полупериодом существования in vivo, его применения и способы получения Download PDFInfo
- Publication number
- RU2528855C2 RU2528855C2 RU2011102366/10A RU2011102366A RU2528855C2 RU 2528855 C2 RU2528855 C2 RU 2528855C2 RU 2011102366/10 A RU2011102366/10 A RU 2011102366/10A RU 2011102366 A RU2011102366 A RU 2011102366A RU 2528855 C2 RU2528855 C2 RU 2528855C2
- Authority
- RU
- Russia
- Prior art keywords
- vwf
- fviii
- modified
- life
- wild
- Prior art date
Links
- 108010047303 von Willebrand Factor Proteins 0.000 title claims abstract description 409
- 102100036537 von Willebrand factor Human genes 0.000 title claims abstract description 407
- 229960001134 von willebrand factor Drugs 0.000 title claims abstract description 400
- 238000001727 in vivo Methods 0.000 title claims description 46
- 238000000034 method Methods 0.000 title claims description 23
- 230000002035 prolonged effect Effects 0.000 title abstract 2
- 102000009027 Albumins Human genes 0.000 claims abstract description 74
- 108010088751 Albumins Proteins 0.000 claims abstract description 74
- 210000004899 c-terminal region Anatomy 0.000 claims abstract description 46
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000013519 translation Methods 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 230000001965 increasing effect Effects 0.000 claims description 58
- 108090000623 proteins and genes Proteins 0.000 claims description 57
- 210000004027 cell Anatomy 0.000 claims description 50
- 102000004169 proteins and genes Human genes 0.000 claims description 49
- 108091033319 polynucleotide Proteins 0.000 claims description 40
- 102000040430 polynucleotide Human genes 0.000 claims description 40
- 239000002157 polynucleotide Substances 0.000 claims description 39
- 239000000427 antigen Substances 0.000 claims description 37
- 108091007433 antigens Proteins 0.000 claims description 37
- 102000036639 antigens Human genes 0.000 claims description 37
- 239000013598 vector Substances 0.000 claims description 30
- 230000004071 biological effect Effects 0.000 claims description 27
- 208000009292 Hemophilia A Diseases 0.000 claims description 23
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims description 20
- 102100026735 Coagulation factor VIII Human genes 0.000 claims description 16
- 201000003542 Factor VIII deficiency Diseases 0.000 claims description 16
- 239000013604 expression vector Substances 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 208000031169 hemorrhagic disease Diseases 0.000 claims description 9
- 238000001415 gene therapy Methods 0.000 claims description 6
- 239000001963 growth medium Substances 0.000 claims description 6
- 230000023555 blood coagulation Effects 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 210000002381 plasma Anatomy 0.000 abstract description 30
- 230000000694 effects Effects 0.000 abstract description 26
- 239000000126 substance Substances 0.000 abstract description 10
- 230000015271 coagulation Effects 0.000 abstract description 7
- 238000005345 coagulation Methods 0.000 abstract description 7
- 238000010188 recombinant method Methods 0.000 abstract 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 99
- 102000004196 processed proteins & peptides Human genes 0.000 description 88
- 229920001184 polypeptide Polymers 0.000 description 85
- 235000018102 proteins Nutrition 0.000 description 48
- 235000001014 amino acid Nutrition 0.000 description 46
- 229940024606 amino acid Drugs 0.000 description 41
- 150000001413 amino acids Chemical class 0.000 description 39
- 239000012634 fragment Substances 0.000 description 36
- 230000004927 fusion Effects 0.000 description 34
- 108020001507 fusion proteins Proteins 0.000 description 29
- 102000037865 fusion proteins Human genes 0.000 description 29
- 239000000872 buffer Substances 0.000 description 24
- 230000014509 gene expression Effects 0.000 description 24
- 239000013612 plasmid Substances 0.000 description 23
- 102000008100 Human Serum Albumin Human genes 0.000 description 22
- 108091006905 Human Serum Albumin Proteins 0.000 description 22
- 238000003776 cleavage reaction Methods 0.000 description 22
- 230000007017 scission Effects 0.000 description 22
- 230000001225 therapeutic effect Effects 0.000 description 20
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 17
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 17
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 17
- 208000027276 Von Willebrand disease Diseases 0.000 description 17
- 239000003114 blood coagulation factor Substances 0.000 description 17
- 238000003780 insertion Methods 0.000 description 17
- 230000037431 insertion Effects 0.000 description 17
- 208000012137 von Willebrand disease (hereditary or acquired) Diseases 0.000 description 17
- 125000003275 alpha amino acid group Chemical group 0.000 description 15
- 239000002299 complementary DNA Substances 0.000 description 15
- 238000012217 deletion Methods 0.000 description 15
- 230000037430 deletion Effects 0.000 description 15
- 229940027941 immunoglobulin g Drugs 0.000 description 14
- 108020004414 DNA Proteins 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 12
- 239000008280 blood Substances 0.000 description 12
- 238000003752 polymerase chain reaction Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 108010054218 Factor VIII Proteins 0.000 description 11
- 102000001690 Factor VIII Human genes 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 108060003951 Immunoglobulin Proteins 0.000 description 9
- 241000700605 Viruses Species 0.000 description 9
- 102000018358 immunoglobulin Human genes 0.000 description 9
- 230000004048 modification Effects 0.000 description 9
- 238000012986 modification Methods 0.000 description 9
- 230000035772 mutation Effects 0.000 description 9
- 102100023635 Alpha-fetoprotein Human genes 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 230000028327 secretion Effects 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 7
- 238000002965 ELISA Methods 0.000 description 7
- 108090001126 Furin Proteins 0.000 description 7
- 239000004471 Glycine Substances 0.000 description 7
- 208000031220 Hemophilia Diseases 0.000 description 7
- 238000004113 cell culture Methods 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 239000013613 expression plasmid Substances 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 238000001802 infusion Methods 0.000 description 7
- 238000010253 intravenous injection Methods 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000003259 recombinant expression Methods 0.000 description 7
- 108010076504 Protein Sorting Signals Proteins 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 108090000190 Thrombin Proteins 0.000 description 6
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 6
- 229940105778 coagulation factor viii Drugs 0.000 description 6
- 238000006471 dimerization reaction Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 150000007523 nucleic acids Chemical class 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 230000006337 proteolytic cleavage Effects 0.000 description 6
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 238000002741 site-directed mutagenesis Methods 0.000 description 6
- 230000000087 stabilizing effect Effects 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229960004072 thrombin Drugs 0.000 description 6
- 102000008186 Collagen Human genes 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- 101150074155 DHFR gene Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 102000035195 Peptidases Human genes 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- 239000004365 Protease Substances 0.000 description 5
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 5
- 210000004102 animal cell Anatomy 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 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 5
- 239000003550 marker Substances 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 235000004400 serine Nutrition 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- PSLCKQYQNVNTQI-BHFSHLQUSA-N (2s)-2-aminobutanedioic acid;(2s)-2-aminopentanedioic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CCC(O)=O PSLCKQYQNVNTQI-BHFSHLQUSA-N 0.000 description 4
- 102000043853 ADAMTS13 Human genes 0.000 description 4
- 108091005670 ADAMTS13 Proteins 0.000 description 4
- 241000282693 Cercopithecidae Species 0.000 description 4
- 102100035233 Furin Human genes 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 101100156611 Homo sapiens VWF gene Proteins 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000012228 culture supernatant Substances 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 229960000301 factor viii Drugs 0.000 description 4
- 230000023597 hemostasis Effects 0.000 description 4
- 102000057593 human F8 Human genes 0.000 description 4
- 230000002779 inactivation Effects 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000002028 premature Effects 0.000 description 4
- 230000002797 proteolythic effect Effects 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108091008146 restriction endonucleases Proteins 0.000 description 4
- 238000013207 serial dilution Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000002103 transcriptional effect Effects 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 208000015316 von Willebrand disease 3 Diseases 0.000 description 4
- 102000002110 C2 domains Human genes 0.000 description 3
- 108050009459 C2 domains Proteins 0.000 description 3
- 102100022641 Coagulation factor IX Human genes 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 102000004961 Furin Human genes 0.000 description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 108010021466 Mutant Proteins Proteins 0.000 description 3
- 102000008300 Mutant Proteins Human genes 0.000 description 3
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 208000026552 Severe hemophilia A Diseases 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- -1 afamine Proteins 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000007068 beta-elimination reaction Methods 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 238000007820 coagulation assay Methods 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 230000002439 hemostatic effect Effects 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 238000004255 ion exchange chromatography Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000006320 pegylation Effects 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229950010131 puromycin Drugs 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 108020004635 Complementary DNA Proteins 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 2
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 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
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 239000012097 Lipofectamine 2000 Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 102000050760 Vitamin D-binding protein Human genes 0.000 description 2
- 101710179590 Vitamin D-binding protein Proteins 0.000 description 2
- 210000001766 X chromosome Anatomy 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 239000011543 agarose gel Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000011210 chromatographic step Methods 0.000 description 2
- 239000003593 chromogenic compound Substances 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000005966 endogenous activation Effects 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 210000002288 golgi apparatus Anatomy 0.000 description 2
- 208000009429 hemophilia B Diseases 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000012743 protein tagging Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000009790 rate-determining step (RDS) Methods 0.000 description 2
- 238000009256 replacement therapy Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000012898 sample dilution Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 150000003355 serines Chemical class 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- 208000017129 von Willebrand disease 2 Diseases 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- YUXKOWPNKJSTPQ-AXWWPMSFSA-N (2s,3r)-2-amino-3-hydroxybutanoic acid;(2s)-2-amino-3-hydroxypropanoic acid Chemical compound OC[C@H](N)C(O)=O.C[C@@H](O)[C@H](N)C(O)=O YUXKOWPNKJSTPQ-AXWWPMSFSA-N 0.000 description 1
- 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 1
- BMGWZHWESYHXHC-UHFFFAOYSA-N 2-amino-3-methylpentanoic acid;2-amino-4-methylpentanoic acid Chemical compound CCC(C)C(N)C(O)=O.CC(C)CC(N)C(O)=O BMGWZHWESYHXHC-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 108010087504 Beta-Globulins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 102100037840 Dehydrogenase/reductase SDR family member 2, mitochondrial Human genes 0.000 description 1
- 229920002307 Dextran Polymers 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
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 108091092566 Extrachromosomal DNA Proteins 0.000 description 1
- 108010079356 FIIa Proteins 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010048049 Factor IXa Proteins 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 102400000321 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 101150112743 HSPA5 gene Proteins 0.000 description 1
- 102000008055 Heparan Sulfate Proteoglycans Human genes 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 241000829111 Human polyomavirus 1 Species 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 229930010555 Inosine Natural products 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
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108010025815 Kanamycin Kinase Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 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
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000033375 Moderate hemophilia A Diseases 0.000 description 1
- 102000005431 Molecular Chaperones Human genes 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 101710176384 Peptide 1 Proteins 0.000 description 1
- 102000015795 Platelet Membrane Glycoproteins Human genes 0.000 description 1
- 108010010336 Platelet Membrane Glycoproteins Proteins 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 102000017975 Protein C Human genes 0.000 description 1
- 101710188053 Protein D Proteins 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 101710132893 Resolvase Proteins 0.000 description 1
- 101100111629 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) KAR2 gene Proteins 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 239000012506 Sephacryl® Substances 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 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
- 108090000054 Syndecan-2 Proteins 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 108700029229 Transcriptional Regulatory Elements Proteins 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 101150045640 VWF gene Proteins 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 208000034286 Von Willebrand disease type 3 Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 102000005421 acetyltransferase Human genes 0.000 description 1
- 108020002494 acetyltransferase Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 102000006646 aminoglycoside phosphotransferase Human genes 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 229940019700 blood coagulation factors Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 108090001015 cancer procoagulant Proteins 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229910010293 ceramic material Inorganic materials 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 230000001112 coagulating effect Effects 0.000 description 1
- 229940105774 coagulation factor ix Drugs 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 101150028578 grp78 gene Proteins 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 229940076144 interleukin-10 Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000031852 maintenance of location in cell Effects 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 210000003593 megakaryocyte Anatomy 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 238000012433 multimodal chromatography Methods 0.000 description 1
- 238000001728 nano-filtration Methods 0.000 description 1
- 238000001821 nucleic acid purification Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 238000002732 pharmacokinetic assay Methods 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
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000003805 procoagulant Substances 0.000 description 1
- 230000002947 procoagulating effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 230000002885 thrombogenetic effect Effects 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000014599 transmission of virus Effects 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 208000020294 von Willebrand disease 1 Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000034365 zymogen activation Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- 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
- C07K14/76—Albumins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
-
- 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
-
- 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)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Diabetes (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08011429 | 2008-06-24 | ||
| EP08011429.1 | 2008-06-24 | ||
| PCT/EP2009/004549 WO2009156137A1 (en) | 2008-06-24 | 2009-06-24 | Factor viii, von willebrand factor or complexes thereof with prolonged in vivo half-life |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2011102366A RU2011102366A (ru) | 2012-07-27 |
| RU2528855C2 true RU2528855C2 (ru) | 2014-09-20 |
Family
ID=40042814
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2011102366/10A RU2528855C2 (ru) | 2008-06-24 | 2009-06-24 | Модифицированный фактор виллебранда с удлиненным полупериодом существования in vivo, его применения и способы получения |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US8575104B2 (enExample) |
| EP (2) | EP2865760B1 (enExample) |
| JP (1) | JP5832285B2 (enExample) |
| KR (2) | KR101507718B1 (enExample) |
| CN (2) | CN102076855A (enExample) |
| AU (1) | AU2009262476C1 (enExample) |
| CA (1) | CA2728012C (enExample) |
| DK (2) | DK2291523T3 (enExample) |
| ES (2) | ES2654336T3 (enExample) |
| PL (1) | PL2291523T3 (enExample) |
| RU (1) | RU2528855C2 (enExample) |
| WO (1) | WO2009156137A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2766118C2 (ru) * | 2017-07-07 | 2022-02-08 | Такеда Фармасьютикал Компани Лимитед | Лечение пациентов с тяжелой формой болезни фон виллебранда, подвергающихся плановому хирургическому вмешательству, путем введения рекомбинантного ффв |
Families Citing this family (49)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6263355A (ja) * | 1985-09-13 | 1987-03-20 | Hitachi Ltd | バツテリバツクアツプｒａｍのチエツク方法 |
| AU2009262476C1 (en) | 2008-06-24 | 2016-06-02 | Csl Behring Gmbh | Factor VIII, von Willebrand factor or complexes thereof with prolonged in vivo half-life |
| US20110046060A1 (en) | 2009-08-24 | 2011-02-24 | Amunix Operating, Inc., | Coagulation factor IX compositions and methods of making and using same |
| 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 |
| US20130040888A1 (en) | 2010-02-16 | 2013-02-14 | Novo Nordisk A/S | Factor VIII Molecules With Reduced VWF Binding |
| EP2536752B1 (en) | 2010-02-16 | 2015-04-08 | Novo Nordisk A/S | Modified recombinant Factor VIII |
| EP2977055A1 (en) | 2010-02-16 | 2016-01-27 | Novo Nordisk A/S | Factor viii fusion protein |
| WO2011150284A2 (en) | 2010-05-26 | 2011-12-01 | Baxter International Inc. | Removal of serine proteases by treatment with finely divided silicon dioxide |
| AU2010202125B1 (en) | 2010-05-26 | 2010-09-02 | Takeda Pharmaceutical Company Limited | A method to produce an immunoglobulin preparation with improved yield |
| EP3858375B1 (en) * | 2011-06-10 | 2024-03-20 | Takeda Pharmaceutical Company Limited | Treatment of coagulation disease by administration of recombinant vwf |
| HRP20191920T1 (hr) * | 2012-01-12 | 2020-01-10 | Bioverativ Therapeutics Inc. | Kimerni polipeptidi faktora viii i njihova uporaba |
| EP2814955A1 (en) * | 2012-02-14 | 2014-12-24 | Portola Pharmaceuticals, Inc. | Process for making recombinant antidote to factor xa inhibitor |
| WO2013123457A1 (en) * | 2012-02-15 | 2013-08-22 | Biogen Idec Ma Inc. | Recombinant factor viii proteins |
| CN119192402A (zh) * | 2012-02-15 | 2024-12-27 | 比奥贝拉蒂治疗公司 | 因子viii组合物及其制备和使用方法 |
| PL2814502T3 (pl) | 2012-02-15 | 2018-02-28 | Csl Behring Gmbh | Warianty czynnika von Willebranda mające ulepszone powinowactwo do wiązania czynnika VIII |
| JP2015515482A (ja) | 2012-04-24 | 2015-05-28 | ノヴォ ノルディスク アー／エス | 血友病の治療に適する化合物 |
| PL2882450T3 (pl) * | 2012-07-11 | 2020-06-29 | Bioverativ Therapeutics Inc. | Kompleks czynnika viii z xten i białkiem czynnika von willebranda oraz jego zastosowania |
| ES2657291T3 (es) * | 2013-04-22 | 2018-03-02 | Csl Ltd. | Un complejo covalente de factor de von Willebrand y factor VIII asociado por un puente disulfuro |
| US10231993B2 (en) | 2013-06-27 | 2019-03-19 | University Of Washington Through Its Center For Commercialization | Biocompatible polymeric system for targeted treatment of thrombotic and hemostatic disorders |
| US20160229903A1 (en) * | 2013-06-28 | 2016-08-11 | Biogen Ma Inc. | Thrombin cleavable linker |
| AU2014302100B2 (en) * | 2013-06-28 | 2020-02-13 | Bioverativ Therapeutics Inc. | Thrombin cleavable linker with XTEN and its uses thereof |
| WO2015023891A2 (en) | 2013-08-14 | 2015-02-19 | Biogen Idec Ma Inc. | Factor viii-xten fusions and uses thereof |
| US10246485B2 (en) | 2013-11-08 | 2019-04-02 | Csl Limited | Method to concentrate von willebrand factor or complexes thereof |
| FI4176894T3 (fi) * | 2014-01-10 | 2024-05-29 | Bioverativ Therapeutics Inc | Kimeerisiä tekijä viii -proteiineja ja niiden käyttötarkoituksia |
| US10829539B2 (en) | 2014-06-13 | 2020-11-10 | Csl Limited | Production of recombinant von Willebrand factor in a bioreactor |
| DE102014011653A1 (de) * | 2014-06-20 | 2015-12-24 | Ulrich Loos | Nachweis von Autoantikörpern gegen den TSH-Rezeptor |
| BR112016030950A2 (pt) | 2014-07-02 | 2018-03-27 | Csl Ltd | polipeptídeo modificado que se liga ao fator viii, complexo, composição farmacêutica, métodos para tratar uma coagulopatia, para produzir um polipeptídeo que compreende um vwf modificado e para aumentar a afinidade de ligação ao fator viii do vwf e a meia-vida do fator viii, uso de um polipeptídeo modificado ou de um complexo, polinucleotídeo, plasmídeo ou vetor, e, célula hospedeira. |
| US10626164B2 (en) | 2014-07-25 | 2020-04-21 | Csl Limited | Purification of VWF |
| KR102554850B1 (ko) * | 2015-02-06 | 2023-07-13 | 더 유니버시티 오브 노쓰 캐롤라이나 엣 채플 힐 | 최적화된 인간 응고 인자 viii 유전자 발현 카세트 및 그의 용도 |
| CN107406493B (zh) | 2015-03-06 | 2021-08-13 | 康诺贝林伦瑙有限公司 | 具有改善的半衰期的经修饰的血管性血友病因子 |
| RU2017145002A (ru) | 2015-05-22 | 2019-06-24 | Цсл Беринг Ленгнау Аг | Способы получения модифицированного фактора фон виллебранда |
| JP6573989B2 (ja) | 2015-05-22 | 2019-09-11 | ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト | 血友病を処置するための切断型フォン・ヴィルブランド因子ポリペプチド |
| CA2994547A1 (en) | 2015-08-03 | 2017-02-09 | Bioverativ Therapeutics Inc. | Factor ix fusion proteins and methods of making and using same |
| WO2017112895A1 (en) * | 2015-12-23 | 2017-06-29 | Haplomics, Inc. | F8 gene repair |
| CN108779165B (zh) * | 2016-01-07 | 2022-12-02 | 康诺贝林伦瑙有限公司 | 突变的冯·维勒布兰德因子 |
| JP6851381B6 (ja) * | 2016-01-07 | 2021-04-21 | ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト | 変異切断型フォンウィルブランド因子 |
| CN109152817A (zh) * | 2016-05-20 | 2019-01-04 | 瑞士奥克特珐玛公司 | 具有改进的药代动力学的糖基化vwf融合蛋白 |
| KR102175878B1 (ko) * | 2016-06-24 | 2020-11-06 | 재단법인 목암생명과학연구소 | Fviii 및 vwf 인자를 포함하는 키메라 단백질 및 그 용도 |
| EP3538133B1 (en) | 2016-11-11 | 2021-02-17 | CSL Behring Lengnau AG | Truncated von willebrand factor polypeptides for treating hemophilia |
| ES2908008T3 (es) | 2016-11-11 | 2022-04-27 | CSL Behring Lengnau AG | Polipéptidos truncados del Factor de von Willebrand para su administración extravascular en el tratamiento o profilaxis de un trastorno de la coagulación sanguínea |
| US12161696B2 (en) | 2016-12-02 | 2024-12-10 | Bioverativ Therapeutics Inc. | Methods of treating hemophilic arthropathy using chimeric clotting factors |
| KR20200018690A (ko) | 2017-06-22 | 2020-02-19 | 체에스엘 베링 렝나우 아게 | 절단된 vwf에 의한 fviii 면역원성의 조절 |
| AU2018298233B2 (en) | 2017-07-07 | 2025-04-24 | Takeda Pharmaceutical Company Limited | Treatment of gastrointestinal bleeding in patients with severe von willebrand disease by administration of recombinant VWF |
| CN110997015A (zh) | 2017-08-23 | 2020-04-10 | 德国杰特贝林生物制品有限公司 | 用于von Willebrand因子的病毒过滤的方法 |
| TW202015723A (zh) | 2018-05-18 | 2020-05-01 | 美商百歐維拉提夫治療公司 | 治療ａ型血友病的方法 |
| BR112021012318A2 (pt) * | 2018-12-23 | 2022-01-18 | Csl Behring Llc | Células t doadoras com interruptor de eliminação |
| CA3128498A1 (en) | 2019-02-01 | 2020-08-06 | Bjorn Mellgard | Methods of prophylactic treatment using recombinant vwf (rvwf) |
| CN111592591B (zh) * | 2020-06-17 | 2021-12-14 | 博雅生物制药集团股份有限公司 | 一种人血管性血友病因子/人凝血因子ⅷ复合物的制备方法及产物和应用 |
| CN117720671B (zh) * | 2024-01-30 | 2024-06-14 | 南通大学 | 具有自组装性能的重复结构单元重组蛋白ⅠAⅠB-ⅠAⅠBrQTY及应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5364771A (en) * | 1992-04-07 | 1994-11-15 | Emory University | Hybrid human/porcine factor VIII |
| WO2001079271A1 (en) * | 2000-04-12 | 2001-10-25 | Principia Pharmaceutical Corporation | Albumin fusion proteins |
| EP1867660A1 (en) * | 2006-06-14 | 2007-12-19 | CSL Behring GmbH | Proteolytically cleavable fusion protein comprising a blood coagulation factor |
Family Cites Families (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4970300A (en) | 1985-02-01 | 1990-11-13 | New York University | Modified factor VIII |
| FR2673632A1 (fr) | 1991-03-08 | 1992-09-11 | Lille Transfusion Sanguine | Procede de preparation de concentre de facteur von willebrand humain de tres haute purete, approprie a un usage therapeutique. |
| FR2686899B1 (fr) | 1992-01-31 | 1995-09-01 | Rhone Poulenc Rorer Sa | Nouveaux polypeptides biologiquement actifs, leur preparation et compositions pharmaceutiques les contenant. |
| AU6029594A (en) | 1993-01-15 | 1994-08-15 | Enzon, Inc. | Factor viii - polymeric conjugates |
| DE4435485C1 (de) | 1994-10-04 | 1996-03-21 | Immuno Ag | Verfahren zur Gewinnung von hochreinem von Willebrand-Faktor |
| JPH11501506A (ja) | 1994-12-12 | 1999-02-09 | ベス イスラエル デアコネス メディカル センター | キメラ型サイトカインおよびその利用 |
| WO1997003193A1 (en) | 1995-07-11 | 1997-01-30 | Chiron Corporation | Novel factor viii:c polypeptide analogs with altered metal-binding properties |
| SE9503380D0 (sv) | 1995-09-29 | 1995-09-29 | Pharmacia Ab | Protein derivatives |
| GB9526733D0 (en) | 1995-12-30 | 1996-02-28 | Delta Biotechnology Ltd | Fusion proteins |
| AT403764B (de) * | 1996-03-15 | 1998-05-25 | Immuno Ag | Stabiler faktor viii/vwf-komplex |
| ATE319817T1 (de) | 1996-04-24 | 2006-03-15 | Univ Michigan | Gegen inaktivierung resistenter faktor viii |
| US20040092442A1 (en) | 1996-04-24 | 2004-05-13 | University Of Michigan | Inactivation resistant factor VIII |
| US6103077A (en) * | 1998-01-02 | 2000-08-15 | De Nora S.P.A. | Structures and methods of manufacture for gas diffusion electrodes and electrode components |
| AU747391B2 (en) | 1998-04-27 | 2002-05-16 | Cantab Biopharmaceuticals Patents Limited | Pharmaceutical composition comprising factor VIII and neutral liposomes |
| US6660843B1 (en) | 1998-10-23 | 2003-12-09 | Amgen Inc. | Modified peptides as therapeutic agents |
| EP1148063A1 (de) | 2000-04-18 | 2001-10-24 | Octapharma AG | Haemostatisch aktives vWF enthaltendes Präparat und Verfahren zu seiner Herstellung |
| AU2002248329B2 (en) | 2001-01-12 | 2007-06-28 | The American National Red Cross | Methods and compositions for reducing heparan sulfate proteoglycan-mediated clearance of factor VIII |
| AU2002310438B2 (en) | 2001-06-14 | 2008-05-01 | The Scripps Research Institute | Stabilized proteins with engineered disulfide bonds |
| EP1572936A2 (en) | 2002-03-05 | 2005-09-14 | Eli Lilly And Company | Heterologous g-csf fusion proteins |
| AU2003227687B2 (en) | 2002-04-29 | 2009-10-15 | Stichting Sanquin Bloedvoorziening | Antagonists of factor VIII interaction with low-density lipoprotein receptor-related protein |
| KR20110079741A (ko) * | 2002-12-09 | 2011-07-07 | 아브락시스 바이오사이언스, 엘엘씨 | 약리학적 물질의 조성물 및 그 전달방법 |
| EP1444986A1 (en) * | 2003-02-07 | 2004-08-11 | Aventis Behring GmbH | Pharmaceutical preparation for the improved treatment of blood-clotting disorders |
| EP2572733A1 (en) | 2003-02-26 | 2013-03-27 | Nektar Therapeutics | Polymer-factor VIII moiety conjugates |
| TWI353991B (en) | 2003-05-06 | 2011-12-11 | Syntonix Pharmaceuticals Inc | Immunoglobulin chimeric monomer-dimer hybrids |
| PT1624891E (pt) * | 2003-05-06 | 2010-01-05 | Syntonix Pharmaceuticals Inc | Proteínas quiméricas de factor de coagulação-fc destinadas ao tratamento da hemofilia |
| NZ543292A (en) | 2003-06-12 | 2008-04-30 | Lilly Co Eli | GLP-1 analog fusion proteins |
| EP1502921A1 (en) * | 2003-07-29 | 2005-02-02 | ZLB Behring GmbH | Recombinant mutated human factor VIII (FVIII) with improved stability |
| EP1670931A2 (en) * | 2003-09-05 | 2006-06-21 | GTC Biotherapeutics, Inc. | Method for the production of fusion proteins in transgenic mammal milk |
| JP2008504008A (ja) | 2003-12-31 | 2008-02-14 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | 改良された薬物動態を有するＦｃ−エリスロポエチン融合タンパク質 |
| US7670595B2 (en) | 2004-06-28 | 2010-03-02 | Merck Patent Gmbh | Fc-interferon-beta fusion proteins |
| LT1824988T (lt) | 2004-11-12 | 2017-10-25 | Bayer Healthcare Llc | Nukreipta į užduotą saitą fviii modifikacija |
| PL1835938T3 (pl) * | 2004-12-27 | 2014-01-31 | Baxalta Inc | Koniugaty polimer-czynnik von Willebrandta |
| JP2008537680A (ja) | 2005-04-14 | 2008-09-25 | ツェー・エス・エル・ベーリング・ゲー・エム・ベー・ハー | 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 |
| JPWO2007049749A1 (ja) | 2005-10-28 | 2009-04-30 | ディナベック株式会社 | 血液凝固異常の治療方法 |
| EP1816201A1 (en) | 2006-02-06 | 2007-08-08 | CSL Behring GmbH | Modified coagulation factor VIIa with extended half-life |
| CA2647314A1 (en) | 2006-03-31 | 2007-11-08 | Baxter International Inc. | Pegylated factor viii |
| EP3896090B1 (en) | 2006-06-14 | 2022-01-12 | CSL Behring GmbH | Proteolytically cleavable fusion protein comprising a blood coagulation factor |
| AU2009262476C1 (en) | 2008-06-24 | 2016-06-02 | Csl Behring Gmbh | Factor VIII, von Willebrand factor or complexes thereof with prolonged in vivo half-life |
| US9402754B2 (en) * | 2010-05-18 | 2016-08-02 | Abbott Cardiovascular Systems, Inc. | Expandable endoprostheses, systems, and methods for treating a bifurcated lumen |
| HRP20191920T1 (hr) | 2012-01-12 | 2020-01-10 | Bioverativ Therapeutics Inc. | Kimerni polipeptidi faktora viii i njihova uporaba |
| JP2015515482A (ja) | 2012-04-24 | 2015-05-28 | ノヴォ ノルディスク アー／エス | 血友病の治療に適する化合物 |
-
2009
- 2009-06-24 AU AU2009262476A patent/AU2009262476C1/en not_active Ceased
- 2009-06-24 PL PL09768986T patent/PL2291523T3/pl unknown
- 2009-06-24 ES ES14192277.3T patent/ES2654336T3/es active Active
- 2009-06-24 CN CN200980123818XA patent/CN102076855A/zh active Pending
- 2009-06-24 EP EP14192277.3A patent/EP2865760B1/en not_active Not-in-force
- 2009-06-24 DK DK09768986T patent/DK2291523T3/en active
- 2009-06-24 CN CN201310596839.1A patent/CN103739712B/zh not_active Expired - Fee Related
- 2009-06-24 US US13/000,938 patent/US8575104B2/en not_active Expired - Fee Related
- 2009-06-24 RU RU2011102366/10A patent/RU2528855C2/ru active
- 2009-06-24 JP JP2011515200A patent/JP5832285B2/ja not_active Expired - Fee Related
- 2009-06-24 DK DK14192277.3T patent/DK2865760T3/en active
- 2009-06-24 WO PCT/EP2009/004549 patent/WO2009156137A1/en not_active Ceased
- 2009-06-24 KR KR1020117001530A patent/KR101507718B1/ko not_active Expired - Fee Related
- 2009-06-24 ES ES09768986.3T patent/ES2531464T3/es active Active
- 2009-06-24 KR KR1020147018123A patent/KR101648734B1/ko not_active Expired - Fee Related
- 2009-06-24 CA CA2728012A patent/CA2728012C/en not_active Expired - Fee Related
- 2009-06-24 EP EP09768986.3A patent/EP2291523B1/en active Active
-
2013
- 2013-09-17 US US14/028,869 patent/US9290561B2/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5364771A (en) * | 1992-04-07 | 1994-11-15 | Emory University | Hybrid human/porcine factor VIII |
| WO2001079271A1 (en) * | 2000-04-12 | 2001-10-25 | Principia Pharmaceutical Corporation | Albumin fusion proteins |
| EP1867660A1 (en) * | 2006-06-14 | 2007-12-19 | CSL Behring GmbH | Proteolytically cleavable fusion protein comprising a blood coagulation factor |
Non-Patent Citations (2)
| Title |
|---|
| CHUANG V.T. ET AL., Pharmaceutical strategies utilizing recombinant human serum albumin, PHARM. RESEARCH, NY, 2002, v.19, n.5, p.569-577. * |
| GENSANA M. et al., Influence of von Willebrand factor on the reactivity of human factor VIII inhibitors with factor VIII, Haemophilia, 2001, v.7, n.4, p.369-374. BJORKMAN S. et al., Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia, Clin. Pharmacokinet., 2001, v.40, n.11, p.815-832. NOGAMI K. et al., A novel mechanism of factor VIII protection by von Willebrand factor from activated protein C-catalyzed inactivation, Blood, 2002, v. 99, n.11, p.3993-3998. KAVERI S.V et al., Factor VIII inhibitors: role of von Willebrand factor on the uptake of factor VIII by dendritic cells, Haemophilia, 2007, suppl.5, p.61-64. GOUDEMAND J., Inhibitor development in haemophilia A: the role of von Willebrand factor/factor VIII concentrates, Haemophilia, 2007, suppl.5, p.47-51. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2766118C2 (ru) * | 2017-07-07 | 2022-02-08 | Такеда Фармасьютикал Компани Лимитед | Лечение пациентов с тяжелой формой болезни фон виллебранда, подвергающихся плановому хирургическому вмешательству, путем введения рекомбинантного ффв |
Also Published As
| Publication number | Publication date |
|---|---|
| PL2291523T3 (pl) | 2015-05-29 |
| ES2531464T3 (es) | 2015-03-16 |
| WO2009156137A1 (en) | 2009-12-30 |
| DK2865760T3 (en) | 2018-01-15 |
| KR101507718B1 (ko) | 2015-04-10 |
| KR101648734B1 (ko) | 2016-08-18 |
| CN103739712A (zh) | 2014-04-23 |
| EP2291523A1 (en) | 2011-03-09 |
| US8575104B2 (en) | 2013-11-05 |
| EP2291523B1 (en) | 2014-12-17 |
| US9290561B2 (en) | 2016-03-22 |
| KR20110044978A (ko) | 2011-05-03 |
| US20110183907A1 (en) | 2011-07-28 |
| CA2728012C (en) | 2017-10-31 |
| KR20140090703A (ko) | 2014-07-17 |
| US20140072561A1 (en) | 2014-03-13 |
| RU2011102366A (ru) | 2012-07-27 |
| CN102076855A (zh) | 2011-05-25 |
| JP5832285B2 (ja) | 2015-12-16 |
| JP2011525363A (ja) | 2011-09-22 |
| CN103739712B (zh) | 2016-10-05 |
| DK2291523T3 (en) | 2015-03-23 |
| AU2009262476A1 (en) | 2009-12-30 |
| AU2009262476B2 (en) | 2014-06-26 |
| EP2865760B1 (en) | 2017-10-11 |
| AU2009262476C1 (en) | 2016-06-02 |
| ES2654336T3 (es) | 2018-02-13 |
| HK1151068A1 (en) | 2012-01-20 |
| EP2865760A1 (en) | 2015-04-29 |
| CA2728012A1 (en) | 2009-12-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2528855C2 (ru) | Модифицированный фактор виллебранда с удлиненным полупериодом существования in vivo, его применения и способы получения | |
| US9458223B2 (en) | Von willebrand factor variants having improved factor VIII binding affinity | |
| KR101542752B1 (ko) | 연장된 생체내 반감기를 갖는 변형된 응고 인자 | |
| US9878017B2 (en) | Covalent complex of von Willebrand Factor and factor VIII, compositions, and uses relating thereto | |
| EP1935430A1 (en) | Modified coagulation factors with prolonged in vivo half-life | |
| AU2013202564B2 (en) | Factor VIII, von Willebrand factor or complexes thereof with prolonged in vivo half-life | |
| HK1151068B (en) | Factor viii, von willebrand factor or complexes thereof with prolonged in vivo half-life |