JP4361786B2 - 操作されたジスルフィド結合を有する安定化蛋白質 - Google Patents
操作されたジスルフィド結合を有する安定化蛋白質 Download PDFInfo
- Publication number
- JP4361786B2 JP4361786B2 JP2003505346A JP2003505346A JP4361786B2 JP 4361786 B2 JP4361786 B2 JP 4361786B2 JP 2003505346 A JP2003505346 A JP 2003505346A JP 2003505346 A JP2003505346 A JP 2003505346A JP 4361786 B2 JP4361786 B2 JP 4361786B2
- Authority
- JP
- Japan
- Prior art keywords
- factor viii
- mammal
- composition
- nucleic acid
- factor
- 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.)
- Expired - Fee Related
Links
- 108090000623 proteins and genes Proteins 0.000 title claims description 34
- 102000004169 proteins and genes Human genes 0.000 title claims description 19
- 102000001690 Factor VIII Human genes 0.000 claims description 117
- 108010054218 Factor VIII Proteins 0.000 claims description 117
- 229960000301 factor viii Drugs 0.000 claims description 116
- 150000007523 nucleic acids Chemical class 0.000 claims description 53
- 108020004707 nucleic acids Proteins 0.000 claims description 50
- 102000039446 nucleic acids Human genes 0.000 claims description 50
- 239000013598 vector Substances 0.000 claims description 35
- 208000009292 Hemophilia A Diseases 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 26
- 235000018417 cysteine Nutrition 0.000 claims description 23
- 230000014509 gene expression Effects 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 201000003542 Factor VIII deficiency Diseases 0.000 claims description 18
- 235000018102 proteins Nutrition 0.000 claims description 18
- 241000124008 Mammalia Species 0.000 claims description 16
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 16
- 208000031220 Hemophilia Diseases 0.000 claims description 15
- 239000002773 nucleotide Substances 0.000 claims description 10
- 125000003729 nucleotide group Chemical group 0.000 claims description 10
- 208000032843 Hemorrhage Diseases 0.000 claims description 9
- 230000000740 bleeding effect Effects 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000023555 blood coagulation Effects 0.000 claims description 3
- 210000002845 virion Anatomy 0.000 claims 5
- 102000008300 Mutant Proteins Human genes 0.000 claims 1
- 108010021466 Mutant Proteins Proteins 0.000 claims 1
- 208000034158 bleeding Diseases 0.000 claims 1
- 230000002708 enhancing effect Effects 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 104
- 229920001184 polypeptide Polymers 0.000 description 100
- 102000004196 processed proteins & peptides Human genes 0.000 description 100
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 60
- 102100026735 Coagulation factor VIII Human genes 0.000 description 49
- 108010014172 Factor V Proteins 0.000 description 43
- 210000004027 cell Anatomy 0.000 description 36
- 238000000034 method Methods 0.000 description 30
- 108090000190 Thrombin Proteins 0.000 description 28
- 238000003776 cleavage reaction Methods 0.000 description 27
- 230000000694 effects Effects 0.000 description 27
- 230000007017 scission Effects 0.000 description 27
- 229960004072 thrombin Drugs 0.000 description 25
- 108020004705 Codon Proteins 0.000 description 24
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 24
- 239000012634 fragment Substances 0.000 description 22
- 108010094028 Prothrombin Proteins 0.000 description 19
- 229940039716 prothrombin Drugs 0.000 description 19
- 102100027378 Prothrombin Human genes 0.000 description 18
- 238000004590 computer program Methods 0.000 description 18
- 238000003119 immunoblot Methods 0.000 description 18
- 235000001014 amino acid Nutrition 0.000 description 16
- 108010043026 HGF activator Proteins 0.000 description 15
- 102100031465 Hepatocyte growth factor activator Human genes 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 15
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 14
- 125000003275 alpha amino acid group Chemical group 0.000 description 13
- 108010011227 meizothrombin Proteins 0.000 description 13
- 230000035772 mutation Effects 0.000 description 13
- 239000013612 plasmid Substances 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- 238000011282 treatment Methods 0.000 description 12
- 238000003556 assay Methods 0.000 description 11
- 241000894007 species Species 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 230000035602 clotting Effects 0.000 description 10
- 230000000875 corresponding effect Effects 0.000 description 10
- 102000057593 human F8 Human genes 0.000 description 10
- 229960000900 human factor viii Drugs 0.000 description 10
- 108010061932 Factor VIIIa Proteins 0.000 description 9
- 108010074860 Factor Xa Proteins 0.000 description 9
- 239000002299 complementary DNA Substances 0.000 description 9
- 238000010494 dissociation reaction Methods 0.000 description 9
- 230000005593 dissociations Effects 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 150000003904 phospholipids Chemical class 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 230000007812 deficiency Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000003612 virological effect Effects 0.000 description 8
- 206010053567 Coagulopathies Diseases 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 150000001945 cysteines Chemical class 0.000 description 7
- 230000002950 deficient Effects 0.000 description 7
- 230000002779 inactivation Effects 0.000 description 7
- 239000013607 AAV vector Substances 0.000 description 6
- 102000004506 Blood Proteins Human genes 0.000 description 6
- 108010017384 Blood Proteins Proteins 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 6
- 108010080865 Factor XII Proteins 0.000 description 6
- 102000000429 Factor XII Human genes 0.000 description 6
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 6
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 6
- 108091005804 Peptidases Proteins 0.000 description 6
- 239000004365 Protease Substances 0.000 description 6
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000017854 proteolysis Effects 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 101710117545 C protein Proteins 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000003636 conditioned culture medium Substances 0.000 description 5
- 238000012217 deletion Methods 0.000 description 5
- 230000037430 deletion Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- RZTAMFZIAATZDJ-UHFFFAOYSA-N felodipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-UHFFFAOYSA-N 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- -1 phosphatidylcholine phospholipid Chemical class 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 230000001177 retroviral effect Effects 0.000 description 5
- 230000006641 stabilisation Effects 0.000 description 5
- 238000011105 stabilization Methods 0.000 description 5
- 239000006163 transport media Substances 0.000 description 5
- 238000011179 visual inspection Methods 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 4
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 4
- 101100007328 Cocos nucifera COS-1 gene Proteins 0.000 description 4
- 108091026890 Coding region Proteins 0.000 description 4
- 108010048049 Factor IXa Proteins 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- 101000651439 Homo sapiens Prothrombin Proteins 0.000 description 4
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 239000003114 blood coagulation factor Substances 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000001415 gene therapy Methods 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 238000006206 glycosylation reaction Methods 0.000 description 4
- 229940039715 human prothrombin Drugs 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 231100000350 mutagenesis Toxicity 0.000 description 4
- 238000002703 mutagenesis Methods 0.000 description 4
- 231100000219 mutagenic Toxicity 0.000 description 4
- 230000003505 mutagenic effect Effects 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 108010089996 B-domain-deleted factor VIII Proteins 0.000 description 3
- 241000282465 Canis Species 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 102000014914 Carrier Proteins Human genes 0.000 description 3
- 102100022641 Coagulation factor IX Human genes 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 108010014173 Factor X Proteins 0.000 description 3
- 108010007267 Hirudins Proteins 0.000 description 3
- 102000007625 Hirudins Human genes 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 108010000499 Thromboplastin Proteins 0.000 description 3
- 102000002262 Thromboplastin Human genes 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 108091008324 binding proteins Proteins 0.000 description 3
- 238000006664 bond formation reaction Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 239000000833 heterodimer Substances 0.000 description 3
- 229940006607 hirudin Drugs 0.000 description 3
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 230000017423 tissue regeneration Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 108010047303 von Willebrand Factor Proteins 0.000 description 3
- 102100036537 von Willebrand factor Human genes 0.000 description 3
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 108700010070 Codon Usage Proteins 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 108010071241 Factor XIIa Proteins 0.000 description 2
- 102100037362 Fibronectin Human genes 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101001035951 Homo sapiens Hyaluronan-binding protein 2 Proteins 0.000 description 2
- 108060005987 Kallikrein Proteins 0.000 description 2
- 102000001399 Kallikrein Human genes 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 102100026966 Thrombomodulin Human genes 0.000 description 2
- 108010079274 Thrombomodulin Proteins 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000011149 active material Substances 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 210000004900 c-terminal fragment Anatomy 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
- 239000003593 chromogenic compound Substances 0.000 description 2
- 230000009852 coagulant defect Effects 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000003599 detergent Substances 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000005714 functional activity Effects 0.000 description 2
- 238000001476 gene delivery Methods 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
- 208000009429 hemophilia B Diseases 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000002947 procoagulating effect Effects 0.000 description 2
- 108010014806 prothrombinase complex Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 229960001134 von willebrand factor Drugs 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- KWPACVJPAFGBEQ-IKGGRYGDSA-N (2s)-1-[(2r)-2-amino-3-phenylpropanoyl]-n-[(3s)-1-chloro-6-(diaminomethylideneamino)-2-oxohexan-3-yl]pyrrolidine-2-carboxamide Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)CCl)C1=CC=CC=C1 KWPACVJPAFGBEQ-IKGGRYGDSA-N 0.000 description 1
- BBYWOYAFBUOUFP-JOCHJYFZSA-N 1-stearoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OCCN BBYWOYAFBUOUFP-JOCHJYFZSA-N 0.000 description 1
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000033316 Acquired hemophilia A Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 208000002109 Argyria Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000035404 Autolysis Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 101710140962 Capsid scaffolding protein Proteins 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical group 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
- 108010010803 Gelatin Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101001066338 Homo sapiens Hepatocyte growth factor activator Proteins 0.000 description 1
- 102100039238 Hyaluronan-binding protein 2 Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-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
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-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
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-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
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000007536 Thrombosis Diseases 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
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 108700029631 X-Linked Genes Proteins 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate 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 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 235000021120 animal protein Nutrition 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 229940019700 blood coagulation factors Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 108090001015 cancer procoagulant Proteins 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000000701 coagulant Substances 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
- 238000010961 commercial manufacture process Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000010217 densitometric analysis Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229940079919 digestives enzyme preparation Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000005584 early death Effects 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 102000048272 human HABP2 Human genes 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 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
- 238000012544 monitoring process Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 238000001683 neutron diffraction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000012753 partial hepatectomy Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009520 phase I clinical trial 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
- 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
- 230000004962 physiological condition Effects 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003805 procoagulant Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 210000001995 reticulocyte Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 102220187448 rs776535574 Human genes 0.000 description 1
- 230000028043 self proteolysis Effects 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 238000007390 skin biopsy Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960003766 thrombin (human) Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 108010036927 trypsin-like serine protease Proteins 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 238000012800 visualization Methods 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
- 210000005253 yeast cell Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1075—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of amino acids or peptide residues
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
-
- 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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Analytical Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US29857801P | 2001-06-14 | 2001-06-14 | |
| PCT/US2002/019017 WO2002103024A2 (en) | 2001-06-14 | 2002-06-14 | Stabilized proteins with engineered disulfide bonds |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008124202A Division JP2008271975A (ja) | 2001-06-14 | 2008-05-12 | 操作されたジスルフィド結合を有する安定化蛋白質 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2005500831A JP2005500831A (ja) | 2005-01-13 |
| JP2005500831A5 JP2005500831A5 (enExample) | 2006-01-05 |
| JP4361786B2 true JP4361786B2 (ja) | 2009-11-11 |
Family
ID=23151124
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2003505346A Expired - Fee Related JP4361786B2 (ja) | 2001-06-14 | 2002-06-14 | 操作されたジスルフィド結合を有する安定化蛋白質 |
| JP2008124202A Pending JP2008271975A (ja) | 2001-06-14 | 2008-05-12 | 操作されたジスルフィド結合を有する安定化蛋白質 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008124202A Pending JP2008271975A (ja) | 2001-06-14 | 2008-05-12 | 操作されたジスルフィド結合を有する安定化蛋白質 |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US7205278B2 (enExample) |
| EP (2) | EP2110385A1 (enExample) |
| JP (2) | JP4361786B2 (enExample) |
| AU (1) | AU2002310438B2 (enExample) |
| CA (1) | CA2450732A1 (enExample) |
| DE (1) | DE60234193D1 (enExample) |
| ES (1) | ES2331909T3 (enExample) |
| WO (1) | WO2002103024A2 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008271975A (ja) * | 2001-06-14 | 2008-11-13 | Scripps Research Inst | 操作されたジスルフィド結合を有する安定化蛋白質 |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1502921A1 (en) * | 2003-07-29 | 2005-02-02 | ZLB Behring GmbH | Recombinant mutated human factor VIII (FVIII) with improved stability |
| WO2005055930A2 (en) * | 2003-12-03 | 2005-06-23 | University Of Rochester | Recombinant factor viii having increased specific activity |
| US20060019893A1 (en) * | 2004-07-02 | 2006-01-26 | Genentech, Inc. | Factor VIIa variants |
| KR101468345B1 (ko) * | 2004-11-12 | 2014-12-03 | 바이엘 헬스케어 엘엘씨 | Ｆｖｉｉｉ의 부위 지향 변형 |
| WO2006108590A1 (en) * | 2005-04-14 | 2006-10-19 | Csl Behring Gmbh | Modified coagulation factor viii with enhanced stability and its derivates |
| GB0514779D0 (en) * | 2005-07-19 | 2005-08-24 | Celltech R&D Ltd | Biological products |
| EP1816201A1 (en) | 2006-02-06 | 2007-08-08 | CSL Behring GmbH | Modified coagulation factor VIIa with extended half-life |
| EP2081589B1 (en) * | 2006-11-16 | 2010-10-06 | Crucell Holland B.V. | Complementation of factor xi deficiency by factor v mutants |
| KR101542752B1 (ko) | 2006-12-22 | 2015-08-10 | 체에스엘 베링 게엠베하 | 연장된 생체내 반감기를 갖는 변형된 응고 인자 |
| CN104152489A (zh) * | 2007-11-01 | 2014-11-19 | 罗切斯特大学 | 具有增加的稳定性的重组因子viii |
| DK2865760T3 (en) | 2008-06-24 | 2018-01-15 | Csl Behring Gmbh | Factor VIII, Von Willebrand Factor or complexes thereof with extended in vivo half-life |
| JP5816097B2 (ja) * | 2009-01-22 | 2015-11-18 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | 安定な成長ホルモン化合物 |
| BR122019021594B1 (pt) * | 2009-10-30 | 2021-10-05 | Agresearch Limited | Oleosina modificada célula hospedeira, corpo oleoso e seu método de produção, emulsão, ração animal, e método para produção de uma planta que acumula mais óleo que uma planta controle adequada |
| BR112012018162A2 (pt) | 2010-01-22 | 2017-10-03 | Novo Nordisk Healthcare Ag | Compostos de hormônio do crescimento estáveis |
| RU2605627C2 (ru) | 2010-01-22 | 2016-12-27 | Ново Нордиск Хелс Кеа Аг | Гормоны роста с пролонгированной эффективностью in vivo |
| EP2593130A2 (en) * | 2010-07-15 | 2013-05-22 | Novo Nordisk A/S | Stabilized factor viii variants |
| CN103269720A (zh) * | 2010-07-22 | 2013-08-28 | 诺沃—诺迪斯克保健股份有限公司 | 生长激素缀合物 |
| ES2651523T3 (es) | 2012-02-15 | 2018-01-26 | Csl Behring Gmbh | Variantes del Factor de von Willebrand que tienen afinidad de unión al Factor VIII mejorada |
| WO2013172954A1 (en) | 2012-05-17 | 2013-11-21 | Ra Pharmaceuticals, Inc | Peptide and peptidomimetic inhibitors |
| JP2016518321A (ja) * | 2013-03-15 | 2016-06-23 | バイエル・ヘルスケア・エルエルシーＢａｙｅｒ ＨｅａｌｔｈＣａｒｅ ＬＬＣ | 組み換え因子ｖｉｉｉ配合物 |
| US11045523B2 (en) | 2013-04-05 | 2021-06-29 | Novo Nordisk Healthcare Ag | Formulation of growth hormone albumin-binder conjugate |
| DK2796145T3 (da) | 2013-04-22 | 2018-01-29 | Csl Ltd | Et kovalent kompleks af von Willebrand-faktor og faktor VIII linket af en disulfidbro |
| EP3065768B1 (en) | 2013-11-04 | 2020-09-23 | The Regents of the University of California | Composition for use in treatment or prevention of conditions associated with bleeding or hypocoagulationcompostion |
| JP6676551B2 (ja) | 2014-07-02 | 2020-04-08 | 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 | 改変フォンウィルブランド因子 |
| ES2772933T3 (es) | 2015-03-06 | 2020-07-08 | CSL Behring Lengnau AG | Factor de von Willebrand modificado que tiene una semivida mejorada |
| US10772936B2 (en) | 2015-05-22 | 2020-09-15 | CSL Behring Lengnau AG | Methods for preparing modified von Willebrand factor |
| SG10201910896UA (en) | 2015-05-22 | 2020-01-30 | CSL Behring Lengnau AG | Truncated von willebrand factor polypeptides for treating hemophilia |
| CN104974228B (zh) * | 2015-06-15 | 2017-10-17 | 四川合泰新光生物科技有限公司 | 一种小分子多肽zy4及其应用 |
| RU2018128613A (ru) | 2016-01-07 | 2020-02-07 | Цсл Беринг Ленгнау Аг | Мутированный фактор фон виллебранда |
| ES2909573T3 (es) | 2016-01-07 | 2022-05-09 | CSL Behring Lengnau AG | Factor de von Willebrand truncado mutado |
| SG11201903950UA (en) | 2016-11-11 | 2019-05-30 | CSL Behring Lengnau AG | Truncated von willebrand factor polypeptides for treating hemophilia |
| DK3538134T3 (da) | 2016-11-11 | 2022-02-07 | CSL Behring Lengnau AG | Trunkeret von willebrand-faktor polypeptider til ekstravaskulær administration til behandling eller profylakse af en blodkoagulationsforstyrrelse |
| WO2019203645A1 (en) * | 2018-04-19 | 2019-10-24 | Stichting Vu | Protein macrocyclization |
| WO2019210187A1 (en) * | 2018-04-26 | 2019-10-31 | The University Of North Carolina At Chapel Hill | Methods and compositions for treatment of hemophilia |
Family Cites Families (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5214033A (en) * | 1983-03-31 | 1993-05-25 | Scripps Clinic & Research Foundation | Factor VIII coagulant polypeptides |
| US4757006A (en) | 1983-10-28 | 1988-07-12 | Genetics Institute, Inc. | Human factor VIII:C gene and recombinant methods for production |
| SE8501050D0 (sv) | 1985-03-05 | 1985-03-05 | Kabivitrum Ab | Biologically active fragments of human antihemophilic factor and method for preparation thereof |
| EP0218712B1 (en) * | 1985-04-12 | 1992-02-26 | Genetics Institute, Inc. | Novel procoagulant proteins |
| US5198349A (en) | 1986-01-03 | 1993-03-30 | Genetics Institute, Inc. | Method for producing factor VIII:C and analogs |
| US5250421A (en) | 1986-01-03 | 1993-10-05 | Genetics Institute, Inc. | Method for producing factor VIII:C-type proteins |
| US5422260A (en) * | 1986-05-29 | 1995-06-06 | Genetics Institute, Inc. -Legal Affairs | Human factor VIII:c muteins |
| US4853871A (en) * | 1987-04-06 | 1989-08-01 | Genex Corporation | Computer-based method for designing stablized proteins |
| US5449759A (en) * | 1987-05-16 | 1995-09-12 | Somatogen, Inc. | Hemoglobins with intersubunit desulfide bonds |
| US5827821A (en) * | 1987-12-10 | 1998-10-27 | The Burnham Institute | Conformationally stabilized cell adhesion peptides |
| US5009889A (en) * | 1987-12-31 | 1991-04-23 | Oklahoma Medical Research Foundation | Treatment of dysfunctional vascular endothelium using activated protein C |
| US4852871A (en) * | 1988-12-02 | 1989-08-01 | John Perko | Hand exercise device |
| US5082767A (en) | 1989-02-27 | 1992-01-21 | Hatfield G Wesley | Codon pair utilization |
| US5610137A (en) * | 1990-12-20 | 1997-03-11 | The Uab Research Foundation | Transgenic, cross-linked hemoglobin |
| US5661008A (en) | 1991-03-15 | 1997-08-26 | Kabi Pharmacia Ab | Recombinant human factor VIII derivatives |
| US5114148A (en) * | 1991-07-09 | 1992-05-19 | Liu Ming Zen | Puzzle device |
| US6174666B1 (en) | 1992-03-27 | 2001-01-16 | The United States Of America As Represented By The Department Of Health And Human Services | Method of eliminating inhibitory/instability regions from mRNA |
| US5364771A (en) | 1992-04-07 | 1994-11-15 | Emory University | Hybrid human/porcine factor VIII |
| US6180371B1 (en) | 1996-06-26 | 2001-01-30 | Emory University | Modified factor VIII |
| US5859204A (en) | 1992-04-07 | 1999-01-12 | Emory University | Modified factor VIII |
| US5453937A (en) * | 1993-04-28 | 1995-09-26 | Immunex Corporation | Method and system for protein modeling |
| US5747654A (en) * | 1993-06-14 | 1998-05-05 | The United States Of America As Represented By The Department Of Health And Human Services | Recombinant disulfide-stabilized polypeptide fragments having binding specificity |
| DE4418635C2 (de) * | 1994-05-27 | 1997-07-24 | Immuno Ag | Pharmazeutische Zusammensetzung zur Vorbeugung und Behandlung von Blutgerinnungsstörungen |
| US5681746A (en) | 1994-12-30 | 1997-10-28 | Chiron Viagene, Inc. | Retroviral delivery of full length factor VIII |
| US5543149A (en) * | 1995-03-01 | 1996-08-06 | Rubin; Stan M. | Treatment for insect bites |
| US5935568A (en) | 1995-05-18 | 1999-08-10 | National Jewish Medical & Research Center | Gene therapy for effector cell regulation |
| US5910481A (en) * | 1995-11-13 | 1999-06-08 | Immuno Ag | Hybrid proteins with modified activity |
| US20040092442A1 (en) * | 1996-04-24 | 2004-05-13 | University Of Michigan | Inactivation resistant factor VIII |
| US6114148C1 (en) | 1996-09-20 | 2012-05-01 | Gen Hospital Corp | High level expression of proteins |
| US6262238B1 (en) * | 1997-01-14 | 2001-07-17 | Roche Diagnostic, Gmbh | Process for modifying the stability of antibodies |
| IL131131A0 (en) | 1997-02-07 | 2001-01-28 | Merck & Co Inc | Synthetic hiv gag genes |
| US6358703B1 (en) | 1998-12-10 | 2002-03-19 | Bayer Corporation | Expression system for factor VIII |
| DE60234193D1 (de) * | 2001-06-14 | 2009-12-10 | Scripps Research Inst | Stabilisierte faktor viii mit gentechnisch konstruierten disulfidbindungen |
-
2002
- 2002-06-14 DE DE60234193T patent/DE60234193D1/de not_active Expired - Lifetime
- 2002-06-14 WO PCT/US2002/019017 patent/WO2002103024A2/en not_active Ceased
- 2002-06-14 AU AU2002310438A patent/AU2002310438B2/en not_active Ceased
- 2002-06-14 JP JP2003505346A patent/JP4361786B2/ja not_active Expired - Fee Related
- 2002-06-14 ES ES02737516T patent/ES2331909T3/es not_active Expired - Lifetime
- 2002-06-14 EP EP09159506A patent/EP2110385A1/en not_active Withdrawn
- 2002-06-14 US US10/172,712 patent/US7205278B2/en not_active Expired - Fee Related
- 2002-06-14 EP EP02737516A patent/EP1421539B1/en not_active Expired - Lifetime
- 2002-06-14 CA CA002450732A patent/CA2450732A1/en not_active Abandoned
-
2007
- 2007-01-25 US US11/627,197 patent/US7928199B2/en not_active Expired - Fee Related
-
2008
- 2008-05-12 JP JP2008124202A patent/JP2008271975A/ja active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008271975A (ja) * | 2001-06-14 | 2008-11-13 | Scripps Research Inst | 操作されたジスルフィド結合を有する安定化蛋白質 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1421539B1 (en) | 2009-10-28 |
| US7205278B2 (en) | 2007-04-17 |
| US20070276128A1 (en) | 2007-11-29 |
| DE60234193D1 (de) | 2009-12-10 |
| EP2110385A8 (en) | 2010-06-02 |
| EP1421539A2 (en) | 2004-05-26 |
| EP1421539A4 (en) | 2005-11-09 |
| JP2008271975A (ja) | 2008-11-13 |
| ES2331909T3 (es) | 2010-01-20 |
| CA2450732A1 (en) | 2002-12-27 |
| US20030125232A1 (en) | 2003-07-03 |
| EP2110385A1 (en) | 2009-10-21 |
| US7928199B2 (en) | 2011-04-19 |
| WO2002103024A2 (en) | 2002-12-27 |
| JP2005500831A (ja) | 2005-01-13 |
| WO2002103024A3 (en) | 2004-03-18 |
| AU2002310438B2 (en) | 2008-05-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4361786B2 (ja) | 操作されたジスルフィド結合を有する安定化蛋白質 | |
| JP3894795B2 (ja) | ヒト細胞株における組換え血液凝固因子の製造 | |
| JP3440097B2 (ja) | ヒト／ブタハイブリッド第ｖｉｉｉ因子 | |
| JP5162635B2 (ja) | 高レベルエキスプレッサー第ｖｉｉｉ因子ポリペプチドをコードする核酸配列およびアミノ酸配列および使用方法 | |
| AU2001238416B2 (en) | Modified factor VIII | |
| ES2363307T3 (es) | Polipéptidos de factor viia mofificados. | |
| AU2002310438A1 (en) | Stabilized proteins with engineered disulfide bonds | |
| AU2001292861A1 (en) | Modified factor VIII | |
| US20050123997A1 (en) | Modified fVIII having reduced immunogenicity through mutagenesis of A2 and C2 epitopes | |
| JP2003508019A (ja) | 修飾されたｖｉｉｉ因子 | |
| EP1062224A4 (en) | MODIFIED FACTOR VIII | |
| JP2005518783A5 (enExample) | ||
| US7211558B2 (en) | Compositions and methods for the treatment of hemophilia A | |
| US20040249134A1 (en) | Factor viii c2 domain variants | |
| US5869292A (en) | Hybrid proteins with modified activity | |
| AU2008202293A1 (en) | Stabilized proteins with engineered disulfide bonds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20050613 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20050613 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20080206 |
|
| RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20080422 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20080502 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20080512 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20080513 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20080901 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20081128 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20081205 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20081222 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20090106 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20090304 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090528 |
|
| A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20090706 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20090722 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20090813 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120821 Year of fee payment: 3 |
|
| LAPS | Cancellation because of no payment of annual fees |