JP6429885B2 - 組換えヒト凝固第ｘａ因子タンパク質の不均一集団を含む組成物 - Google Patents
組換えヒト凝固第ｘａ因子タンパク質の不均一集団を含む組成物 Download PDFInfo
- Publication number
- JP6429885B2 JP6429885B2 JP2016543477A JP2016543477A JP6429885B2 JP 6429885 B2 JP6429885 B2 JP 6429885B2 JP 2016543477 A JP2016543477 A JP 2016543477A JP 2016543477 A JP2016543477 A JP 2016543477A JP 6429885 B2 JP6429885 B2 JP 6429885B2
- Authority
- JP
- Japan
- Prior art keywords
- fxa variant
- seq
- protein
- light chain
- composition
- 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
- 239000000203 mixture Substances 0.000 title claims description 130
- 108010074860 Factor Xa Proteins 0.000 title claims description 66
- 108090000623 proteins and genes Proteins 0.000 claims description 377
- 102000004169 proteins and genes Human genes 0.000 claims description 371
- 150000001413 amino acids Chemical class 0.000 claims description 124
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 110
- 150000002402 hexoses Chemical class 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 31
- 238000001819 mass spectrum Methods 0.000 claims description 29
- 150000004676 glycans Chemical class 0.000 claims description 25
- 238000012434 mixed-mode chromatography Methods 0.000 claims description 18
- 208000032843 Hemorrhage Diseases 0.000 claims description 17
- 230000000740 bleeding effect Effects 0.000 claims description 17
- 241000700605 Viruses Species 0.000 claims description 12
- 239000012501 chromatography medium Substances 0.000 claims description 11
- 230000023597 hemostasis Effects 0.000 claims description 10
- 239000002609 medium Substances 0.000 claims description 10
- 208000009292 Hemophilia A Diseases 0.000 claims description 9
- 230000003993 interaction Effects 0.000 claims description 8
- 102100022641 Coagulation factor IX Human genes 0.000 claims description 7
- 102100026735 Coagulation factor VIII Human genes 0.000 claims description 6
- 201000003542 Factor VIII deficiency Diseases 0.000 claims description 6
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims description 6
- 238000005571 anion exchange chromatography Methods 0.000 claims description 6
- 208000009429 hemophilia B Diseases 0.000 claims description 6
- 238000005277 cation exchange chromatography Methods 0.000 claims description 5
- 208000014674 injury Diseases 0.000 claims description 5
- 239000006143 cell culture medium Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 230000002209 hydrophobic effect Effects 0.000 claims description 3
- 230000008733 trauma Effects 0.000 claims description 3
- 238000013060 ultrafiltration and diafiltration Methods 0.000 claims description 3
- 230000009881 electrostatic interaction Effects 0.000 claims description 2
- 230000000415 inactivating effect Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 5
- 239000012614 Q-Sepharose Substances 0.000 claims 1
- 239000012141 concentrate Substances 0.000 claims 1
- 235000018102 proteins Nutrition 0.000 description 272
- UHBYWPGGCSDKFX-VKHMYHEASA-N gamma-carboxy-L-glutamic acid Chemical group OC(=O)[C@@H](N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-VKHMYHEASA-N 0.000 description 117
- 235000001014 amino acid Nutrition 0.000 description 95
- 229940024606 amino acid Drugs 0.000 description 95
- 210000004027 cell Anatomy 0.000 description 73
- 230000004481 post-translational protein modification Effects 0.000 description 65
- 108010014173 Factor X Proteins 0.000 description 60
- 241000894007 species Species 0.000 description 47
- 108090000765 processed proteins & peptides Proteins 0.000 description 43
- 108090001126 Furin Proteins 0.000 description 40
- 102100035233 Furin Human genes 0.000 description 37
- 102000001708 Protein Isoforms Human genes 0.000 description 36
- 108010029485 Protein Isoforms Proteins 0.000 description 36
- 238000006467 substitution reaction Methods 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 22
- 230000000670 limiting effect Effects 0.000 description 21
- 239000013598 vector Substances 0.000 description 21
- 238000003776 cleavage reaction Methods 0.000 description 20
- 230000007017 scission Effects 0.000 description 20
- 230000035602 clotting Effects 0.000 description 19
- 101800001401 Activation peptide Proteins 0.000 description 16
- 102400000069 Activation peptide Human genes 0.000 description 16
- 230000014509 gene expression Effects 0.000 description 15
- 102000004196 processed proteins & peptides Human genes 0.000 description 15
- 206010053567 Coagulopathies Diseases 0.000 description 14
- FSNVAJOPUDVQAR-UHFFFAOYSA-N 2-[[6-amino-2-[[2-amino-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(N)=NCCCC(N)C(=O)NC(CCCCN)C(=O)NC(CCCN=C(N)N)C(O)=O FSNVAJOPUDVQAR-UHFFFAOYSA-N 0.000 description 12
- 150000007523 nucleic acids Chemical class 0.000 description 12
- 239000011347 resin Substances 0.000 description 12
- 229920005989 resin Polymers 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- 102000035195 Peptidases Human genes 0.000 description 10
- 108091005804 Peptidases Proteins 0.000 description 10
- 239000004365 Protease Substances 0.000 description 10
- 229920002684 Sepharose Polymers 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000012545 processing Methods 0.000 description 10
- 238000004007 reversed phase HPLC Methods 0.000 description 10
- 210000004899 c-terminal region Anatomy 0.000 description 9
- 238000004949 mass spectrometry Methods 0.000 description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 239000002299 complementary DNA Substances 0.000 description 8
- 238000001437 electrospray ionisation time-of-flight quadrupole detection Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 7
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 7
- 108090000317 Chymotrypsin Proteins 0.000 description 7
- 102220501226 Scaffold attachment factor B1_I16L_mutation Human genes 0.000 description 7
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 7
- 239000003114 blood coagulation factor Substances 0.000 description 7
- 229960002376 chymotrypsin Drugs 0.000 description 7
- 238000004255 ion exchange chromatography Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 125000005629 sialic acid group Chemical group 0.000 description 7
- 241000196324 Embryophyta Species 0.000 description 6
- 108010062466 Enzyme Precursors Proteins 0.000 description 6
- 102000010911 Enzyme Precursors Human genes 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- 229920005654 Sephadex Polymers 0.000 description 6
- 239000012507 Sephadex™ Substances 0.000 description 6
- 239000003623 enhancer Substances 0.000 description 6
- 238000012510 peptide mapping method Methods 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 108010074105 Factor Va Proteins 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 101001052793 Homo sapiens GDP-L-fucose synthase Proteins 0.000 description 5
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 5
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 5
- SQVRNKJHWKZAKO-LUWBGTNYSA-N N-acetylneuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)CC(O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-LUWBGTNYSA-N 0.000 description 5
- 230000029936 alkylation Effects 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 102000050085 human TSTA3 Human genes 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- 229940060155 neuac Drugs 0.000 description 5
- CERZMXAJYMMUDR-UHFFFAOYSA-N neuraminic acid Natural products NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO CERZMXAJYMMUDR-UHFFFAOYSA-N 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- FSNVAJOPUDVQAR-AVGNSLFASA-N Arg-Lys-Arg Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FSNVAJOPUDVQAR-AVGNSLFASA-N 0.000 description 4
- 241000238631 Hexapoda Species 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- 108010076504 Protein Sorting Signals Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000005805 hydroxylation reaction Methods 0.000 description 4
- 230000002779 inactivation Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000012500 ion exchange media Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 101001030665 Dictyostelium discoideum GDP-L-fucose synthase Proteins 0.000 description 3
- 108010054218 Factor VIII Proteins 0.000 description 3
- 102000001690 Factor VIII Human genes 0.000 description 3
- 102000004961 Furin Human genes 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000031220 Hemophilia Diseases 0.000 description 3
- 101000651439 Homo sapiens Prothrombin Proteins 0.000 description 3
- 230000004989 O-glycosylation Effects 0.000 description 3
- 108010033276 Peptide Fragments Proteins 0.000 description 3
- 102000007079 Peptide Fragments Human genes 0.000 description 3
- 108010094028 Prothrombin Proteins 0.000 description 3
- 102100027378 Prothrombin Human genes 0.000 description 3
- 239000012564 Q sepharose fast flow resin Substances 0.000 description 3
- 108010000499 Thromboplastin Proteins 0.000 description 3
- 102000002262 Thromboplastin Human genes 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 150000001720 carbohydrates Chemical group 0.000 description 3
- 230000021523 carboxylation Effects 0.000 description 3
- 238000006473 carboxylation reaction Methods 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 3
- 230000004186 co-expression Effects 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- 238000005345 coagulation Methods 0.000 description 3
- -1 cyclic hemiacetal Chemical class 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000003599 detergent Substances 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229960000301 factor viii Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000006251 gamma-carboxylation Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229930195712 glutamate Natural products 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 229940039715 human prothrombin Drugs 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000001323 posttranslational effect Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000002797 proteolythic effect Effects 0.000 description 3
- 229940039716 prothrombin Drugs 0.000 description 3
- 108010014806 prothrombinase complex Proteins 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 238000005406 washing Methods 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
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 241000271032 Daboia russelii Species 0.000 description 2
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 2
- 108010054265 Factor VIIa Proteins 0.000 description 2
- 239000012541 Fractogel® Substances 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 2
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 101001018085 Lysobacter enzymogenes Lysyl endopeptidase Proteins 0.000 description 2
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 108700007498 PF-05230907 Proteins 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical group N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N aspartic acid group Chemical group N[C@@H](CC(=O)O)C(=O)O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 208000015294 blood coagulation disease Diseases 0.000 description 2
- 239000013622 capto Q Substances 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000011118 depth filtration Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 230000002439 hemostatic effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000013411 master cell bank Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- SXTAYKAGBXMACB-UHFFFAOYSA-N methionine sulfoximine Chemical compound CS(=N)(=O)CCC(N)C(O)=O SXTAYKAGBXMACB-UHFFFAOYSA-N 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 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 2
- 239000013612 plasmid Substances 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 229940024790 prothrombin complex concentrate Drugs 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 238000009256 replacement therapy Methods 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000009450 sialylation Effects 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 239000002821 viper venom Substances 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 210000005253 yeast cell Anatomy 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- GZCGUPFRVQAUEE-UHFFFAOYSA-N 2,3,4,5,6-pentahydroxyhexanal Chemical compound OCC(O)C(O)C(O)C(O)C=O GZCGUPFRVQAUEE-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-UHFFFAOYSA-N 3,4,5,6-tetrahydroxyoxane-2-carboxylic acid Chemical compound OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 description 1
- 101000793340 Achromobacter lyticus Protease 1 Proteins 0.000 description 1
- 241000219194 Arabidopsis Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 208000001593 Bernard-Soulier syndrome Diseases 0.000 description 1
- 241000701489 Cauliflower mosaic virus Species 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 102100029117 Coagulation factor X Human genes 0.000 description 1
- 206010067787 Coagulation factor deficiency Diseases 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 208000028702 Congenital thrombocyte disease Diseases 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010048049 Factor IXa Proteins 0.000 description 1
- 108010071241 Factor XIIa Proteins 0.000 description 1
- 108010080805 Factor XIa Proteins 0.000 description 1
- 101150096839 Fcmr gene Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 1
- GRRNUXAQVGOGFE-UHFFFAOYSA-N Hygromycin-B Natural products OC1C(NC)CC(N)C(O)C1OC1C2OC3(C(C(O)C(O)C(C(N)CO)O3)O)OC2C(O)C(CO)O1 GRRNUXAQVGOGFE-UHFFFAOYSA-N 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 244000207740 Lemna minor Species 0.000 description 1
- 235000006439 Lemna minor Nutrition 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ABSPRNADVQNDOU-UHFFFAOYSA-N Menaquinone 1 Natural products C1=CC=C2C(=O)C(CC=C(C)C)=C(C)C(=O)C2=C1 ABSPRNADVQNDOU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 241001045988 Neogene Species 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 235000001855 Portulaca oleracea Nutrition 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000235347 Schizosaccharomyces pombe Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 208000006011 Stroke Diseases 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
- 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
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 241000723873 Tobacco mosaic virus Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 101710181748 Venom protease Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 102000004210 Vitamin K Epoxide Reductases Human genes 0.000 description 1
- 108090000779 Vitamin K Epoxide Reductases Proteins 0.000 description 1
- 102100038182 Vitamin K-dependent gamma-carboxylase Human genes 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 108091005588 alkylated proteins Proteins 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 108010018823 anti-inhibitor coagulant complex Proteins 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 238000007068 beta-elimination reaction Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000013019 capto adhere Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011098 chromatofocusing Methods 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 229940105756 coagulation factor x Drugs 0.000 description 1
- 208000014763 coagulation protein disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 229940012414 factor viia Drugs 0.000 description 1
- 229940105776 factor viii inhibitor bypassing activity Drugs 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 108010013113 glutamyl carboxylase Proteins 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 101150029559 hph gene Proteins 0.000 description 1
- GRRNUXAQVGOGFE-NZSRVPFOSA-N hygromycin B Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H](C(N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-NZSRVPFOSA-N 0.000 description 1
- 229940097277 hygromycin b Drugs 0.000 description 1
- 230000006303 immediate early viral mRNA transcription Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003125 jurkat cell Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 238000012433 multimodal chromatography Methods 0.000 description 1
- 101150091879 neo gene Proteins 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000019175 phylloquinone Nutrition 0.000 description 1
- 239000011772 phylloquinone Substances 0.000 description 1
- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 description 1
- 229960001898 phytomenadione Drugs 0.000 description 1
- 208000004521 platelet storage pool deficiency Diseases 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000007026 protein scission Effects 0.000 description 1
- 238000000734 protein sequencing Methods 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 238000001269 time-of-flight mass spectrometry Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000009385 viral infection Effects 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
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
-
- 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
-
- 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
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6432—Coagulation factor Xa (3.4.21.6)
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Wood Science & Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Analytical Chemistry (AREA)
- Biophysics (AREA)
- Water Supply & Treatment (AREA)
- Toxicology (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361881834P | 2013-09-24 | 2013-09-24 | |
| US61/881,834 | 2013-09-24 | ||
| PCT/IB2014/064564 WO2015044836A1 (en) | 2013-09-24 | 2014-09-16 | Compositions comprising heterogeneous populations of recombinant human clotting factor xa proteins |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2016535071A JP2016535071A (ja) | 2016-11-10 |
| JP2016535071A5 JP2016535071A5 (enExample) | 2017-10-12 |
| JP6429885B2 true JP6429885B2 (ja) | 2018-11-28 |
Family
ID=51844797
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016543477A Expired - Fee Related JP6429885B2 (ja) | 2013-09-24 | 2014-09-16 | 組換えヒト凝固第ｘａ因子タンパク質の不均一集団を含む組成物 |
Country Status (19)
| Country | Link |
|---|---|
| US (3) | US9757434B2 (enExample) |
| EP (1) | EP3049434A1 (enExample) |
| JP (1) | JP6429885B2 (enExample) |
| KR (1) | KR101988705B1 (enExample) |
| CN (2) | CN105579468A (enExample) |
| AR (1) | AR097732A1 (enExample) |
| AU (1) | AU2014326257B2 (enExample) |
| BR (1) | BR112016005899A8 (enExample) |
| CA (1) | CA2924981C (enExample) |
| HK (1) | HK1218760A1 (enExample) |
| IL (2) | IL244258A0 (enExample) |
| MX (1) | MX373466B (enExample) |
| MY (1) | MY173548A (enExample) |
| PE (1) | PE20160877A1 (enExample) |
| RU (1) | RU2648144C2 (enExample) |
| SA (1) | SA516370751B1 (enExample) |
| SG (1) | SG11201601221XA (enExample) |
| TW (1) | TWI631134B (enExample) |
| WO (1) | WO2015044836A1 (enExample) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150343034A1 (en) | 2013-01-31 | 2015-12-03 | Pfizer Inc. | Compositions and methods for counteracting factor xa inhibition |
| CN105579468A (zh) | 2013-09-24 | 2016-05-11 | 辉瑞大药厂 | 包含重组人凝血因子Xa蛋白的异质性群体的组合物 |
| ES2875538T3 (es) | 2016-06-17 | 2021-11-10 | Alexion Pharma Inc | Preparación de derivados del factor Xa |
| EP3722418A1 (en) * | 2019-04-08 | 2020-10-14 | AB Enzymes Oy | Solution stable enzyme composition |
Family Cites Families (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5597799A (en) | 1990-09-04 | 1997-01-28 | Cor Therapeutics, Inc. | Recombinant agents affecting thrombosis |
| AT405517B (de) | 1997-02-27 | 1999-09-27 | Immuno Ag | Faktor x-deletionsmutanten und analoge davon |
| AT405516B (de) | 1997-02-27 | 1999-09-27 | Immuno Ag | Faktor x-analoge mit modifizierter proteasespaltstelle |
| AT410216B (de) | 1999-08-10 | 2003-03-25 | Baxter Ag | Faktor x-analogon mit verbesserter aktivierbarkeit |
| AU2001249389A1 (en) | 2000-03-22 | 2001-10-03 | The Children's Hospital Of Philadelphia | Modified blood clotting factors and methods of use |
| FR2831170B1 (fr) | 2001-10-19 | 2004-03-19 | Inst Nat Sante Rech Med | Proteines c modifiees activables directement par la thrombine |
| FR2841904B1 (fr) | 2002-07-03 | 2004-08-20 | Inst Nat Sante Rech Med | Analogues de facteurs x clivables par la thrombine |
| DK1781782T3 (da) | 2004-08-17 | 2010-08-23 | Csl Behring Gmbh | Modificerede vitamin K-afhængige polypeptider |
| EP1728798A1 (en) | 2005-06-01 | 2006-12-06 | ZLB Behring GmbH | Coagulation factor X polypeptides with modified activation properties |
| MX336958B (es) * | 2005-11-15 | 2016-02-05 | Philadelphia Children Hospital | Metodos y composiciones para modular la hemostasia. |
| EP1820508A1 (en) | 2006-02-21 | 2007-08-22 | CSL Behring GmbH | Coagulation factor X polypeptides with modified activation properties |
| KR102069498B1 (ko) * | 2007-09-28 | 2020-01-23 | 포톨라 파마슈티컬스, 인코포레이티드 | 인자 Ｘａ 저해제에 대한 안티도트 및 그것을 사용하는 방법 |
| PL2300497T3 (pl) | 2008-06-24 | 2013-02-28 | Octapharma Ag | Sposób oczyszczania czynnika krzepnięcia VIII |
| US8455439B2 (en) | 2008-11-14 | 2013-06-04 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same in combination with blood coagulating agents |
| KR20110114587A (ko) | 2008-12-19 | 2011-10-19 | 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) | 세린 프로테아제 유도체 및 혈액응고 장애의 치료 또는 예방의 용도 |
| ES2605801T3 (es) | 2009-07-15 | 2017-03-16 | Portola Pharmaceuticals, Inc. | Formulación de dosis unitaria de antídoto para inhibidores del factor Xa para su uso en la prevención de la hemorragia |
| SI2591006T1 (sl) * | 2010-07-09 | 2019-10-30 | Bioverativ Therapeutics Inc | Enoverižne molekule, ki jih lahko obdelujemo in polipeptidi izdelani z njihovo uporabo |
| FR2972114B1 (fr) | 2011-03-01 | 2013-03-15 | Univ Grenoble 1 | Un nouveau leurre moleculaire procoagulant pour le traitement des hemophiles a ou b avec ou sans inhibiteur |
| EP2760887B1 (en) | 2011-09-30 | 2024-10-23 | The Children's Hospital of Philadelphia | Compositions and methods for modulating hemostasis |
| CN104755492A (zh) | 2012-07-25 | 2015-07-01 | 催化剂生物科学公司 | 修饰的因子x多肽及其应用 |
| US20150343034A1 (en) | 2013-01-31 | 2015-12-03 | Pfizer Inc. | Compositions and methods for counteracting factor xa inhibition |
| CN105579468A (zh) | 2013-09-24 | 2016-05-11 | 辉瑞大药厂 | 包含重组人凝血因子Xa蛋白的异质性群体的组合物 |
| WO2015066606A2 (en) | 2013-11-01 | 2015-05-07 | The Children's Hospital Of Philadelphia | Compositions and methods for increasing the half-life of factor xa |
| PT3096779T (pt) | 2014-01-24 | 2020-02-21 | Pfizer | Composições e métodos para tratamento de hemorragia intracerebral |
-
2014
- 2014-09-16 CN CN201480052212.2A patent/CN105579468A/zh active Pending
- 2014-09-16 CN CN202011112690.1A patent/CN112195169A/zh active Pending
- 2014-09-16 RU RU2016108608A patent/RU2648144C2/ru active
- 2014-09-16 AU AU2014326257A patent/AU2014326257B2/en not_active Ceased
- 2014-09-16 SG SG11201601221XA patent/SG11201601221XA/en unknown
- 2014-09-16 KR KR1020167007373A patent/KR101988705B1/ko not_active Expired - Fee Related
- 2014-09-16 CA CA2924981A patent/CA2924981C/en not_active Expired - Fee Related
- 2014-09-16 WO PCT/IB2014/064564 patent/WO2015044836A1/en not_active Ceased
- 2014-09-16 BR BR112016005899A patent/BR112016005899A8/pt not_active IP Right Cessation
- 2014-09-16 JP JP2016543477A patent/JP6429885B2/ja not_active Expired - Fee Related
- 2014-09-16 EP EP14792595.2A patent/EP3049434A1/en not_active Withdrawn
- 2014-09-16 HK HK16106674.2A patent/HK1218760A1/zh unknown
- 2014-09-16 MX MX2016003871A patent/MX373466B/es active IP Right Grant
- 2014-09-16 PE PE2016000398A patent/PE20160877A1/es unknown
- 2014-09-16 MY MYPI2016700985A patent/MY173548A/en unknown
- 2014-09-23 AR ARP140103512A patent/AR097732A1/es unknown
- 2014-09-23 TW TW103132803A patent/TWI631134B/zh not_active IP Right Cessation
- 2014-09-24 US US14/495,478 patent/US9757434B2/en not_active Expired - Fee Related
-
2016
- 2016-02-23 IL IL244258A patent/IL244258A0/en unknown
- 2016-03-17 SA SA516370751A patent/SA516370751B1/ar unknown
-
2017
- 2017-08-04 US US15/669,340 patent/US10660946B2/en active Active
-
2020
- 2020-05-25 US US16/882,598 patent/US20210106658A1/en not_active Abandoned
- 2020-12-13 IL IL279396A patent/IL279396A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MY173548A (en) | 2020-02-04 |
| HK1218760A1 (zh) | 2017-03-10 |
| IL244258A0 (en) | 2016-04-21 |
| US9757434B2 (en) | 2017-09-12 |
| US20210106658A1 (en) | 2021-04-15 |
| AU2014326257B2 (en) | 2017-08-10 |
| CN112195169A (zh) | 2021-01-08 |
| US10660946B2 (en) | 2020-05-26 |
| KR20160044034A (ko) | 2016-04-22 |
| IL279396A (en) | 2021-01-31 |
| BR112016005899A2 (pt) | 2017-09-26 |
| CN105579468A (zh) | 2016-05-11 |
| TW201524996A (zh) | 2015-07-01 |
| PE20160877A1 (es) | 2016-09-11 |
| MX373466B (es) | 2020-05-25 |
| BR112016005899A8 (pt) | 2018-02-06 |
| TWI631134B (zh) | 2018-08-01 |
| CA2924981A1 (en) | 2015-04-02 |
| US20150182604A1 (en) | 2015-07-02 |
| AR097732A1 (es) | 2016-04-13 |
| AU2014326257A1 (en) | 2016-03-10 |
| SA516370751B1 (ar) | 2018-04-05 |
| MX2016003871A (es) | 2016-08-04 |
| KR101988705B1 (ko) | 2019-06-12 |
| EP3049434A1 (en) | 2016-08-03 |
| RU2648144C2 (ru) | 2018-03-22 |
| SG11201601221XA (en) | 2016-04-28 |
| WO2015044836A1 (en) | 2015-04-02 |
| RU2016108608A (ru) | 2017-10-26 |
| US20170333535A1 (en) | 2017-11-23 |
| JP2016535071A (ja) | 2016-11-10 |
| CA2924981C (en) | 2020-03-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210106658A1 (en) | Compositions comprising heterogeneous populations of recombinant human clotting factor xa proteins | |
| US20250230426A1 (en) | Recombinant vitamin k dependent proteins with high sialic acid content and methods of preparing same | |
| JP4772905B2 (ja) | アンチトロンビン組成物の製造方法 | |
| US20250257347A1 (en) | Coagulation factor x activating enzyme and use thereof | |
| CN103814137A (zh) | 处理凝血因子的方法 | |
| AU2014202989B2 (en) | Recombinant vitamin k dependent proteins with high sialic acid content and methods of preparing same | |
| US20190264188A1 (en) | Recombinant vitamin k dependent proteins with high sialic acid content and methods of preparing same | |
| KR100708403B1 (ko) | 항혈전 항체의 정제방법 | |
| AU2016238889B2 (en) | Recombinant vitamin K dependent proteins with high sialic acid content and methods of preparing same | |
| HK40007078A (en) | Method for isolation of recombinantly produced proteins | |
| HK1178048A (en) | Recombinant vitamin k dependent proteins with high sialic acid content and methods of preparing same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170901 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170901 |
|
| A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20170901 |
|
| A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20170913 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20171030 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180116 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180326 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180425 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180625 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180802 |
|
| 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: 20181009 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20181030 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6429885 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |