IL81937A - Modified human tissue-type plasminogen activator devoid of functional carbohydrate structure at amino acid residue 117 having increased in vivo half-life, its preparation and pharmaceutical composition containing said molecule - Google Patents

Modified human tissue-type plasminogen activator devoid of functional carbohydrate structure at amino acid residue 117 having increased in vivo half-life, its preparation and pharmaceutical composition containing said molecule

Info

Publication number: IL81937A
Authority: IL; Israel
Prior art keywords: human tissue; plasminogen activator; type plasminogen; amino acid; type
Prior art date: 1986-03-18

Application number

IL8193787A

Other languages

English (en)

Other versions

IL81937A0 (en

Original Assignee

Genentech Inc

Priority date (The priority date 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 date listed.)

1986-03-18

Filing date

1987-03-18

Publication date

1994-07-31

1987-03-18 Application filed by Genentech Inc filed Critical Genentech Inc

1987-10-20 Publication of IL81937A0 publication Critical patent/IL81937A0/xx

1994-07-31 Publication of IL81937A publication Critical patent/IL81937A/en

Links

125000000539 amino acid group Chemical group 0.000 title claims abstract description 24
125000000837 carbohydrate group Chemical group 0.000 title claims abstract 5
101000801481 Homo sapiens Tissue-type plasminogen activator Proteins 0.000 title claims description 86
238000001727 in vivo Methods 0.000 title claims description 10
239000008194 pharmaceutical composition Substances 0.000 title claims description 4
238000002360 preparation method Methods 0.000 title abstract description 4
238000000034 method Methods 0.000 claims description 25
108020004414 DNA Proteins 0.000 claims description 19
108020004705 Codon Proteins 0.000 claims description 17
235000001014 amino acid Nutrition 0.000 claims description 16
229940024606 amino acid Drugs 0.000 claims description 15
150000001413 amino acids Chemical class 0.000 claims description 15
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 10
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 7
DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 6
230000004071 biological effect Effects 0.000 claims description 6
DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 5
108020004511 Recombinant DNA Proteins 0.000 claims description 5
229960001230 asparagine Drugs 0.000 claims description 5
235000009582 asparagine Nutrition 0.000 claims description 5
235000013922 glutamic acid Nutrition 0.000 claims description 5
239000004220 glutamic acid Substances 0.000 claims description 5
230000000717 retained effect Effects 0.000 claims description 5
MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical group OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 4
AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 4
125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 claims description 4
MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 3
AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Chemical group CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 3
239000004473 Threonine Chemical group 0.000 claims description 3
229930182817 methionine Natural products 0.000 claims description 3
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims description 2
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims 1
125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims 1
125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims 1
102000001938 Plasminogen Activators Human genes 0.000 abstract description 13
108010001014 Plasminogen Activators Proteins 0.000 abstract description 13
229940127126 plasminogen activator Drugs 0.000 abstract description 13
238000003556 assay Methods 0.000 abstract description 7
239000012190 activator Substances 0.000 abstract 1
108050006955 Tissue-type plasminogen activator Proteins 0.000 description 53
102100033571 Tissue-type plasminogen activator Human genes 0.000 description 48
150000001720 carbohydrates Chemical group 0.000 description 24
239000012634 fragment Substances 0.000 description 23
239000013612 plasmid Substances 0.000 description 18
BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 13
229950003499 fibrin Drugs 0.000 description 13
229920001542 oligosaccharide Polymers 0.000 description 13
102000009123 Fibrin Human genes 0.000 description 12
108010073385 Fibrin Proteins 0.000 description 12
239000000203 mixture Substances 0.000 description 12
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 10
102000035195 Peptidases Human genes 0.000 description 9
108091005804 Peptidases Proteins 0.000 description 9
239000004365 Protease Substances 0.000 description 8
230000013595 glycosylation Effects 0.000 description 8
238000006206 glycosylation reaction Methods 0.000 description 8
239000000463 material Substances 0.000 description 8
150000002482 oligosaccharides Chemical class 0.000 description 8
238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 8
102000003978 Tissue Plasminogen Activator Human genes 0.000 description 7
108090000373 Tissue Plasminogen Activator Proteins 0.000 description 7
235000014633 carbohydrates Nutrition 0.000 description 7
230000029087 digestion Effects 0.000 description 7
230000000694 effects Effects 0.000 description 7
210000004027 cell Anatomy 0.000 description 6
102000047823 human PLAT Human genes 0.000 description 6
230000004048 modification Effects 0.000 description 6
238000012986 modification Methods 0.000 description 6
238000002703 mutagenesis Methods 0.000 description 6
231100000350 mutagenesis Toxicity 0.000 description 6
229940012957 plasmin Drugs 0.000 description 6
238000002741 site-directed mutagenesis Methods 0.000 description 6
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 5
OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 5
MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 5
229960000485 methotrexate Drugs 0.000 description 5
108090000623 proteins and genes Proteins 0.000 description 5
239000000523 sample Substances 0.000 description 5
239000000243 solution Substances 0.000 description 5
SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 4
102000004190 Enzymes Human genes 0.000 description 4
108090000790 Enzymes Proteins 0.000 description 4
OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 4
108091028043 Nucleic acid sequence Proteins 0.000 description 4
241000283973 Oryctolagus cuniculus Species 0.000 description 4
102000000447 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Human genes 0.000 description 4
108010055817 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Proteins 0.000 description 4
102000013566 Plasminogen Human genes 0.000 description 4
108010051456 Plasminogen Proteins 0.000 description 4
108091036066 Three prime untranslated region Proteins 0.000 description 4
208000007536 Thrombosis Diseases 0.000 description 4
125000003275 alpha amino acid group Chemical group 0.000 description 4
238000004458 analytical method Methods 0.000 description 4
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 4
230000008859 change Effects 0.000 description 4
229940088598 enzyme Drugs 0.000 description 4
239000012537 formulation buffer Substances 0.000 description 4
230000035772 mutation Effects 0.000 description 4
239000003981 vehicle Substances 0.000 description 4
WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 3
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
102000003886 Glycoproteins Human genes 0.000 description 3
108090000288 Glycoproteins Proteins 0.000 description 3
108010031186 Glycoside Hydrolases Proteins 0.000 description 3
102000005744 Glycoside Hydrolases Human genes 0.000 description 3
SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 3
OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 3
108091034117 Oligonucleotide Proteins 0.000 description 3
101000895926 Streptomyces plicatus Endo-beta-N-acetylglucosaminidase H Proteins 0.000 description 3
102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 3
108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 3
239000000872 buffer Substances 0.000 description 3
238000006243 chemical reaction Methods 0.000 description 3
229930182830 galactose Natural products 0.000 description 3
230000026045 iodination Effects 0.000 description 3
238000006192 iodination reaction Methods 0.000 description 3
229950006780 n-acetylglucosamine Drugs 0.000 description 3
235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
229920000053 polysorbate 80 Polymers 0.000 description 3
230000002537 thrombolytic effect Effects 0.000 description 3
229960005356 urokinase Drugs 0.000 description 3
239000013598 vector Substances 0.000 description 3
239000004475 Arginine Substances 0.000 description 2
-1 Asn amino acid Chemical class 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
102000012410 DNA Ligases Human genes 0.000 description 2
108010061982 DNA Ligases Proteins 0.000 description 2
102100024746 Dihydrofolate reductase Human genes 0.000 description 2
238000002965 ELISA Methods 0.000 description 2
108010049003 Fibrinogen Proteins 0.000 description 2
102000008946 Fibrinogen Human genes 0.000 description 2
PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 2
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
230000002950 deficient Effects 0.000 description 2
108020001096 dihydrofolate reductase Proteins 0.000 description 2
239000013604 expression vector Substances 0.000 description 2
230000003480 fibrinolytic effect Effects 0.000 description 2
239000000499 gel Substances 0.000 description 2
238000004519 manufacturing process Methods 0.000 description 2
230000003647 oxidation Effects 0.000 description 2
238000007254 oxidation reaction Methods 0.000 description 2
KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 2
239000012071 phase Substances 0.000 description 2
238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 2
229920001184 polypeptide Polymers 0.000 description 2
108090000765 processed proteins & peptides Proteins 0.000 description 2
102000004196 processed proteins & peptides Human genes 0.000 description 2
235000018102 proteins Nutrition 0.000 description 2
102000004169 proteins and genes Human genes 0.000 description 2
230000003248 secreting effect Effects 0.000 description 2
SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 2
JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
239000001488 sodium phosphate Substances 0.000 description 2
229910000162 sodium phosphate Inorganic materials 0.000 description 2
238000010561 standard procedure Methods 0.000 description 2
238000012360 testing method Methods 0.000 description 2
RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
WEQJQNWXCSUVMA-NEPJUHHUSA-N (2s)-1-[(2r)-2-azaniumyl-3-phenylpropanoyl]pyrrolidine-2-carboxylate Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 WEQJQNWXCSUVMA-NEPJUHHUSA-N 0.000 description 1
229920001817 Agar Polymers 0.000 description 1
DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
208000024172 Cardiovascular disease Diseases 0.000 description 1
108010075016 Ceruloplasmin Proteins 0.000 description 1
102100023321 Ceruloplasmin Human genes 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
101150074155 DHFR gene Proteins 0.000 description 1
102000053602 DNA Human genes 0.000 description 1
102000004594 DNA Polymerase I Human genes 0.000 description 1
108010017826 DNA Polymerase I Proteins 0.000 description 1
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 1
238000012286 ELISA Assay Methods 0.000 description 1
241000588724 Escherichia coli Species 0.000 description 1
241001524679 Escherichia virus M13 Species 0.000 description 1
239000004471 Glycine Substances 0.000 description 1
108090000144 Human Proteins Proteins 0.000 description 1
102000003839 Human Proteins Human genes 0.000 description 1
102000008100 Human Serum Albumin Human genes 0.000 description 1
108091006905 Human Serum Albumin Proteins 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
239000012741 Laemmli sample buffer Substances 0.000 description 1
DUKURNFHYQXCJG-UHFFFAOYSA-N Lewis A pentasaccharide Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(O)C(O)C(CO)O2)O)C(NC(C)=O)C(OC2C(C(OC3C(OC(O)C(O)C3O)CO)OC(CO)C2O)O)OC1CO DUKURNFHYQXCJG-UHFFFAOYSA-N 0.000 description 1
108010090665 Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase Proteins 0.000 description 1
230000004988 N-glycosylation Effects 0.000 description 1
206010035148 Plague Diseases 0.000 description 1
208000010378 Pulmonary Embolism Diseases 0.000 description 1
206010038563 Reocclusion Diseases 0.000 description 1
108090000190 Thrombin Proteins 0.000 description 1
102000004338 Transferrin Human genes 0.000 description 1
108090000901 Transferrin Proteins 0.000 description 1
239000007983 Tris buffer Substances 0.000 description 1
206010053648 Vascular occlusion Diseases 0.000 description 1
241000607479 Yersinia pestis Species 0.000 description 1
239000002253 acid Substances 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
239000008272 agar Substances 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
230000004075 alteration Effects 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
230000003321 amplification Effects 0.000 description 1
239000003146 anticoagulant agent Substances 0.000 description 1
239000000427 antigen Substances 0.000 description 1
102000036639 antigens Human genes 0.000 description 1
108091007433 antigens Proteins 0.000 description 1
229960003121 arginine Drugs 0.000 description 1
238000000376 autoradiography Methods 0.000 description 1
IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
210000004369 blood Anatomy 0.000 description 1
239000008280 blood Substances 0.000 description 1
230000037396 body weight Effects 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
238000004113 cell culture Methods 0.000 description 1
238000012512 characterization method Methods 0.000 description 1
239000003593 chromogenic compound Substances 0.000 description 1
238000003776 cleavage reaction Methods 0.000 description 1
150000001875 compounds Chemical class 0.000 description 1
238000010276 construction Methods 0.000 description 1
230000009089 cytolysis Effects 0.000 description 1
230000007423 decrease Effects 0.000 description 1
230000022811 deglycosylation Effects 0.000 description 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
208000035475 disorder Diseases 0.000 description 1
238000004090 dissolution Methods 0.000 description 1
VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
230000002526 effect on cardiovascular system Effects 0.000 description 1
230000008030 elimination Effects 0.000 description 1
238000003379 elimination reaction Methods 0.000 description 1
108010092809 exonuclease Bal 31 Proteins 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
238000000605 extraction Methods 0.000 description 1
229940012952 fibrinogen Drugs 0.000 description 1
239000003527 fibrinolytic agent Substances 0.000 description 1
238000009472 formulation Methods 0.000 description 1
238000001641 gel filtration chromatography Methods 0.000 description 1
238000007429 general method Methods 0.000 description 1
230000002068 genetic effect Effects 0.000 description 1
230000023597 hemostasis Effects 0.000 description 1
238000011534 incubation Methods 0.000 description 1
238000001361 intraarterial administration Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
238000010253 intravenous injection Methods 0.000 description 1
238000011835 investigation Methods 0.000 description 1
JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 1
229920002521 macromolecule Polymers 0.000 description 1
230000014759 maintenance of location Effects 0.000 description 1
125000000311 mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
239000002609 medium Substances 0.000 description 1
208000010125 myocardial infarction Diseases 0.000 description 1
238000003199 nucleic acid amplification method Methods 0.000 description 1
108020004707 nucleic acids Proteins 0.000 description 1
102000039446 nucleic acids Human genes 0.000 description 1
150000007523 nucleic acids Chemical class 0.000 description 1
239000002773 nucleotide Substances 0.000 description 1
125000003729 nucleotide group Chemical group 0.000 description 1
230000037361 pathway Effects 0.000 description 1
230000002093 peripheral effect Effects 0.000 description 1
108010088904 phenylalanylproline Proteins 0.000 description 1
CCTIOCVIZPCTGO-BYPYZUCNSA-N phosphoarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)NP(O)(O)=O CCTIOCVIZPCTGO-BYPYZUCNSA-N 0.000 description 1
229960004838 phosphoric acid Drugs 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
229940068968 polysorbate 80 Drugs 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
230000008569 process Effects 0.000 description 1
229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
238000000746 purification Methods 0.000 description 1
238000012207 quantitative assay Methods 0.000 description 1
230000002285 radioactive effect Effects 0.000 description 1
230000009467 reduction Effects 0.000 description 1
230000003362 replicative effect Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
238000003118 sandwich ELISA Methods 0.000 description 1
230000007017 scission Effects 0.000 description 1
238000012216 screening Methods 0.000 description 1
239000006152 selective media Substances 0.000 description 1
230000035945 sensitivity Effects 0.000 description 1
210000002966 serum Anatomy 0.000 description 1
235000021309 simple sugar Nutrition 0.000 description 1
239000008354 sodium chloride injection Substances 0.000 description 1
239000012064 sodium phosphate buffer Substances 0.000 description 1
239000007790 solid phase Substances 0.000 description 1
239000008227 sterile water for injection Substances 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
229960004072 thrombin Drugs 0.000 description 1
229960000103 thrombolytic agent Drugs 0.000 description 1
229940104230 thymidine Drugs 0.000 description 1
229960000187 tissue plasminogen activator Drugs 0.000 description 1
239000012581 transferrin Substances 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
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
208000021331 vascular occlusion disease Diseases 0.000 description 1
239000011800 void material Substances 0.000 description 1

Classifications

- 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)
- C12N9/6456—Plasminogen activators
- C12N9/6459—Plasminogen activators t-plasminogen activator (3.4.21.68), i.e. tPA
- 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
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21069—Protein C activated (3.4.21.69)
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Engineering & Computer Science (AREA)
Life Sciences & Earth Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Zoology (AREA)
Wood Science & Technology (AREA)
Genetics & Genomics (AREA)
General Health & Medical Sciences (AREA)
Biochemistry (AREA)
Medicinal Chemistry (AREA)
General Engineering & Computer Science (AREA)
Biomedical Technology (AREA)
Microbiology (AREA)
Hematology (AREA)
Veterinary Medicine (AREA)
Animal Behavior & Ethology (AREA)
Molecular Biology (AREA)
Biotechnology (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Public Health (AREA)
Diabetes (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Enzymes And Modification Thereof (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Peptides Or Proteins (AREA)
Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Medicines Containing Material From Animals Or Micro-Organisms (AREA)

IL8193787A 1986-03-18 1987-03-18 Modified human tissue-type plasminogen activator devoid of functional carbohydrate structure at amino acid residue 117 having increased in vivo half-life, its preparation and pharmaceutical composition containing said molecule IL81937A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US84107586A	1986-03-18	1986-03-18
US2189387A	1987-03-04	1987-03-04

Publications (2)

Publication Number	Publication Date
IL81937A0 IL81937A0 (en)	1987-10-20
IL81937A true IL81937A (en)	1994-07-31

Family

ID=26695219

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL8193787A IL81937A (en)	1986-03-18	1987-03-18	Modified human tissue-type plasminogen activator devoid of functional carbohydrate structure at amino acid residue 117 having increased in vivo half-life, its preparation and pharmaceutical composition containing said molecule

Country Status (19)

Country	Link
EP (1)	EP0238304B1 (de)
JP (1)	JP2972812B2 (de)
AT (1)	ATE139569T1 (de)
AU (1)	AU602510B2 (de)
CA (1)	CA1341597C (de)
DD (1)	DD258999A5 (de)
DE (2)	DE3751842T2 (de)
DK (1)	DK175490B1 (de)
ES (1)	ES2088860T3 (de)
FI (1)	FI100802B (de)
FR (1)	FR2597883B1 (de)
GB (1)	GB2189249B (de)
GR (1)	GR3020850T3 (de)
HU (1)	HU202276B (de)
IE (1)	IE81073B1 (de)
IL (1)	IL81937A (de)
NO (1)	NO172133C (de)
NZ (1)	NZ219654A (de)
PT (1)	PT84493B (de)

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
ES8702945A1 (es) *	1984-10-01	1987-01-16	Integrated Genetics Inc	Un metodo de producir activador de plasminogeno de tejido uterino humano
US5108909A (en) *	1985-03-22	1992-04-28	Chiron Corporation	Expression of TPA in mammalian cells
DE3684680D1 (de) *	1985-12-23	1992-05-07	Chiron Corp	Peptidplasminogenaktivatoren.
WO1987004722A1 (en) *	1986-01-31	1987-08-13	Genetics Institute, Inc.	Novel thrombolytic proteins
US4851517A (en) *	1986-02-26	1989-07-25	Monsanto Company	Tissue plasminogen activator oligosaccharide from normal human colon cells
US4927630A (en) *	1986-02-26	1990-05-22	Monsanto Company	Tissue plasminogen activator from normal human colon cells
JPH084501B2 (ja) *	1987-03-20	1996-01-24	エーザイ株式会社	糖鎖に関する変異ｔＰＡ
ZA883958B (en) *	1987-06-04	1989-07-26	Zymogenetics Inc	Mutant t-pa with ringle replacement
IL86909A0 (en) *	1987-07-01	1988-11-30	Beecham Group Plc	Hybrid plasminogen activator,dna coding therefor,derivatives of said plasminogen activator and pharmaceutical compositions containing said plasminogen activator or said derivatives
US5244676A (en) *	1987-10-09	1993-09-14	Monsanto Company	Modified tissue plasminogen activator with modified glycosylation site
IL88247A0 (en) *	1987-11-06	1989-06-30	Genentech Inc	Novel human tissue-type plasminogen activator variant
IL90146A (en) *	1988-05-20	1994-10-07	Genentech Inc	Glycosylation derivatives of tissue plasminogen activator
US5346824A (en) *	1988-05-20	1994-09-13	Genentech, Inc.	DNA encoding variants of tissue plasminogen activators and expression vectors and hosts thereof
US5270198A (en) *	1988-05-20	1993-12-14	Genentech, Inc.	DNA molecules encoding variants of tissue plasminogen activators, vectors, and host cells
US5108901A (en) *	1988-09-02	1992-04-28	Genentech, Inc.	Tissue plasminogen activator having zymogenic or fibrin specific properties
US5262170A (en) *	1988-09-02	1993-11-16	Genentech, Inc.	Tissue plasminogen activator having zymogenic or fibrin specific properties and substituted at amino acid positions 296-299, DNA molecules encoding them, vectors, and host cells
US5714145A (en) *	1988-09-02	1998-02-03	Genentech, Inc.	Tissue plasminogen activator having zymogenic or fibrin specific properties
DE3841296A1 (de) *	1988-12-08	1990-06-13	Bosch Gmbh Robert	Antiblockierregelsystem
US5070021A (en) *	1989-01-10	1991-12-03	Monsanto Company	Method of modifying oligosaccharide structure of tissue plasminogen activator
US5242688A (en) *	1990-12-24	1993-09-07	Eli Lilly And Company	Method of treating thromboembolic disorders by administration of diglycosylated t-pa variants
US5223408A (en) *	1991-07-11	1993-06-29	Genentech, Inc.	Method for making variant secreted proteins with altered properties
JP3559559B2 (ja) *	1992-06-03	2004-09-02	ジェネンテク，インコーポレイテッド	向上した治療特性を有する組織プラスミノーゲン活性化因子グリコシル化変異体
US6706504B1 (en)	1996-11-12	2004-03-16	The Scripps Research Institute	Tissue type plasminogen activator (t-PA) variants: compositions and methods of use
CA2368797C (en)	1999-04-26	2010-08-17	Genentech, Inc.	Cell culture process
US7084118B2 (en)	2002-02-22	2006-08-01	Genentech, Inc.	Combination treatment with t-PA variant and low molecular weight heparin

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
ZA833174B (en) *	1982-05-05	1984-08-29	Genentech Inc	Human tissue plasminogen activator
EP0125254A1 (de) *	1982-10-28	1984-11-21	Beecham Group Plc	Enzymderivate und deren verwendung bei der behandlung von trombosen
EP0125269A1 (de) *	1982-11-11	1984-11-21	Beecham Group Plc	Pharmazeutisch aktive verbindungen
ES8702945A1 (es) *	1984-10-01	1987-01-16	Integrated Genetics Inc	Un metodo de producir activador de plasminogeno de tejido uterino humano
DE3537176C2 (de) *	1984-10-18	1994-06-09	Zymogenetics Inc	Gewebeplasminogenaktivator und Verfahren zu seiner Herstellung
JPS61247384A (ja) *	1984-10-18	1986-11-04	チモ−ジエネテイツクス　インコ−ポレ−テツド	酵母中でプラスミノ−ゲン活性化因子を発現する方法
DE3613390C2 (de) *	1985-04-22	2001-10-11	Genentech Inc	Einkettige Human-Gewebeplasminogen-Aktivator (t-PA)-Mutanten, kodierende DNA, Expressionsvektor, Mikroorganismus, Zellkultur und pharmazeutische Zusammensetzung
JPH0811066B2 (ja) *	1985-09-30	1996-02-07	インテグレーテッド・ジエネティックス・インコーポレーテッド	組換えｄｎａが生産するヒト子宮プラスミノ−ゲンアクチベ−タ−
GB8528321D0 (en) *	1985-11-18	1985-12-24	Ciba Geigy Ag	Modified fibrinolytic agents
DE3684680D1 (de) *	1985-12-23	1992-05-07	Chiron Corp	Peptidplasminogenaktivatoren.
WO1987004722A1 (en) *	1986-01-31	1987-08-13	Genetics Institute, Inc.	Novel thrombolytic proteins

1987
- 1987-03-16 IE IE69187A patent/IE81073B1/en not_active IP Right Cessation
- 1987-03-17 FR FR878703644A patent/FR2597883B1/fr not_active Expired - Lifetime
- 1987-03-17 NZ NZ219654A patent/NZ219654A/xx unknown
- 1987-03-17 NO NO871086A patent/NO172133C/no unknown
- 1987-03-17 DK DK198701358A patent/DK175490B1/da not_active IP Right Cessation
- 1987-03-17 DE DE3751842T patent/DE3751842T2/de not_active Expired - Lifetime
- 1987-03-17 PT PT84493A patent/PT84493B/pt unknown
- 1987-03-17 AT AT87302267T patent/ATE139569T1/de not_active IP Right Cessation
- 1987-03-17 GB GB8706249A patent/GB2189249B/en not_active Expired - Lifetime
- 1987-03-17 EP EP87302267A patent/EP0238304B1/de not_active Expired - Lifetime
- 1987-03-17 AU AU70088/87A patent/AU602510B2/en not_active Expired
- 1987-03-17 ES ES87302267T patent/ES2088860T3/es not_active Expired - Lifetime
- 1987-03-17 HU HU871152A patent/HU202276B/hu unknown
- 1987-03-17 DE DE3708681A patent/DE3708681C2/de not_active Expired - Lifetime
- 1987-03-18 JP JP62065536A patent/JP2972812B2/ja not_active Expired - Lifetime
- 1987-03-18 IL IL8193787A patent/IL81937A/en not_active IP Right Cessation
- 1987-03-18 DD DD30090087A patent/DD258999A5/de unknown
- 1987-03-18 FI FI871175A patent/FI100802B/fi not_active IP Right Cessation
- 1987-03-18 CA CA000532353A patent/CA1341597C/en not_active Expired - Fee Related
1996
- 1996-08-22 GR GR960402207T patent/GR3020850T3/el unknown

Also Published As

Publication number	Publication date
DE3751842T2 (de)	1996-11-28
CA1341597C (en)	2009-06-23
HUT43108A (en)	1987-09-28
GR3020850T3 (en)	1996-11-30
FI871175A0 (fi)	1987-03-18
FI871175L (fi)	1987-09-19
DE3751842D1 (de)	1996-07-25
NO172133B (no)	1993-03-01
IL81937A0 (en)	1987-10-20
DD258999A5 (de)	1988-08-10
GB2189249B (en)	1990-10-31
DK175490B1 (da)	2004-11-08
HU202276B (en)	1991-02-28
IE870691L (en)	1987-09-18
FI100802B (fi)	1998-02-27
DE3708681A1 (de)	1987-10-01
AU602510B2 (en)	1990-10-18
NO871086D0 (no)	1987-03-17
JP2972812B2 (ja)	1999-11-08
JPS62282582A (ja)	1987-12-08
PT84493A (en)	1987-04-01
EP0238304A3 (en)	1988-07-06
ES2088860T3 (es)	1996-10-01
GB2189249A (en)	1987-10-21
GB8706249D0 (en)	1987-04-23
NO871086L (no)	1987-09-21
AU7008887A (en)	1987-09-24
EP0238304A2 (de)	1987-09-23
DE3708681C2 (de)	1995-08-17
PT84493B (pt)	1989-11-10
DK135887D0 (da)	1987-03-17
NZ219654A (en)	1990-08-28
DK135887A (da)	1987-09-19
EP0238304B1 (de)	1996-06-19
FR2597883B1 (fr)	1990-04-20
IE81073B1 (en)	2000-01-12
FR2597883A1 (fr)	1987-10-30
ATE139569T1 (de)	1996-07-15
NO172133C (no)	1993-06-09

Legal Events

Date	Code	Title
1997-06-10	KB	Patent renewed
2001-06-14	KB	Patent renewed
2005-05-17	KB	Patent renewed
2007-07-24	EXP	Patent expired

Publication	Publication Date	Title
CA1341597C (en)	2009-06-23	Mutant human tissue-type plasminogen activator with a modified carbohydrate structure at amino acid residue 117
US5308617A (en)	1994-05-03	Protein heparin conjugates
US4853330A (en)	1989-08-01	Human tissue plasminogen activator
Lau et al.	1987	A Modified Human Tissue Plasminogen Activator with Extended Half–Life In Vivo
US5753224A (en)	1998-05-19	Hybrid protein C
Cole et al.	1993	In vivo clearance of tissue plasminogen activator: the complex role of sites of glycosylation and level of sialylation
AU624158B2 (en)	1992-06-04	Variants of plasminogen activators and processes for their production
EP0297066B1 (de)	1993-08-18	Neue fibrinolytische Enzyme
CA1341609C (en)	2011-02-01	Novel human tissue-type plasminogen activator variant
US5589361A (en)	1996-12-31	Human tissue-type plasminogen activator variant
HK1009289A (en)	1999-05-28	Novel human tissue-type plasminogen activator variant
IL104953A (en)	2002-08-14	Method for producing tissue-type plasminogen activator by transforming and cultivating a host cell incapable of forming complex glycoproteins
Li et al.	1992	Biochemical properties of recombinant mutants of nonglycosylated single chain urokinase-type plasminogen activator
US6682733B1 (en)	2004-01-27	Fibrinolytic enzymes
WO1989007641A1 (en)	1989-08-24	Enhancement of the therapeutic properties of glycoprotein