BR112015000267B1 - Proteínas quiméricas, e composição farmacêutica - Google Patents
Proteínas quiméricas, e composição farmacêutica Download PDFInfo
- Publication number
- BR112015000267B1 BR112015000267B1 BR112015000267-6A BR112015000267A BR112015000267B1 BR 112015000267 B1 BR112015000267 B1 BR 112015000267B1 BR 112015000267 A BR112015000267 A BR 112015000267A BR 112015000267 B1 BR112015000267 B1 BR 112015000267B1
- Authority
- BR
- Brazil
- Prior art keywords
- seq
- fviii
- xten
- amino acid
- domain
- Prior art date
Links
- 108020001507 fusion proteins Proteins 0.000 title claims abstract description 124
- 102000037865 fusion proteins Human genes 0.000 title claims abstract description 124
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 4
- 102100036537 von Willebrand factor Human genes 0.000 claims abstract description 442
- 239000012634 fragment Substances 0.000 claims abstract description 318
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 209
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 197
- 229920001184 polypeptide Polymers 0.000 claims abstract description 195
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims abstract description 37
- 235000001014 amino acid Nutrition 0.000 claims description 529
- 150000001413 amino acids Chemical class 0.000 claims description 503
- 108010047303 von Willebrand Factor Proteins 0.000 claims description 432
- 229960001134 von willebrand factor Drugs 0.000 claims description 432
- 108090000623 proteins and genes Proteins 0.000 claims description 418
- 102000004169 proteins and genes Human genes 0.000 claims description 393
- 235000018102 proteins Nutrition 0.000 claims description 392
- 238000003780 insertion Methods 0.000 claims description 118
- 230000037431 insertion Effects 0.000 claims description 118
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 91
- 230000003993 interaction Effects 0.000 claims description 53
- 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 claims description 39
- 238000006467 substitution reaction Methods 0.000 claims description 36
- 238000012217 deletion Methods 0.000 claims description 27
- 230000037430 deletion Effects 0.000 claims description 27
- 102000057593 human F8 Human genes 0.000 claims description 25
- 230000036961 partial effect Effects 0.000 claims description 10
- 235000004279 alanine Nutrition 0.000 claims description 8
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 7
- 235000018417 cysteine Nutrition 0.000 claims description 7
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 6
- 101001082397 Human adenovirus B serotype 3 Hexon-associated protein Proteins 0.000 claims 1
- 101001120093 Pseudoalteromonas phage PM2 Protein P8 Proteins 0.000 claims 1
- 230000027455 binding Effects 0.000 abstract description 125
- 102000040430 polynucleotide Human genes 0.000 abstract description 42
- 108091033319 polynucleotide Proteins 0.000 abstract description 42
- 239000002157 polynucleotide Substances 0.000 abstract description 42
- 239000013598 vector Substances 0.000 abstract description 40
- 239000002773 nucleotide Substances 0.000 abstract description 29
- 125000003729 nucleotide group Chemical group 0.000 abstract description 29
- 230000000670 limiting effect Effects 0.000 abstract description 14
- 102100026735 Coagulation factor VIII Human genes 0.000 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- -1 HOST CELL Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 229940024606 amino acid Drugs 0.000 description 497
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 159
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 158
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 79
- 238000003776 cleavage reaction Methods 0.000 description 40
- 230000007017 scission Effects 0.000 description 40
- 125000000539 amino acid group Chemical group 0.000 description 38
- 210000004027 cell Anatomy 0.000 description 37
- 230000000694 effects Effects 0.000 description 35
- 239000000126 substance Substances 0.000 description 35
- 102000002110 C2 domains Human genes 0.000 description 33
- 108050009459 C2 domains Proteins 0.000 description 33
- 238000000034 method Methods 0.000 description 31
- 208000032843 Hemorrhage Diseases 0.000 description 29
- 102000001690 Factor VIII Human genes 0.000 description 28
- 108010054218 Factor VIII Proteins 0.000 description 28
- 208000034158 bleeding Diseases 0.000 description 26
- 230000000740 bleeding effect Effects 0.000 description 26
- 229960000301 factor viii Drugs 0.000 description 25
- 230000006870 function Effects 0.000 description 25
- 150000007523 nucleic acids Chemical class 0.000 description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 23
- 241000699670 Mus sp. Species 0.000 description 22
- 230000035772 mutation Effects 0.000 description 20
- 102000039446 nucleic acids Human genes 0.000 description 20
- 108020004707 nucleic acids Proteins 0.000 description 20
- 102000005962 receptors Human genes 0.000 description 20
- 108020003175 receptors Proteins 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- 210000002381 plasma Anatomy 0.000 description 18
- 238000012545 processing Methods 0.000 description 18
- 230000035602 clotting Effects 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 17
- 102000004190 Enzymes Human genes 0.000 description 16
- 108090000790 Enzymes Proteins 0.000 description 16
- 108010076504 Protein Sorting Signals Proteins 0.000 description 16
- 229940088598 enzyme Drugs 0.000 description 16
- 108091026890 Coding region Proteins 0.000 description 15
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 14
- 108090000190 Thrombin Proteins 0.000 description 14
- 238000003556 assay Methods 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 238000001727 in vivo Methods 0.000 description 14
- 230000001965 increasing effect Effects 0.000 description 14
- 229960004072 thrombin Drugs 0.000 description 14
- 108020004414 DNA Proteins 0.000 description 13
- 239000000539 dimer Substances 0.000 description 13
- 230000003834 intracellular effect Effects 0.000 description 13
- 102100035233 Furin Human genes 0.000 description 12
- 239000004365 Protease Substances 0.000 description 12
- 108090001126 Furin Proteins 0.000 description 11
- 102000035195 Peptidases Human genes 0.000 description 11
- 108091005804 Peptidases Proteins 0.000 description 11
- 230000004913 activation Effects 0.000 description 11
- 210000004899 c-terminal region Anatomy 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 239000000833 heterodimer Substances 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 230000002209 hydrophobic effect Effects 0.000 description 11
- 239000000178 monomer Substances 0.000 description 11
- 235000019419 proteases Nutrition 0.000 description 11
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 10
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 10
- 108091028043 Nucleic acid sequence Proteins 0.000 description 10
- 230000002378 acidificating effect Effects 0.000 description 10
- 229960000900 human factor viii Drugs 0.000 description 10
- 230000004048 modification Effects 0.000 description 10
- 238000012986 modification Methods 0.000 description 10
- 230000037361 pathway Effects 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 9
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 9
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 9
- 206010053567 Coagulopathies Diseases 0.000 description 9
- 239000003114 blood coagulation factor Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 8
- 239000004475 Arginine Substances 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 8
- 230000008030 elimination Effects 0.000 description 8
- 238000003379 elimination reaction Methods 0.000 description 8
- 108020004999 messenger RNA Proteins 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 7
- 102100036365 Proprotein convertase subtilisin/kexin type 5 Human genes 0.000 description 7
- 102100038950 Proprotein convertase subtilisin/kexin type 7 Human genes 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 230000004087 circulation Effects 0.000 description 7
- 239000012636 effector Substances 0.000 description 7
- 208000031169 hemorrhagic disease Diseases 0.000 description 7
- 208000014674 injury Diseases 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- 238000011144 upstream manufacturing Methods 0.000 description 7
- 201000003542 Factor VIII deficiency Diseases 0.000 description 6
- 108010014173 Factor X Proteins 0.000 description 6
- 239000004606 Fillers/Extenders Substances 0.000 description 6
- 208000009292 Hemophilia A Diseases 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
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 6
- 108700026244 Open Reading Frames Proteins 0.000 description 6
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 6
- 108010022052 Proprotein Convertase 5 Proteins 0.000 description 6
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 6
- 239000004473 Threonine Substances 0.000 description 6
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 6
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 230000015271 coagulation Effects 0.000 description 6
- 238000005345 coagulation Methods 0.000 description 6
- 239000002299 complementary DNA Substances 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 230000002255 enzymatic effect Effects 0.000 description 6
- 229940012426 factor x Drugs 0.000 description 6
- 230000004927 fusion Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 230000010076 replication Effects 0.000 description 6
- 102000014452 scavenger receptors Human genes 0.000 description 6
- 108010078070 scavenger receptors Proteins 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 238000013518 transcription Methods 0.000 description 6
- 230000035897 transcription Effects 0.000 description 6
- 230000014616 translation Effects 0.000 description 6
- 238000013519 translation Methods 0.000 description 6
- 230000008733 trauma Effects 0.000 description 6
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 6
- 102100022641 Coagulation factor IX Human genes 0.000 description 5
- 108010074860 Factor Xa Proteins 0.000 description 5
- 108010087819 Fc receptors Proteins 0.000 description 5
- 102000009109 Fc receptors Human genes 0.000 description 5
- 108010073385 Fibrin Proteins 0.000 description 5
- 102000009123 Fibrin Human genes 0.000 description 5
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 5
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 5
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 5
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 5
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 5
- 101710180647 Proprotein convertase subtilisin/kexin type 7 Proteins 0.000 description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 5
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 5
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 5
- 102220359803 c.10G>A Human genes 0.000 description 5
- 238000010367 cloning Methods 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 229950003499 fibrin Drugs 0.000 description 5
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 5
- 229960000310 isoleucine Drugs 0.000 description 5
- 229930182817 methionine Natural products 0.000 description 5
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 5
- 230000002000 scavenging effect Effects 0.000 description 5
- 108010093297 tetrapeptide carbamate Proteins 0.000 description 5
- 239000004474 valine Substances 0.000 description 5
- 235000014393 valine Nutrition 0.000 description 5
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 4
- 108010076282 Factor IX Proteins 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 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
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 206010028309 Muscle haemorrhage Diseases 0.000 description 4
- 230000004988 N-glycosylation Effects 0.000 description 4
- 108010029485 Protein Isoforms Proteins 0.000 description 4
- 102000001708 Protein Isoforms Human genes 0.000 description 4
- 108010094028 Prothrombin Proteins 0.000 description 4
- 102100027378 Prothrombin Human genes 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 235000009582 asparagine Nutrition 0.000 description 4
- 229960001230 asparagine Drugs 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- 108700019309 factor VIII-Fc fusion Proteins 0.000 description 4
- 229960004222 factor ix Drugs 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- 235000004554 glutamine Nutrition 0.000 description 4
- 230000023597 hemostasis Effects 0.000 description 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
- 239000000710 homodimer Substances 0.000 description 4
- 230000005847 immunogenicity Effects 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000006337 proteolytic cleavage Effects 0.000 description 4
- 229940039716 prothrombin Drugs 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 239000004055 small Interfering RNA Substances 0.000 description 4
- 125000006850 spacer group Chemical group 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 230000000087 stabilizing effect Effects 0.000 description 4
- 230000032258 transport Effects 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- 108010048049 Factor IXa Proteins 0.000 description 3
- 108010049003 Fibrinogen Proteins 0.000 description 3
- 102000008946 Fibrinogen 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
- 101100156611 Homo sapiens VWF gene Proteins 0.000 description 3
- 108091092195 Intron Proteins 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 108090001015 cancer procoagulant Proteins 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 229910003460 diamond Inorganic materials 0.000 description 3
- 239000010432 diamond Substances 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 210000003527 eukaryotic cell Anatomy 0.000 description 3
- 201000007219 factor XI deficiency Diseases 0.000 description 3
- 229940012952 fibrinogen Drugs 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 208000009429 hemophilia B Diseases 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 210000004962 mammalian cell Anatomy 0.000 description 3
- 108010068617 neonatal Fc receptor Proteins 0.000 description 3
- 230000008488 polyadenylation Effects 0.000 description 3
- 230000002028 premature Effects 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000013169 thromboelastometry Methods 0.000 description 3
- 230000005030 transcription termination Effects 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 206010072043 Central nervous system haemorrhage Diseases 0.000 description 2
- 108010035563 Chloramphenicol O-acetyltransferase Proteins 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 108010014172 Factor V Proteins 0.000 description 2
- 201000007176 Factor XII Deficiency Diseases 0.000 description 2
- 108010071289 Factor XIII Proteins 0.000 description 2
- 108010080805 Factor XIa Proteins 0.000 description 2
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 2
- 102000053187 Glucuronidase Human genes 0.000 description 2
- 108010060309 Glucuronidase Proteins 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- 206010018985 Haemorrhage intracranial Diseases 0.000 description 2
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 2
- 101001098833 Homo sapiens Proprotein convertase subtilisin/kexin type 6 Proteins 0.000 description 2
- 101000782195 Homo sapiens von Willebrand factor Proteins 0.000 description 2
- 206010061249 Intra-abdominal haemorrhage Diseases 0.000 description 2
- 208000008574 Intracranial Hemorrhages Diseases 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- 102000011965 Lipoprotein Receptors Human genes 0.000 description 2
- 108010061306 Lipoprotein Receptors Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102100037732 Neuroendocrine convertase 2 Human genes 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 241000282577 Pan troglodytes Species 0.000 description 2
- 108091093037 Peptide nucleic acid Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102100036371 Proprotein convertase subtilisin/kexin type 4 Human genes 0.000 description 2
- 102100038946 Proprotein convertase subtilisin/kexin type 6 Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 108091027967 Small hairpin RNA Proteins 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 108091081024 Start codon Proteins 0.000 description 2
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
- 108700009124 Transcription Initiation Site Proteins 0.000 description 2
- 108020004566 Transfer RNA Proteins 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 2
- 208000011664 congenital factor XI deficiency Diseases 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000006334 disulfide bridging Effects 0.000 description 2
- 229940012444 factor xiii Drugs 0.000 description 2
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 2
- 239000005090 green fluorescent protein Substances 0.000 description 2
- 208000002085 hemarthrosis Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 230000008884 pinocytosis Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 210000000574 retroperitoneal space Anatomy 0.000 description 2
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 229960000187 tissue plasminogen activator Drugs 0.000 description 2
- 230000014621 translational initiation Effects 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- 230000003612 virological effect Effects 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 1
- FDKWRPBBCBCIGA-REOHCLBHSA-N (2r)-2-azaniumyl-3-$l^{1}-selanylpropanoate Chemical compound [Se]C[C@H](N)C(O)=O FDKWRPBBCBCIGA-REOHCLBHSA-N 0.000 description 1
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 108091022885 ADAM Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000001593 Bernard-Soulier syndrome Diseases 0.000 description 1
- 102100026189 Beta-galactosidase Human genes 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 102100023804 Coagulation factor VII Human genes 0.000 description 1
- 102100027995 Collagenase 3 Human genes 0.000 description 1
- 108050005238 Collagenase 3 Proteins 0.000 description 1
- 102000000989 Complement System Proteins Human genes 0.000 description 1
- 108010069112 Complement System Proteins Proteins 0.000 description 1
- 208000028702 Congenital thrombocyte disease Diseases 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 239000003154 D dimer Substances 0.000 description 1
- FDKWRPBBCBCIGA-UWTATZPHSA-N D-Selenocysteine Natural products [Se]C[C@@H](N)C(O)=O FDKWRPBBCBCIGA-UWTATZPHSA-N 0.000 description 1
- 241000271032 Daboia russelii Species 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 238000004435 EPR spectroscopy Methods 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 108010013369 Enteropeptidase Proteins 0.000 description 1
- 102100029727 Enteropeptidase Human genes 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 108010029144 Factor IIa Proteins 0.000 description 1
- 206010016077 Factor IX deficiency Diseases 0.000 description 1
- 108010023321 Factor VII Proteins 0.000 description 1
- 108010054265 Factor VIIa Proteins 0.000 description 1
- 108010071241 Factor XIIa Proteins 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 208000013607 Glanzmann thrombasthenia Diseases 0.000 description 1
- 208000032371 Glanzmann thrombasthenia 1 Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 108060005986 Granzyme Proteins 0.000 description 1
- 102000001398 Granzyme Human genes 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 1
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000024659 Hemostatic disease Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 101001022148 Homo sapiens Furin Proteins 0.000 description 1
- 101001128694 Homo sapiens Neuroendocrine convertase 1 Proteins 0.000 description 1
- 101000601394 Homo sapiens Neuroendocrine convertase 2 Proteins 0.000 description 1
- 101001072067 Homo sapiens Proprotein convertase subtilisin/kexin type 4 Proteins 0.000 description 1
- 101001072081 Homo sapiens Proprotein convertase subtilisin/kexin type 5 Proteins 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- ZFOMKMMPBOQKMC-KXUCPTDWSA-N L-pyrrolysine Chemical compound C[C@@H]1CC=N[C@H]1C(=O)NCCCC[C@H]([NH3+])C([O-])=O ZFOMKMMPBOQKMC-KXUCPTDWSA-N 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 1
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 1
- 101710187853 Macrophage metalloelastase Proteins 0.000 description 1
- 102100030219 Matrix metalloproteinase-17 Human genes 0.000 description 1
- 108090000585 Matrix metalloproteinase-17 Proteins 0.000 description 1
- 102100029693 Matrix metalloproteinase-20 Human genes 0.000 description 1
- 108090000609 Matrix metalloproteinase-20 Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101000933447 Mus musculus Beta-glucuronidase Proteins 0.000 description 1
- 102100032132 Neuroendocrine convertase 1 Human genes 0.000 description 1
- 102100033174 Neutrophil elastase Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 208000013544 Platelet disease Diseases 0.000 description 1
- 108090000545 Proprotein Convertase 2 Proteins 0.000 description 1
- 102000006437 Proprotein Convertases Human genes 0.000 description 1
- 108010044159 Proprotein Convertases Proteins 0.000 description 1
- 101710180646 Proprotein convertase subtilisin/kexin type 4 Proteins 0.000 description 1
- 101800001491 Protease 3C Proteins 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 102000017975 Protein C Human genes 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 101000913100 Rattus norvegicus IgG receptor FcRn large subunit p51 Proteins 0.000 description 1
- 108700005075 Regulator Genes Proteins 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 108020005038 Terminator Codon Proteins 0.000 description 1
- 208000000392 Thrombasthenia Diseases 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 102000002938 Thrombospondin Human genes 0.000 description 1
- 108060008245 Thrombospondin Proteins 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 208000027276 Von Willebrand disease Diseases 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940031675 advate Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 238000001286 analytical centrifugation Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229930002877 anthocyanin Natural products 0.000 description 1
- 235000010208 anthocyanin Nutrition 0.000 description 1
- 239000004410 anthocyanin Substances 0.000 description 1
- 150000004636 anthocyanins Chemical class 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 229940030225 antihemorrhagics Drugs 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 210000004082 barrier epithelial cell Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- GINJFDRNADDBIN-FXQIFTODSA-N bilanafos Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCP(C)(O)=O GINJFDRNADDBIN-FXQIFTODSA-N 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 238000012575 bio-layer interferometry Methods 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 208000014759 blood platelet disease Diseases 0.000 description 1
- 108010006025 bovine growth hormone Proteins 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
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229940015047 chorionic gonadotropin Drugs 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 208000014763 coagulation protein disease Diseases 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 229940066758 endopeptidases Drugs 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000004890 epithelial barrier function Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 230000006624 extrinsic pathway Effects 0.000 description 1
- 108010091897 factor V Leiden Proteins 0.000 description 1
- 201000007386 factor VII deficiency Diseases 0.000 description 1
- 229940012413 factor vii Drugs 0.000 description 1
- 229940012414 factor viia Drugs 0.000 description 1
- 108010052295 fibrin fragment D Proteins 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000010189 intracellular transport Effects 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 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
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000003593 megakaryocyte Anatomy 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 108090000155 pancreatic elastase II Proteins 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000019525 primary metabolic process Effects 0.000 description 1
- 230000002947 procoagulating effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 230000012743 protein tagging Effects 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000003935 rough endoplasmic reticulum Anatomy 0.000 description 1
- 229940055619 selenocysteine Drugs 0.000 description 1
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Natural products [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 description 1
- 235000016491 selenocysteine Nutrition 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 108090000250 sortase A Proteins 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000001052 transient effect 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
- 239000013638 trimer Substances 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 239000002821 viper venom Substances 0.000 description 1
- 208000012137 von Willebrand disease (hereditary or acquired) Diseases 0.000 description 1
- 108010060284 von Willebrand factor receptor Proteins 0.000 description 1
- 210000004269 weibel-palade body Anatomy 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/35—Fusion polypeptide containing a fusion for enhanced stability/folding during expression, e.g. fusions with chaperones or thioredoxin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/50—Fusion polypeptide containing protease site
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Toxicology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Diabetes (AREA)
- Mycology (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261670401P | 2012-07-11 | 2012-07-11 | |
| US61/670,401 | 2012-07-11 | ||
| US201361759819P | 2013-02-01 | 2013-02-01 | |
| US61/759,819 | 2013-02-01 | ||
| US201361801504P | 2013-03-15 | 2013-03-15 | |
| US201361801544P | 2013-03-15 | 2013-03-15 | |
| US61/801,504 | 2013-03-15 | ||
| US61/801,544 | 2013-03-15 | ||
| US201361827158P | 2013-05-24 | 2013-05-24 | |
| US61/827,158 | 2013-05-24 | ||
| US201361840811P | 2013-06-28 | 2013-06-28 | |
| US61/840,811 | 2013-06-28 | ||
| PCT/US2013/049989 WO2014011819A2 (en) | 2012-07-11 | 2013-07-10 | Factor viii complex with xten and von willebrand factor protein, and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| BR112015000267A2 BR112015000267A2 (pt) | 2018-03-06 |
| BR112015000267B1 true BR112015000267B1 (pt) | 2023-01-24 |
Family
ID=49916682
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BR112015000267-6A BR112015000267B1 (pt) | 2012-07-11 | 2013-07-10 | Proteínas quiméricas, e composição farmacêutica |
Country Status (29)
| Country | Link |
|---|---|
| US (3) | US10138291B2 (enExample) |
| EP (3) | EP3674410A1 (enExample) |
| JP (6) | JP6603128B2 (enExample) |
| KR (2) | KR102403545B1 (enExample) |
| CN (2) | CN104661674A (enExample) |
| AR (1) | AR091735A1 (enExample) |
| AU (4) | AU2013290173B2 (enExample) |
| BR (1) | BR112015000267B1 (enExample) |
| CL (1) | CL2015000060A1 (enExample) |
| CO (1) | CO7170123A2 (enExample) |
| CY (1) | CY1122729T1 (enExample) |
| DK (1) | DK2882450T3 (enExample) |
| EA (2) | EA201792485A3 (enExample) |
| ES (1) | ES2770501T3 (enExample) |
| HR (1) | HRP20200007T1 (enExample) |
| HU (1) | HUE047088T2 (enExample) |
| IL (1) | IL236412B (enExample) |
| LT (1) | LT2882450T (enExample) |
| MX (1) | MX381011B (enExample) |
| NZ (1) | NZ703366A (enExample) |
| PH (1) | PH12015500039B1 (enExample) |
| PL (1) | PL2882450T3 (enExample) |
| PT (1) | PT2882450T (enExample) |
| RS (1) | RS59876B1 (enExample) |
| SG (3) | SG11201500045RA (enExample) |
| SI (1) | SI2882450T1 (enExample) |
| TW (1) | TWI667258B (enExample) |
| UA (1) | UA116632C2 (enExample) |
| WO (1) | WO2014011819A2 (enExample) |
Families Citing this family (60)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL2393828T3 (pl) * | 2009-02-03 | 2017-06-30 | Amunix Operating Inc. | Wydłużone rekombinowane polipeptydy i zawierające je kompozycje |
| US20110046060A1 (en) | 2009-08-24 | 2011-02-24 | Amunix Operating, Inc., | Coagulation factor IX compositions and methods of making and using same |
| HRP20191920T1 (hr) * | 2012-01-12 | 2020-01-10 | Bioverativ Therapeutics Inc. | Kimerni polipeptidi faktora viii i njihova uporaba |
| CN119192402A (zh) | 2012-02-15 | 2024-12-27 | 比奥贝拉蒂治疗公司 | 因子viii组合物及其制备和使用方法 |
| WO2013123457A1 (en) | 2012-02-15 | 2013-08-22 | Biogen Idec Ma Inc. | Recombinant factor viii proteins |
| EP3404105A1 (en) | 2012-07-06 | 2018-11-21 | Bioverativ Therapeutics Inc. | Cell line expressing single chain factor viii polypeptides and uses thereof |
| PL2882450T3 (pl) * | 2012-07-11 | 2020-06-29 | Bioverativ Therapeutics Inc. | Kompleks czynnika viii z xten i białkiem czynnika von willebranda oraz jego zastosowania |
| PL2956477T5 (pl) | 2013-02-15 | 2024-05-27 | Bioverativ Therapeutics Inc. | Zoptymalizowany gen czynnika viii |
| WO2014144549A1 (en) | 2013-03-15 | 2014-09-18 | Biogen Idec Ma Inc. | Factor ix polypeptide formulations |
| ES2657291T3 (es) * | 2013-04-22 | 2018-03-02 | Csl Ltd. | Un complejo covalente de factor de von Willebrand y factor VIII asociado por un puente disulfuro |
| AU2014302100B2 (en) * | 2013-06-28 | 2020-02-13 | Bioverativ Therapeutics Inc. | Thrombin cleavable linker with XTEN and its uses thereof |
| US10947269B2 (en) * | 2013-08-08 | 2021-03-16 | Bioverativ Therapeutics Inc. | Purification of chimeric FVIII molecules |
| WO2015023891A2 (en) | 2013-08-14 | 2015-02-19 | Biogen Idec Ma Inc. | Factor viii-xten fusions and uses thereof |
| FI4176894T3 (fi) * | 2014-01-10 | 2024-05-29 | Bioverativ Therapeutics Inc | Kimeerisiä tekijä viii -proteiineja ja niiden käyttötarkoituksia |
| WO2016004113A1 (en) | 2014-06-30 | 2016-01-07 | Biogen Ma Inc. | Optimized factor ix gene |
| WO2016142289A1 (en) * | 2015-03-06 | 2016-09-15 | Csl Behring Recombinant Facility Ag | Compounds for improving the half-life of von willebrand factor |
| JP6573989B2 (ja) * | 2015-05-22 | 2019-09-11 | ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト | 血友病を処置するための切断型フォン・ヴィルブランド因子ポリペプチド |
| CA2994547A1 (en) | 2015-08-03 | 2017-02-09 | Bioverativ Therapeutics Inc. | Factor ix fusion proteins and methods of making and using same |
| WO2017027545A1 (en) | 2015-08-12 | 2017-02-16 | Cell Machines, Inc. | Methods and compositions related to long half-life coagulation complexes |
| IL319047A (en) * | 2015-08-28 | 2025-04-01 | Amunix Operating Inc | Chimeric polypeptide composition and methods for its preparation and use |
| JP6851381B6 (ja) | 2016-01-07 | 2021-04-21 | ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト | 変異切断型フォンウィルブランド因子 |
| PT3411478T (pt) | 2016-02-01 | 2022-09-13 | Bioverativ Therapeutics Inc | Genes do fator viii otimizados |
| CN109152817A (zh) | 2016-05-20 | 2019-01-04 | 瑞士奥克特珐玛公司 | 具有改进的药代动力学的糖基化vwf融合蛋白 |
| KR102175878B1 (ko) * | 2016-06-24 | 2020-11-06 | 재단법인 목암생명과학연구소 | Fviii 및 vwf 인자를 포함하는 키메라 단백질 및 그 용도 |
| CN106279437B (zh) * | 2016-08-19 | 2017-10-31 | 安源医药科技(上海)有限公司 | 高糖基化人凝血因子viii融合蛋白及其制备方法与用途 |
| CN107759697B (zh) | 2016-08-19 | 2023-03-24 | 安源医药科技(上海)有限公司 | 制备融合蛋白的方法 |
| US10738338B2 (en) | 2016-10-18 | 2020-08-11 | The Research Foundation for the State University | Method and composition for biocatalytic protein-oligonucleotide conjugation and protein-oligonucleotide conjugate |
| EP3538133B1 (en) | 2016-11-11 | 2021-02-17 | CSL Behring Lengnau AG | Truncated von willebrand factor polypeptides for treating hemophilia |
| ES2908008T3 (es) | 2016-11-11 | 2022-04-27 | CSL Behring Lengnau AG | Polipéptidos truncados del Factor de von Willebrand para su administración extravascular en el tratamiento o profilaxis de un trastorno de la coagulación sanguínea |
| US12161696B2 (en) | 2016-12-02 | 2024-12-10 | Bioverativ Therapeutics Inc. | Methods of treating hemophilic arthropathy using chimeric clotting factors |
| BR112019011198A2 (pt) | 2016-12-02 | 2019-12-17 | Bioverativ Therapeutics Inc | métodos de indução de tolerância imune a fatores de coagulação |
| CR20190389A (es) | 2017-01-31 | 2019-11-26 | Bioverativ Therapeutics Inc | Proteínas de fusión del factor ix y procedimientos de preparación y utilización de las mismas |
| GB201707139D0 (en) * | 2017-05-04 | 2017-06-21 | Imp Innovations Ltd | Polypeptides |
| WO2019032898A1 (en) | 2017-08-09 | 2019-02-14 | Bioverativ Therapeutics Inc. | NUCLEIC ACID MOLECULES AND USES THEREOF |
| WO2019126576A1 (en) * | 2017-12-21 | 2019-06-27 | Amunix Pharmaceuticals, Inc. | Release segments and binding compositions comprising same |
| TW202015723A (zh) | 2018-05-18 | 2020-05-01 | 美商百歐維拉提夫治療公司 | 治療a型血友病的方法 |
| SG11202101157VA (en) | 2018-08-09 | 2021-03-30 | Bioverativ Therapeutics Inc | Nucleic acid molecules and uses thereof for non-viral gene therapy |
| MY204234A (en) | 2018-08-27 | 2024-08-16 | Regeneron Pharma | Use of raman spectroscopy in downstream purification |
| JP2022507516A (ja) | 2018-11-15 | 2022-01-18 | クアンタム-エスアイ インコーポレイテッド | タンパク質シーケンシングのための方法及び組成物 |
| SG11202105880TA (en) | 2018-12-06 | 2021-07-29 | Bioverativ Therapeutics Inc | Use of lentiviral vectors expressing factor ix |
| US10654911B1 (en) * | 2019-04-02 | 2020-05-19 | Beijing Neoletix Biological Technology Co., Ltd. | Vector co-expressing truncated von Willebrand factor and factor VIII |
| TW202115127A (zh) * | 2019-06-19 | 2021-04-16 | 美商百歐維拉提夫治療公司 | 治療血友病及低骨質密度之方法及組成物 |
| CN112175088B (zh) * | 2019-07-02 | 2023-03-28 | 江苏晟斯生物制药有限公司 | 改进的fix融合蛋白、缀合物及其应用 |
| CN114364796B (zh) * | 2019-09-02 | 2023-07-11 | 甘李药业股份有限公司 | 嵌合蛋白 |
| WO2021067389A1 (en) | 2019-09-30 | 2021-04-08 | Bioverativ Therapeutics Inc. | Lentiviral vector formulations |
| CA3157605A1 (en) | 2019-11-13 | 2021-05-20 | Volker Schellenberger | Barcoded xten polypeptides and compositions thereof, and methods for making and using the same |
| CN116925237A (zh) | 2019-12-31 | 2023-10-24 | 北京质肽生物医药科技有限公司 | Glp-1和gdf15的融合蛋白以及其缀合物 |
| CN113728013B (zh) | 2020-01-11 | 2022-06-14 | 北京质肽生物医药科技有限公司 | Glp-1和fgf21的融合蛋白的缀合物 |
| CA3177375A1 (en) * | 2020-05-20 | 2021-11-25 | Quantum-Si Incorporated | Methods and compositions for protein sequencing |
| US12173307B2 (en) | 2020-06-24 | 2024-12-24 | Bioverativ Therapeutics Inc. | Methods for the purification of viral vectors |
| WO2021263058A1 (en) | 2020-06-25 | 2021-12-30 | Amunix Pharmaceuticals, Inc. | Her-2 targeted bispecific compositions and methods for making and using the same |
| CN115925994B (zh) | 2020-09-30 | 2023-09-22 | 北京质肽生物医药科技有限公司 | 多肽缀合物和使用方法 |
| US20240287158A1 (en) | 2021-06-23 | 2024-08-29 | Bioverativ Therapeutics Inc. | Formulations of factor viii chimeric proteins and uses thereof |
| CN113862301A (zh) * | 2021-08-25 | 2021-12-31 | 上海交通大学医学院附属瑞金医院 | 一种vwf前肽表达载体及其制备方法和应用 |
| JP2025512832A (ja) | 2022-03-30 | 2025-04-22 | ベイジン キューエル バイオファーマシューティカル カンパニー,リミテッド | ポリペプチドコンジュゲートの液体医薬組成物およびその使用の方法 |
| IL322564A (en) | 2023-02-10 | 2025-10-01 | Amunix Pharmaceuticals Inc | Prostate-specific membrane antigen (PSMA)-targeting compositions and methods for their preparation and use |
| AU2024242164A1 (en) | 2023-03-31 | 2025-09-11 | Octapharma Ag | Fviii-vwf fusion proteins with improved pharmacokinetics |
| KR20250166225A (ko) | 2023-04-17 | 2025-11-27 | 아뮤닉스 파마슈티컬스, 인크. | 표피 성장 인자 수용체를 표적화하는 조성물 및 이의 제조 방법 및 사용 방법 |
| WO2025122957A1 (en) | 2023-12-08 | 2025-06-12 | Amunix Pharmaceuticals, Inc. | Protease activatable cytokines and methods for making and using the same |
| WO2025181343A1 (en) | 2024-02-29 | 2025-09-04 | Octapharma Ag | Cystine knot domain fusion protein dimers |
Family Cites Families (144)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
| US4215051A (en) | 1979-08-29 | 1980-07-29 | Standard Oil Company (Indiana) | Formation, purification and recovery of phthalic anhydride |
| US4713339A (en) | 1983-01-19 | 1987-12-15 | Genentech, Inc. | Polycistronic expression vector construction |
| US4757006A (en) | 1983-10-28 | 1988-07-12 | Genetics Institute, Inc. | Human factor VIII:C gene and recombinant methods for production |
| US4965199A (en) | 1984-04-20 | 1990-10-23 | Genentech, Inc. | Preparation of functional human factor VIII in mammalian cells using methotrexate based selection |
| US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
| US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
| US4965188A (en) | 1986-08-22 | 1990-10-23 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences using a thermostable enzyme |
| US5981216A (en) | 1985-04-01 | 1999-11-09 | Alusuisse Holdings A.G. | Transformed myeloma cell-line and a process for the expression of a gene coding for a eukaryotic polypeptide employing same |
| JPH0788399B2 (ja) | 1985-04-12 | 1995-09-27 | ジェネティックス・インスチチュ−ト・インコ−ポレ−テッド | 新規プロコアギュラント蛋白質 |
| KR910006424B1 (ko) | 1985-08-21 | 1991-08-24 | 인코텍스 비.브이 | 편성브리프(brief) 제조방법 |
| DE3785102T2 (de) | 1986-01-03 | 1993-07-22 | Genetics Inst | Verfahren zur herstellung von faktor-viii:c-typ-proteinen. |
| US5595886A (en) | 1986-01-27 | 1997-01-21 | Chiron Corporation | Protein complexes having Factor VIII:C activity and production thereof |
| US4800159A (en) | 1986-02-07 | 1989-01-24 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences |
| US5543502A (en) | 1986-06-24 | 1996-08-06 | Novo Nordisk A/S | Process for producing a coagulation active complex of factor VIII fragments |
| US4912040A (en) | 1986-11-14 | 1990-03-27 | Genetics Institute, Inc. | Eucaryotic expression system |
| DE3883899T3 (de) | 1987-03-18 | 1999-04-22 | Sb2, Inc., Danville, Calif. | Geänderte antikörper. |
| CA1331157C (en) | 1987-04-06 | 1994-08-02 | Randal J. Kaufman | Method for producing factor viii:c-type proteins |
| US6060447A (en) | 1987-05-19 | 2000-05-09 | Chiron Corporation | Protein complexes having Factor VIII:C activity and production thereof |
| US5171844A (en) | 1987-06-12 | 1992-12-15 | Gist-Brocades N.W. | Proteins with factor viii activity: process for their preparation using genetically-engineered cells and pharmaceutical compositions containing them |
| US6346513B1 (en) | 1987-06-12 | 2002-02-12 | Baxter Trading Gmbh | Proteins with factor VIII activity: process for their preparation using genetically-engineered cells and pharmaceutical compositions containing them |
| DE3720246A1 (de) | 1987-06-19 | 1988-12-29 | Behringwerke Ag | Faktor viii:c-aehnliches molekuel mit koagulationsaktivitaet |
| FR2619314B1 (fr) | 1987-08-11 | 1990-06-15 | Transgene Sa | Analogue du facteur viii, procede de preparation et composition pharmaceutique le contenant |
| US4994371A (en) | 1987-08-28 | 1991-02-19 | Davie Earl W | DNA preparation of Christmas factor and use of DNA sequences |
| US6780613B1 (en) | 1988-10-28 | 2004-08-24 | Genentech, Inc. | Growth hormone variants |
| US5004803A (en) | 1988-11-14 | 1991-04-02 | Genetics Institute, Inc. | Production of procoagulant proteins |
| SE465222C5 (sv) | 1989-12-15 | 1998-02-10 | Pharmacia & Upjohn Ab | Ett rekombinant, humant faktor VIII-derivat och förfarande för dess framställning |
| US5846951A (en) | 1991-06-06 | 1998-12-08 | The School Of Pharmacy, University Of London | Pharmaceutical compositions |
| MX9204374A (es) | 1991-07-25 | 1993-03-01 | Idec Pharma Corp | Anticuerpo recombinante y metodo para su produccion. |
| US5364771A (en) | 1992-04-07 | 1994-11-15 | Emory University | Hybrid human/porcine factor VIII |
| US6376463B1 (en) | 1992-04-07 | 2002-04-23 | Emory University | Modified factor VIII |
| US5859204A (en) | 1992-04-07 | 1999-01-12 | Emory University | Modified factor VIII |
| US6037452A (en) | 1992-04-10 | 2000-03-14 | Alpha Therapeutic Corporation | Poly(alkylene oxide)-Factor VIII or Factor IX conjugate |
| US5563045A (en) | 1992-11-13 | 1996-10-08 | Genetics Institute, Inc. | Chimeric procoagulant proteins |
| SE504074C2 (sv) | 1993-07-05 | 1996-11-04 | Pharmacia Ab | Proteinberedning för subkutan, intramuskulär eller intradermal administrering |
| US5643575A (en) | 1993-10-27 | 1997-07-01 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
| GB9422383D0 (en) | 1994-11-05 | 1995-01-04 | Wellcome Found | Antibodies |
| US6818439B1 (en) | 1994-12-30 | 2004-11-16 | Chiron Corporation | Methods for administration of recombinant gene delivery vehicles for treatment of hemophilia and other disorders |
| US6086875A (en) | 1995-01-17 | 2000-07-11 | The Brigham And Women's Hospital, Inc. | Receptor specific transepithelial transport of immunogens |
| US6485726B1 (en) | 1995-01-17 | 2002-11-26 | The Brigham And Women's Hospital, Inc. | Receptor specific transepithelial transport of therapeutics |
| US6030613A (en) | 1995-01-17 | 2000-02-29 | The Brigham And Women's Hospital, Inc. | Receptor specific transepithelial transport of therapeutics |
| US6096871A (en) | 1995-04-14 | 2000-08-01 | Genentech, Inc. | Polypeptides altered to contain an epitope from the Fc region of an IgG molecule for increased half-life |
| US5869046A (en) | 1995-04-14 | 1999-02-09 | Genentech, Inc. | Altered polypeptides with increased half-life |
| US5739277A (en) | 1995-04-14 | 1998-04-14 | Genentech Inc. | Altered polypeptides with increased half-life |
| US6121022A (en) | 1995-04-14 | 2000-09-19 | Genentech, Inc. | Altered polypeptides with increased half-life |
| SE9503380D0 (sv) | 1995-09-29 | 1995-09-29 | Pharmacia Ab | Protein derivatives |
| US6458563B1 (en) | 1996-06-26 | 2002-10-01 | Emory University | Modified factor VIII |
| ATE386809T1 (de) | 1996-08-02 | 2008-03-15 | Bristol Myers Squibb Co | Ein verfahren zur inhibierung immunglobulininduzierter toxizität aufgrund von der verwendung von immunoglobinen in therapie und in vivo diagnostik |
| WO1998023289A1 (en) | 1996-11-27 | 1998-06-04 | The General Hospital Corporation | MODULATION OF IgG BINDING TO FcRn |
| US6277375B1 (en) | 1997-03-03 | 2001-08-21 | Board Of Regents, The University Of Texas System | Immunoglobulin-like domains with increased half-lives |
| CA2225189C (en) | 1997-03-06 | 2010-05-25 | Queen's University At Kingston | Canine factor viii gene, protein and methods of use |
| GB9722131D0 (en) | 1997-10-20 | 1997-12-17 | Medical Res Council | Method |
| US6242195B1 (en) | 1998-04-02 | 2001-06-05 | Genentech, Inc. | Methods for determining binding of an analyte to a receptor |
| US6528624B1 (en) | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
| US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
| PT1068241E (pt) | 1998-04-02 | 2007-11-19 | Genentech Inc | Variantes de anticorpos e respectivos fragmentos |
| GB9809951D0 (en) | 1998-05-08 | 1998-07-08 | Univ Cambridge Tech | Binding molecules |
| US20020142374A1 (en) | 1998-08-17 | 2002-10-03 | Michael Gallo | Generation of modified molecules with increased serum half-lives |
| EP1006183A1 (en) | 1998-12-03 | 2000-06-07 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Recombinant soluble Fc receptors |
| KR101077001B1 (ko) | 1999-01-15 | 2011-10-26 | 제넨테크, 인크. | 효과기 기능이 변화된 폴리펩티드 변이체 |
| US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
| US7829085B2 (en) | 1999-07-14 | 2010-11-09 | Life Sciences Research Partners Vzw | Methods of treating hemostasis disorders using antibodies binding the C1 domain of factor VIII |
| EP2275557A1 (en) | 2000-04-12 | 2011-01-19 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| DE60116137T2 (de) | 2000-05-16 | 2006-08-24 | Lipoxen Technologies Ltd. | Derivatisierung von proteinen in wässrigem lösungsmittel |
| GB0029407D0 (en) | 2000-12-01 | 2001-01-17 | Affitech As | Product |
| DK1355919T3 (da) | 2000-12-12 | 2011-03-14 | Medimmune Llc | Molekyler med længere halveringstider, sammensætninger og anvendelser deraf |
| CA2440582A1 (en) | 2001-03-09 | 2002-10-03 | Dyax Corp. | Serum albumin binding moieties |
| KR101271635B1 (ko) | 2001-12-21 | 2013-06-12 | 휴먼 게놈 사이언시즈, 인코포레이티드 | 알부민 융합 단백질 |
| EP2990417A1 (en) | 2001-12-21 | 2016-03-02 | Human Genome Sciences, Inc. | Albumin insulin fusion protein |
| US20080194481A1 (en) | 2001-12-21 | 2008-08-14 | Human Genome Sciences, Inc. | Albumin Fusion Proteins |
| US20040002587A1 (en) | 2002-02-20 | 2004-01-01 | Watkins Jeffry D. | Fc region variants |
| US20040132101A1 (en) | 2002-09-27 | 2004-07-08 | Xencor | Optimized Fc variants and methods for their generation |
| US7317091B2 (en) | 2002-03-01 | 2008-01-08 | Xencor, Inc. | Optimized Fc variants |
| AU2003209446B2 (en) | 2002-03-01 | 2008-09-25 | Immunomedics, Inc. | Bispecific antibody point mutations for enhancing rate of clearance |
| CN100343393C (zh) | 2002-03-15 | 2007-10-17 | 布赖汉姆妇女医院 | 适合治疗剂全身性递送的中央气道给药 |
| DK1534335T4 (en) | 2002-08-14 | 2015-10-05 | Macrogenics Inc | FCGAMMARIIB-SPECIFIC ANTIBODIES AND PROCEDURES FOR USE THEREOF |
| AU2003275103A1 (en) | 2002-09-17 | 2004-04-08 | Diffusion Science, Inc. | Electrochemical generation, storage and reaction of hydrogen and oxygen using gas permeable catalyst-coated hollow microspheres |
| EP2298805A3 (en) | 2002-09-27 | 2011-04-13 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
| CA2502904C (en) | 2002-10-15 | 2013-05-28 | Protein Design Labs, Inc. | Alteration of fcrn binding affinities or serum half-lives of antibodies by mutagenesis |
| GB2395337B (en) | 2002-11-14 | 2005-12-28 | Gary Michael Wilson | Warning Unit |
| CA2512729C (en) | 2003-01-09 | 2014-09-16 | Macrogenics, Inc. | Identification and engineering of antibodies with variant fc regions and methods of using same |
| US7041635B2 (en) | 2003-01-28 | 2006-05-09 | In2Gen Co., Ltd. | Factor VIII polypeptide |
| EP2572733A1 (en) | 2003-02-26 | 2013-03-27 | Nektar Therapeutics | Polymer-factor VIII moiety conjugates |
| EP1605005B1 (en) | 2003-02-28 | 2013-12-04 | Kuraray Co., Ltd. | Curable resin composition |
| US20090010920A1 (en) | 2003-03-03 | 2009-01-08 | Xencor, Inc. | Fc Variants Having Decreased Affinity for FcyRIIb |
| US8388955B2 (en) | 2003-03-03 | 2013-03-05 | Xencor, Inc. | Fc variants |
| TWI353991B (en) | 2003-05-06 | 2011-12-11 | Syntonix Pharmaceuticals Inc | Immunoglobulin chimeric monomer-dimer hybrids |
| PT1624891E (pt) | 2003-05-06 | 2010-01-05 | Syntonix Pharmaceuticals Inc | Proteínas quiméricas de factor de coagulação-fc destinadas ao tratamento da hemofilia |
| US7348004B2 (en) | 2003-05-06 | 2008-03-25 | Syntonix Pharmaceuticals, Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
| EP1654290B1 (en) | 2003-08-12 | 2019-03-13 | Lipoxen Technologies Limited | Sialic acid derivatives for protein derivatisation and conjugation |
| GB0324368D0 (en) | 2003-10-17 | 2003-11-19 | Univ Cambridge Tech | Polypeptides including modified constant regions |
| US7211559B2 (en) | 2003-10-31 | 2007-05-01 | University Of Maryland, Baltimore | Factor VIII compositions and methods |
| EP1697415A1 (en) | 2003-11-12 | 2006-09-06 | Biogen Idec MA Inc. | NEONATAL Fc RECEPTOR (FcRn)-BINDING POLYPEPTIDE VARIANTS, DIMERIC Fc BINDING PROTEINS AND METHODS RELATED THERETO |
| WO2005077981A2 (en) | 2003-12-22 | 2005-08-25 | Xencor, Inc. | Fc POLYPEPTIDES WITH NOVEL Fc LIGAND BINDING SITES |
| DE602005015542D1 (de) | 2004-01-12 | 2009-09-03 | Applied Molecular Evolution | Varianten der fc-region |
| WO2005092925A2 (en) | 2004-03-24 | 2005-10-06 | Xencor, Inc. | Immunoglobulin variants outside the fc region |
| WO2005123780A2 (en) | 2004-04-09 | 2005-12-29 | Protein Design Labs, Inc. | Alteration of fcrn binding affinities or serum half-lives of antibodies by mutagenesis |
| WO2006085967A2 (en) | 2004-07-09 | 2006-08-17 | Xencor, Inc. | OPTIMIZED ANTI-CD20 MONOCONAL ANTIBODIES HAVING Fc VARIANTS |
| JP2008505174A (ja) | 2004-07-15 | 2008-02-21 | ゼンコー・インコーポレイテッド | 最適化Fc変異体 |
| US7566701B2 (en) | 2004-09-07 | 2009-07-28 | Archemix Corp. | Aptamers to von Willebrand Factor and their use as thrombotic disease therapeutics |
| WO2006047350A2 (en) | 2004-10-21 | 2006-05-04 | Xencor, Inc. | IgG IMMUNOGLOBULIN VARIANTS WITH OPTIMIZED EFFECTOR FUNCTION |
| PL1835938T3 (pl) * | 2004-12-27 | 2014-01-31 | Baxalta Inc | Koniugaty polimer-czynnik von Willebrandta |
| BRPI0614761A2 (pt) | 2005-08-12 | 2009-05-19 | Human Genome Sciences Inc | proteìnas de fusão de albumina |
| US7846445B2 (en) * | 2005-09-27 | 2010-12-07 | Amunix Operating, Inc. | Methods for production of unstructured recombinant polymers and uses thereof |
| WO2007103515A2 (en) | 2006-03-06 | 2007-09-13 | Amunix, Inc. | Unstructured recombinant polymers and uses thereof |
| EP3896090B1 (en) | 2006-06-14 | 2022-01-12 | CSL Behring GmbH | Proteolytically cleavable fusion protein comprising a blood coagulation factor |
| US9187532B2 (en) | 2006-07-21 | 2015-11-17 | Novo Nordisk A/S | Glycosylation of peptides via O-linked glycosylation sequences |
| KR20090064453A (ko) | 2006-09-14 | 2009-06-18 | 휴먼 게놈 사이언시즈, 인코포레이티드 | 알부민 융합 단백질 |
| WO2008057683A2 (en) | 2006-10-03 | 2008-05-15 | Novo Nordisk A/S | Methods for the purification of polypeptide conjugates |
| CN101600448B (zh) | 2006-10-04 | 2015-11-25 | 诺和诺德公司 | 甘油连接的peg化的糖和糖肽 |
| KR101542752B1 (ko) * | 2006-12-22 | 2015-08-10 | 체에스엘 베링 게엠베하 | 연장된 생체내 반감기를 갖는 변형된 응고 인자 |
| EP1935430A1 (en) | 2006-12-22 | 2008-06-25 | CSL Behring GmbH | Modified coagulation factors with prolonged in vivo half-life |
| ATE502114T1 (de) | 2007-06-21 | 2011-04-15 | Univ Muenchen Tech | Biologisch aktive proteine mit erhöhter in-vivo- und/oder in-vitro-stabilität |
| BRPI0815416A2 (pt) | 2007-08-15 | 2014-10-21 | Amunix Inc | Composições e métodos para modificar propriedades de polipeptídeos biologicamente ativos |
| CN104152489A (zh) | 2007-11-01 | 2014-11-19 | 罗切斯特大学 | 具有增加的稳定性的重组因子viii |
| EP2222329A1 (en) * | 2007-11-09 | 2010-09-01 | Baxter International Inc. | Modified recombinant factor viii and von willebrand factor and methods of use |
| AU2008345135C1 (en) | 2007-12-28 | 2015-04-30 | Takeda Pharmaceutical Company Limited | Recombinant VWF formulations |
| AU2009262476C1 (en) * | 2008-06-24 | 2016-06-02 | Csl Behring Gmbh | Factor VIII, von Willebrand factor or complexes thereof with prolonged in vivo half-life |
| WO2010060081A1 (en) | 2008-11-24 | 2010-05-27 | Bayer Healthcare Llc | Method of determining pegylated blood coagulation factor activity in a silica-based activated partial thromboplastin time assay |
| US8680050B2 (en) | 2009-02-03 | 2014-03-25 | Amunix Operating Inc. | Growth hormone polypeptides fused to extended recombinant polypeptides and methods of making and using same |
| US8703717B2 (en) | 2009-02-03 | 2014-04-22 | Amunix Operating Inc. | Growth hormone polypeptides and methods of making and using same |
| PL2393828T3 (pl) * | 2009-02-03 | 2017-06-30 | Amunix Operating Inc. | Wydłużone rekombinowane polipeptydy i zawierające je kompozycje |
| US20110046060A1 (en) | 2009-08-24 | 2011-02-24 | Amunix Operating, Inc., | Coagulation factor IX compositions and methods of making and using same |
| EP2990051B1 (en) | 2009-04-10 | 2016-10-26 | Tufts Medical Center, Inc. | Par-1 activation by metalloproteinase-1 (mmp-1) |
| ES2643641T3 (es) | 2009-06-08 | 2017-11-23 | Amunix Operating Inc. | Polipéptidos de hormona del crecimiento y métodos de producción y uso de los mismos |
| EP2440228B8 (en) | 2009-06-08 | 2023-02-22 | Amunix Operating Inc. | Glucose-regulating polypeptides and methods of making and using same |
| AU2010284977A1 (en) | 2009-08-20 | 2012-03-29 | Csl Behring Gmbh | Albumin fused coagulation factors for non-intravenous administration in the therapy and prophylactic treatment of bleeding disorders |
| WO2011028344A2 (en) | 2009-08-25 | 2011-03-10 | Amunix Operating Inc. | Interleukin-1 receptor antagonist compositions and methods of making and using same |
| RU2579977C2 (ru) | 2009-11-13 | 2016-04-10 | Грифольс Терапьютикс Инк. | СОДЕРЖАЩИЕ ФАКТОР ФОН ВИЛЛЕБРАНДА (vWF) ПРЕПАРАТЫ И СПОСОБЫ, НАБОРЫ И ПРИМЕНЕНИЯ, СВЯЗАННЫЕ С НИМИ |
| AU2010325787B2 (en) * | 2009-12-06 | 2016-05-12 | Bioverativ Therapeutics Inc. | Factor VIII-Fc chimeric and hybrid polypeptides, and methods of use thereof |
| EP2977055A1 (en) | 2010-02-16 | 2016-01-27 | Novo Nordisk A/S | Factor viii fusion protein |
| US20130040888A1 (en) * | 2010-02-16 | 2013-02-14 | Novo Nordisk A/S | Factor VIII Molecules With Reduced VWF Binding |
| UA108646C2 (xx) | 2010-05-20 | 2015-05-25 | Клостридіальні токсини, що руйнуються | |
| AU2011274423B2 (en) | 2010-07-09 | 2016-02-11 | Bioverativ Therapeutics Inc. | Chimeric clotting factors |
| US9611310B2 (en) | 2010-07-09 | 2017-04-04 | Bioverativ Therapeutics Inc. | Systems for factor VIII processing and methods thereof |
| US20130017997A1 (en) | 2010-08-19 | 2013-01-17 | Amunix Operating Inc. | Factor VIII Compositions and Methods of Making and Using Same |
| HRP20191920T1 (hr) * | 2012-01-12 | 2020-01-10 | Bioverativ Therapeutics Inc. | Kimerni polipeptidi faktora viii i njihova uporaba |
| WO2013123457A1 (en) | 2012-02-15 | 2013-08-22 | Biogen Idec Ma Inc. | Recombinant factor viii proteins |
| CN119192402A (zh) | 2012-02-15 | 2024-12-27 | 比奥贝拉蒂治疗公司 | 因子viii组合物及其制备和使用方法 |
| PL2882450T3 (pl) | 2012-07-11 | 2020-06-29 | Bioverativ Therapeutics Inc. | Kompleks czynnika viii z xten i białkiem czynnika von willebranda oraz jego zastosowania |
| US20160229903A1 (en) | 2013-06-28 | 2016-08-11 | Biogen Ma Inc. | Thrombin cleavable linker |
| AU2014302100B2 (en) | 2013-06-28 | 2020-02-13 | Bioverativ Therapeutics Inc. | Thrombin cleavable linker with XTEN and its uses thereof |
| FI4176894T3 (fi) * | 2014-01-10 | 2024-05-29 | Bioverativ Therapeutics Inc | Kimeerisiä tekijä viii -proteiineja ja niiden käyttötarkoituksia |
| TW202015723A (zh) * | 2018-05-18 | 2020-05-01 | 美商百歐維拉提夫治療公司 | 治療a型血友病的方法 |
-
2013
- 2013-07-10 PL PL13816031T patent/PL2882450T3/pl unknown
- 2013-07-10 PH PH1/2015/500039A patent/PH12015500039B1/en unknown
- 2013-07-10 EP EP19210390.1A patent/EP3674410A1/en not_active Withdrawn
- 2013-07-10 SG SG11201500045RA patent/SG11201500045RA/en unknown
- 2013-07-10 DK DK13816031.2T patent/DK2882450T3/da active
- 2013-07-10 EA EA201792485A patent/EA201792485A3/ru unknown
- 2013-07-10 EA EA201590198A patent/EA029685B1/ru unknown
- 2013-07-10 CN CN201380046914.5A patent/CN104661674A/zh active Pending
- 2013-07-10 PT PT138160312T patent/PT2882450T/pt unknown
- 2013-07-10 MX MX2015000397A patent/MX381011B/es unknown
- 2013-07-10 US US14/413,765 patent/US10138291B2/en active Active
- 2013-07-10 AU AU2013290173A patent/AU2013290173B2/en active Active
- 2013-07-10 SG SG10201701037WA patent/SG10201701037WA/en unknown
- 2013-07-10 LT LTEP13816031.2T patent/LT2882450T/lt unknown
- 2013-07-10 ES ES13816031T patent/ES2770501T3/es active Active
- 2013-07-10 WO PCT/US2013/049989 patent/WO2014011819A2/en not_active Ceased
- 2013-07-10 NZ NZ703366A patent/NZ703366A/en unknown
- 2013-07-10 HU HUE13816031A patent/HUE047088T2/hu unknown
- 2013-07-10 EP EP23179872.9A patent/EP4269431A1/en active Pending
- 2013-07-10 RS RS20200123A patent/RS59876B1/sr unknown
- 2013-07-10 JP JP2015521785A patent/JP6603128B2/ja active Active
- 2013-07-10 BR BR112015000267-6A patent/BR112015000267B1/pt active IP Right Grant
- 2013-07-10 KR KR1020217037450A patent/KR102403545B1/ko active Active
- 2013-07-10 SI SI201331656T patent/SI2882450T1/sl unknown
- 2013-07-10 CN CN201811639711.8A patent/CN110054699A/zh active Pending
- 2013-07-10 EP EP13816031.2A patent/EP2882450B1/en active Active
- 2013-07-10 SG SG10201913893XA patent/SG10201913893XA/en unknown
- 2013-07-10 HR HRP20200007TT patent/HRP20200007T1/hr unknown
- 2013-07-10 KR KR1020157003523A patent/KR102329315B1/ko active Active
- 2013-07-11 TW TW102124926A patent/TWI667258B/zh active
- 2013-07-11 AR ARP130102467A patent/AR091735A1/es not_active Application Discontinuation
- 2013-10-07 UA UAA201500228A patent/UA116632C2/uk unknown
-
2014
- 2014-12-23 IL IL236412A patent/IL236412B/en active IP Right Grant
-
2015
- 2015-01-09 CL CL2015000060A patent/CL2015000060A1/es unknown
- 2015-01-16 CO CO15008422A patent/CO7170123A2/es unknown
-
2018
- 2018-04-06 JP JP2018073823A patent/JP2018102323A/ja not_active Withdrawn
- 2018-05-08 AU AU2018203206A patent/AU2018203206B2/en active Active
- 2018-10-08 US US16/154,310 patent/US11091534B2/en active Active
-
2020
- 2020-02-05 CY CY20201100105T patent/CY1122729T1/el unknown
- 2020-03-04 JP JP2020036624A patent/JP7022165B2/ja active Active
- 2020-11-05 AU AU2020264355A patent/AU2020264355A1/en not_active Abandoned
-
2021
- 2021-06-25 US US17/358,142 patent/US20220056108A1/en active Pending
- 2021-10-04 JP JP2021163423A patent/JP2022000471A/ja not_active Withdrawn
-
2022
- 2022-10-10 AU AU2022252703A patent/AU2022252703B2/en active Active
-
2023
- 2023-10-02 JP JP2023171467A patent/JP7682968B2/ja active Active
-
2025
- 2025-05-13 JP JP2025080421A patent/JP2025134089A/ja active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7682968B2 (ja) | XTENおよびvon Willebrand因子タンパク質を有する第VIII因子の複合体、および、その使用 | |
| JP7612637B2 (ja) | 第viii因子キメラタンパク質及びその使用 | |
| EP3033097B1 (en) | Factor viii-xten fusions and uses thereof | |
| TWI826778B (zh) | 嵌合因子 viii 多肽及其用途 | |
| HK40099494A (en) | Factor viii complex with xten and von willebrand factor protein, and uses thereof | |
| HK40092414B (en) | Factor viii chimeric proteins and uses thereof | |
| HK40092414A (en) | Factor viii chimeric proteins and uses thereof | |
| HK40113039A (en) | Factor viii chimeric proteins and uses thereof | |
| HK1211228B (en) | Factor viii complex with xten and von willebrand factor protein, and uses thereof | |
| HK1230526B (en) | Factor viii chimeric proteins and uses thereof | |
| HK1230526A1 (en) | Factor viii chimeric proteins and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B06F | Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette] | ||
| B25D | Requested change of name of applicant approved |
Owner name: AMUNIX OPERATING INC. (US) , BIOGEN MA INC. (US) |
|
| B25A | Requested transfer of rights approved |
Owner name: AMUNIX OPERATING INC. (US) , BIOVERATIV THERAPEUTI |
|
| B07D | Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette] |
Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NAO 10196/2001, QUE MODIFICOU A LEI NAO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUAANCIA PRA VIA DA ANVISA. CONSIDERANDO A APROVAA AO DOS TERMOS DO PARECER NAO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NAO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDAANCIAS CABA-VEIS. |
|
| B07E | Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette] | ||
| B06U | Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette] | ||
| B06A | Patent application procedure suspended [chapter 6.1 patent gazette] | ||
| B09A | Decision: intention to grant [chapter 9.1 patent gazette] | ||
| B16A | Patent or certificate of addition of invention granted [chapter 16.1 patent gazette] |
Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 10/07/2013, OBSERVADAS AS CONDICOES LEGAIS |