JP2008109939A - 細胞膜に固定された抗凝固性融合タンパク質 - Google Patents
細胞膜に固定された抗凝固性融合タンパク質 Download PDFInfo
- Publication number
- JP2008109939A JP2008109939A JP2008007332A JP2008007332A JP2008109939A JP 2008109939 A JP2008109939 A JP 2008109939A JP 2008007332 A JP2008007332 A JP 2008007332A JP 2008007332 A JP2008007332 A JP 2008007332A JP 2008109939 A JP2008109939 A JP 2008109939A
- Authority
- JP
- Japan
- Prior art keywords
- hirudin
- tfpi
- cells
- thrombin
- cell
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000003146 anticoagulant agent Substances 0.000 title abstract description 22
- 229940127219 anticoagulant drug Drugs 0.000 title abstract description 22
- 210000000170 cell membrane Anatomy 0.000 title abstract description 16
- 108020001507 fusion proteins Proteins 0.000 title description 12
- 102000037865 fusion proteins Human genes 0.000 title description 12
- 210000004027 cell Anatomy 0.000 abstract description 156
- 102100030951 Tissue factor pathway inhibitor Human genes 0.000 abstract description 64
- 108010013555 lipoprotein-associated coagulation inhibitor Proteins 0.000 abstract description 64
- 229940006607 hirudin Drugs 0.000 abstract description 61
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 abstract description 56
- 108010007267 Hirudins Proteins 0.000 abstract description 52
- 102000007625 Hirudins Human genes 0.000 abstract description 52
- 108090000623 proteins and genes Proteins 0.000 abstract description 48
- 102000004169 proteins and genes Human genes 0.000 abstract description 46
- 210000001519 tissue Anatomy 0.000 abstract description 22
- 230000014509 gene expression Effects 0.000 abstract description 21
- 210000000056 organ Anatomy 0.000 abstract description 21
- 230000008685 targeting Effects 0.000 abstract description 17
- 238000002054 transplantation Methods 0.000 abstract description 13
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 108010065972 tick anticoagulant peptide Proteins 0.000 abstract description 11
- 210000004739 secretory vesicle Anatomy 0.000 abstract description 10
- 238000002689 xenotransplantation Methods 0.000 abstract description 7
- 230000003111 delayed effect Effects 0.000 abstract description 5
- 230000002792 vascular Effects 0.000 abstract description 5
- 239000002506 anticoagulant protein Substances 0.000 abstract description 4
- 230000020411 cell activation Effects 0.000 abstract description 4
- 239000003998 snake venom Substances 0.000 abstract description 4
- 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 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 3
- 239000004019 antithrombin Substances 0.000 abstract description 2
- 230000023555 blood coagulation Effects 0.000 abstract description 2
- 229960002897 heparin Drugs 0.000 abstract description 2
- 229920000669 heparin Polymers 0.000 abstract description 2
- 101710181904 Venom factor Proteins 0.000 abstract 1
- 229960004072 thrombin Drugs 0.000 description 63
- 108090000190 Thrombin Proteins 0.000 description 60
- 230000027455 binding Effects 0.000 description 50
- 108010000499 Thromboplastin Proteins 0.000 description 37
- 102000002262 Thromboplastin Human genes 0.000 description 37
- 210000002889 endothelial cell Anatomy 0.000 description 30
- 241001465754 Metazoa Species 0.000 description 25
- 102100023472 P-selectin Human genes 0.000 description 21
- 239000013598 vector Substances 0.000 description 20
- 108010035766 P-Selectin Proteins 0.000 description 19
- 230000035602 clotting Effects 0.000 description 17
- 230000009261 transgenic effect Effects 0.000 description 17
- 206010053567 Coagulopathies Diseases 0.000 description 15
- 108060003951 Immunoglobulin Proteins 0.000 description 14
- 102000018358 immunoglobulin Human genes 0.000 description 14
- 238000000034 method Methods 0.000 description 12
- 108020004414 DNA Proteins 0.000 description 11
- 239000002299 complementary DNA Substances 0.000 description 11
- 230000001965 increasing effect Effects 0.000 description 11
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 239000002953 phosphate buffered saline Substances 0.000 description 10
- 229920001184 polypeptide Polymers 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- 230000001086 cytosolic effect Effects 0.000 description 9
- 239000008187 granular material Substances 0.000 description 9
- 239000004471 Glycine Substances 0.000 description 8
- 230000015271 coagulation Effects 0.000 description 8
- 238000005345 coagulation Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 108091033319 polynucleotide Proteins 0.000 description 8
- 102000040430 polynucleotide Human genes 0.000 description 8
- 239000002157 polynucleotide Substances 0.000 description 8
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
- 101000622137 Homo sapiens P-selectin Proteins 0.000 description 7
- 101000635804 Homo sapiens Tissue factor Proteins 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)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)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 7
- 229960000258 corticotropin Drugs 0.000 description 7
- 230000014508 negative regulation of coagulation Effects 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 230000004913 activation Effects 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 239000003130 blood coagulation factor inhibitor Substances 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 238000000684 flow cytometry Methods 0.000 description 6
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229940039716 prothrombin Drugs 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 241000282887 Suidae Species 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 5
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 5
- 229960000951 mycophenolic acid Drugs 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 4
- 102000009123 Fibrin Human genes 0.000 description 4
- 108010073385 Fibrin Proteins 0.000 description 4
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 241001494479 Pecora Species 0.000 description 4
- 101710111620 Protein C activator Proteins 0.000 description 4
- 108010076504 Protein Sorting Signals Proteins 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000004873 anchoring Methods 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 238000004520 electroporation Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229950003499 fibrin Drugs 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 238000011533 pre-incubation Methods 0.000 description 4
- 239000003805 procoagulant Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 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 4
- 238000001890 transfection Methods 0.000 description 4
- 239000003656 tris buffered saline Substances 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 3
- 108010054265 Factor VIIa Proteins 0.000 description 3
- 108010074860 Factor Xa Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000897400 Homo sapiens CD59 glycoprotein Proteins 0.000 description 3
- 108010052285 Membrane Proteins Proteins 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 101800004937 Protein C Proteins 0.000 description 3
- 102000017975 Protein C Human genes 0.000 description 3
- 101800001700 Saposin-D Proteins 0.000 description 3
- 229910003460 diamond Inorganic materials 0.000 description 3
- 239000010432 diamond Substances 0.000 description 3
- 210000001671 embryonic stem cell Anatomy 0.000 description 3
- 229940012414 factor viia Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000000520 microinjection Methods 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 229960000856 protein c Drugs 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- 241000271045 Agkistrodon contortrix contortrix Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 108010024212 E-Selectin Proteins 0.000 description 2
- 102100023471 E-selectin Human genes 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 2
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 239000000232 Lipid Bilayer Substances 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 102000016611 Proteoglycans Human genes 0.000 description 2
- 108010067787 Proteoglycans Proteins 0.000 description 2
- 108020004682 Single-Stranded DNA Proteins 0.000 description 2
- 102000003790 Thrombin receptors Human genes 0.000 description 2
- 108090000166 Thrombin receptors Proteins 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- 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 2
- 230000002429 anti-coagulating effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003593 chromogenic compound Substances 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 230000004186 co-expression Effects 0.000 description 2
- 230000024203 complement activation Effects 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 210000002257 embryonic structure Anatomy 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 210000002064 heart cell Anatomy 0.000 description 2
- 102000051442 human CD59 Human genes 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000002644 phorbol ester Substances 0.000 description 2
- 230000001817 pituitary effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 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 2
- 239000002435 venom Substances 0.000 description 2
- 210000001048 venom Anatomy 0.000 description 2
- 231100000611 venom Toxicity 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 229940075420 xanthine Drugs 0.000 description 2
- YDMBNDUHUNWWRP-VJBWXMMDSA-N (2s)-1-[(2r)-2-amino-3-phenylpropanoyl]-n-[(2s)-5-(diaminomethylideneamino)-1-(4-nitroanilino)-1-oxopentan-2-yl]piperidine-2-carboxamide Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)C1=CC=CC=C1 YDMBNDUHUNWWRP-VJBWXMMDSA-N 0.000 description 1
- KWPACVJPAFGBEQ-IKGGRYGDSA-N (2s)-1-[(2r)-2-amino-3-phenylpropanoyl]-n-[(3s)-1-chloro-6-(diaminomethylideneamino)-2-oxohexan-3-yl]pyrrolidine-2-carboxamide Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)CCl)C1=CC=CC=C1 KWPACVJPAFGBEQ-IKGGRYGDSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- MGVRBUNKWISLAM-DQWUKECYSA-N (4s)-5-[[(2s)-1-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]-[(2s)-4-methyl-1-oxo-1-sulfooxypentan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-[[(2s)-1-[(2s,3s)-2-[[(2s)-4-carboxy-2-[[(2s)-4-carboxy-2-[[(2s)-2-[[(2s)-3-carboxy-2-[[2-[[(2s)-2,4-diamino- Chemical group C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N([C@@H](CC(C)C)C(=O)OS(O)(=O)=O)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(N)=O)C1=CC=CC=C1 MGVRBUNKWISLAM-DQWUKECYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 206010001258 Adenoviral infections Diseases 0.000 description 1
- 102000004411 Antithrombin III Human genes 0.000 description 1
- 108090000935 Antithrombin III Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102100022002 CD59 glycoprotein Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 108700010070 Codon Usage Proteins 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 102000006354 HLA-DR Antigens Human genes 0.000 description 1
- 108010058597 HLA-DR Antigens Proteins 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- 101710154944 Hirudin variant-1 Proteins 0.000 description 1
- 241000545744 Hirudinea Species 0.000 description 1
- 241000237902 Hirudo medicinalis Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000756632 Homo sapiens Actin, cytoplasmic 1 Proteins 0.000 description 1
- 101100386242 Homo sapiens CD55 gene Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 241000238890 Ornithodoros moubata Species 0.000 description 1
- 206010051077 Post procedural haemorrhage Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 108010039286 S 2238 Proteins 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102000012607 Thrombomodulin Human genes 0.000 description 1
- 108010079274 Thrombomodulin Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 108010055460 bivalirudin Proteins 0.000 description 1
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 description 1
- 229960001500 bivalirudin Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 108010089376 hirudisin Proteins 0.000 description 1
- 229940039715 human prothrombin Drugs 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000007154 intracellular accumulation Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- FIBJDTSHOUXTKV-BRHMIFOHSA-N lepirudin Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)CNC2=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)[C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1)C(C)C)C(C)C)[C@@H](C)O)[C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O FIBJDTSHOUXTKV-BRHMIFOHSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000031852 maintenance of location in cell Effects 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 150000004633 phorbol derivatives Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000000580 secretagogue effect Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000004865 vascular response Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 210000004269 weibel-palade body Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- 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
- C12N15/62—DNA sequences coding for fusion proteins
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70514—CD4
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70539—MHC-molecules, e.g. HLA-molecules
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/7056—Lectin superfamily, e.g. CD23, CD72
- C07K14/70564—Selectins, e.g. CD62
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70571—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8114—Kunitz type inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/815—Protease inhibitors from leeches, e.g. hirudin, eglin
-
- 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
-
- 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
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6402—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from non-mammals
- C12N9/6418—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from non-mammals from snakes
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
- A01K2207/15—Humanized animals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/103—Ovine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/108—Swine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/01—Animal expressing industrially exogenous proteins
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/02—Animal zootechnically ameliorated
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/02—Animal zootechnically ameliorated
- A01K2267/025—Animal producing cells or organs for transplantation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/033—Fusion polypeptide containing a localisation/targetting motif containing a motif for targeting to the internal surface of the plasma membrane, e.g. containing a myristoylation motif
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
-
- 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
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
-
- 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
- C12N2799/00—Uses of viruses
- C12N2799/02—Uses of viruses as vector
- C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
- C12N2799/027—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a retrovirus
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Wood Science & Technology (AREA)
- Immunology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Tropical Medicine & Parasitology (AREA)
- Neurology (AREA)
- Environmental Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Animal Husbandry (AREA)
- Biodiversity & Conservation Biology (AREA)
- Transplantation (AREA)
Abstract
【解決手段】本発明は、細胞膜に固定された抗凝固性タンパク質を提供する。抗凝固機能は、好ましくは、ヘパリン、アンチトロンビン、ヒルジン、TFPI、ダニ抗凝固性ペプチド、またはヘビ毒液因子により提供される。これらの抗凝固性タンパク質は、好ましくは、細胞表面で構成的に発現されることが妨げられる。特に、細胞表面での発現は、細胞活性化に従って(例えば、タンパク質を適切な分泌顆粒に標的化することにより)調節される。これらのタンパク質の発現は、細胞、組織、および器官を、移植後の(例えば、異種移植後の)拒絶に受け難くさせる。
【選択図】なし
Description
本発明は、(特に、器官拒絶の間の)血液凝固の阻害に関する。
器官移植の外科技術はもう数十年間首尾良く行われており、そしてその成功のためにこの手順は普及しており、そして論証可能に日常的になった。しかし、適切な移植片器官の供給は、絶え間なく増大する需要とつり合うことができない。
本発明の第1の局面によれば、タンパク質であって、抗凝固活性を有する領域およびこのタンパク質を細胞膜に固定(anchor)し得る領域を含むタンパク質が提供される。好ましくは、これはキメラタンパク質であり、すなわち、固定領域(anchorregion)と抗凝固性領域とは異なるタンパク質に由来する。
1.タンパク質であって、抗凝固活性を有する領域、該タンパク質を細胞の膜に固定し得る領域、および該タンパク質が該細胞の表面で構成的に発現されるのを防止する標的化配列を含む、タンパク質。
2.前記抗凝固性領域が、ヒルジン、組織因子系凝固インヒビター、ダニ抗凝固性ペプチド、またはプロテインCアクチベーターの配列を含む、項目1に記載のタンパク質。
3.前記固定領域が、前記タンパク質を脂質二重層に付着させ得る配列である、項目1または項目2に記載のタンパク質。
4.前記固定領域が、膜タンパク質に由来する膜貫通配列を含む、項目3に記載のタンパク質。
5.前記標的化配列が、新生ポリペプチドを分泌顆粒に標的化し得る配列である、項目1または項目2に記載のタンパク質。
6.前記分泌顆粒は、前記細胞が適切に刺激されるまで該細胞の原形質膜と融合しない、項目5に記載のタンパク質。
7.前記分泌顆粒がヴァイベル-パラーデ体である、項目6に記載のタンパク質。
8.前記標的化配列がP-セレクチンの細胞質ドメインである、項目7に記載のタンパク質。
9.前記固定配列がP-セレクチンの配列である、項目1〜8のいずれか1項に記載のタンパク質。
10.項目1〜9のいずれか1項に記載のタンパク質をコードするポリヌクレオチド。
11.項目10に記載のポリヌクレオチドを含むベクター。
12.項目1から9のいずれか1項に記載のタンパク質、項目10に記載のポリヌクレオチド、または項目11に記載のベクターを含む、送達系。
13.細胞を項目11に記載のベクターでトランスフェクトする、方法。
14.項目13に従ってトランスフェクトされた、細胞。
15.項目14に記載の細胞を含む、生物学的組織。
16.項目15に記載の生物学的組織および/または項目14に記載の細胞を含む、動物。
17.前記動物がトランスジェニックブタまたはヒツジである、項目16に記載の動物。
18.組織または器官を移植に適切にする方法であって、項目1または9のいずれか1項に記載のタンパク質を、前記組織または器官における内皮細胞上で発現させる工程を包含する、方法。
19.ドナー動物に由来する項目15に記載の生物学的組織をレシピエント動物に移植する工程を包含する、移植方法。
20.タンパク質であって、抗凝固活性を有する領域および該タンパク質を細胞の膜に固定し得る領域を含み、該抗凝固性領域が、ヒルジン、組織因子系凝固インヒビター、ダニ抗凝固性ペプチド、またはプロテインCアクチベーターの配列を含む、タンパク質。
1.HLAクラスIシグナルペプチドと融合され、そしてヒトCD4のドメイン3およびドメイン4に連結されたヒルジンは、細胞膜につなぎ止められる。
5’-cagtgtcgacggatccatggccgtcatggcgccccga-3’[hla-1] <配列番号1>
(SalI制限部位およびBamHI制限部位を導入する)および:
5’-gtcagtgtaaacaaccgcccaggtctgggtcagg-3’ <配列番号2>
ヒルジン配列を以下のプライマーを用いて増幅した:
5’-acccagacctgggcggttgtttacactgactgcacc-3’および <配列番号3>
5’-gacgctgcagaattcttgcaggtattcttccgggatt-3’[hir-3] <配列番号4>
(遠位のEcoRI部位およびPstI部位を導入する)
得られたPCR産物(108および228bp)をアガロースゲル電気泳動により精製し、次いで、隣接プライマーhla-1およびhir-3を用いて第3のPCRにおいて使用した。得られたPCR産物(300bp)をSalIおよびBamHIで消化し、そしてpBluescriptSK(+)(Stratagene)にサブクローニングした。
−グリシンリンカー1(G1;GGSGG)について、オリゴヌクレオチド対は、5’-aattaggaggttctggaggctgca-3’<配列番号5>(変異EcoRI認識配列およびPstI部位を含む)および5’-gcctccagaacctcct-3’<配列番号6>からなっていた;
−グリシンリンカー2(G2)およびグリシンリンカー3(G3)は、それぞれ、2または3回反復するコア配列(GGSGG)からなっていた。
5’-tgtctgcaggaaccagaagaaggtggaattca-3’ <配列番号7>
(PstI部位およびEcoRI部位を導入する)および:
5’-gtgggatccgcctggcctcgtgcctcaa-3’ <配列番号8>
(遠位BamHIを含む)。
5’-tgtctgcaggaaccagaagaaggtggaattca-3’[CD4-5] <配列番号7>
(PstI制限部位およびEcoRI制限部位を導入する)および:
5’-gtctgaaacgctttctgaagaagatgcctagcccaatgaaaagcaggaggccg-3’
<配列番号9>
を使用した。並行して、P-セレクチンのC末端領域を増幅するために、以下のプライマー:
5’-tgggctaggcatcttcttcagaaagcgtttcagacaaaaaga-3’および <配列番号10>
5’-gaccaggatccggacaggtctctta-3’[P-selN3] <配列番号11>
(遠位BamHI部位を導入する)を使用した。
−10倍モル過剰のネイティブな完全長ヒルジン(Biopharm);
−100倍モル過剰のD-Phe-Pro-Argクロロメチルケトンジヒドロクロリド(「PPACK-HCl」)(Calbiochem);または
−100倍モル過剰の、スルファト-Tyr64を有するヒルジン残基53-64を含む合成C末端ヒルジンドデカペプチドアナログ(AmericanDiagnostica)。
5’-catcgtcgacggatcctagatgatttacacaatgaagaaagtacatgcactttgggc-3’
<配列番号12>
(SalI制限部位およびBamHI制限部位を導入する);および
5’-ggacctgcagaattcaaaaaggctgg-3’ <配列番号13>
(EcoRI部位およびPstI部位を含む)。
5’-agcctttttgaattccacggtccctcat-3’ <配列番号14>
(EcoRI部位を有する);および
5’-cattgctataacaactgcagatatttttaac-3’ <配列番号15>
(PstI部位を含む)。
Agkistrodon contortrix contortrixの毒液から精製されたプロテインCアクチベーター(McMullen,1989;Kisiel,1987)を含む異種構築物を発現するために、このタンパク質をコードするcDNAを合成した。タンパク質配列は、<配列番号16>である:
(以下余白)
参考文献(これらの内容は、本明細書中に援用される)
Claims (1)
- 明細書に記載の発明。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9706327.5A GB9706327D0 (en) | 1997-03-26 | 1997-03-26 | Coagulation inhibition |
GBGB9720248.5A GB9720248D0 (en) | 1997-09-23 | 1997-09-23 | Coagulation inhibition |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP54522098A Division JP4243355B2 (ja) | 1997-03-26 | 1998-03-26 | 細胞膜に固定された抗凝固性融合タンパク質 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009269347A Division JP2010279348A (ja) | 1997-03-26 | 2009-11-26 | 細胞膜に固定された抗凝固性融合タンパク質 |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2008109939A true JP2008109939A (ja) | 2008-05-15 |
Family
ID=26311272
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP54522098A Expired - Lifetime JP4243355B2 (ja) | 1997-03-26 | 1998-03-26 | 細胞膜に固定された抗凝固性融合タンパク質 |
JP2008007332A Withdrawn JP2008109939A (ja) | 1997-03-26 | 2008-01-16 | 細胞膜に固定された抗凝固性融合タンパク質 |
JP2009269347A Pending JP2010279348A (ja) | 1997-03-26 | 2009-11-26 | 細胞膜に固定された抗凝固性融合タンパク質 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP54522098A Expired - Lifetime JP4243355B2 (ja) | 1997-03-26 | 1998-03-26 | 細胞膜に固定された抗凝固性融合タンパク質 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009269347A Pending JP2010279348A (ja) | 1997-03-26 | 2009-11-26 | 細胞膜に固定された抗凝固性融合タンパク質 |
Country Status (12)
Country | Link |
---|---|
US (3) | US6423316B1 (ja) |
EP (2) | EP1676920B1 (ja) |
JP (3) | JP4243355B2 (ja) |
KR (1) | KR100561055B1 (ja) |
CN (1) | CN1192109C (ja) |
AT (1) | ATE318316T1 (ja) |
AU (1) | AU733681B2 (ja) |
CA (1) | CA2285702C (ja) |
DE (1) | DE69833545T2 (ja) |
ES (2) | ES2513043T3 (ja) |
NZ (1) | NZ500007A (ja) |
WO (1) | WO1998042850A1 (ja) |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6395338B1 (en) * | 1999-03-19 | 2002-05-28 | Rhodia Chimie | Process and device for coating a support using a crosslinkable silicone composition |
AU733681B2 (en) | 1997-03-26 | 2001-05-24 | Imperial College Innovations Ltd. | Anticoagulant fusion protein anchored to cell membrane |
EP1010762A1 (en) * | 1998-12-02 | 2000-06-21 | Aventis Behring Gesellschaft mit beschränkter Haftung | DNA constructs of blood clotting factors and P-Selectin |
EP1026250A1 (en) * | 1998-12-02 | 2000-08-09 | Aventis Behring GmbH | DNA-constructs of blood clotting factors and P-selectin |
SE523817C2 (sv) * | 1999-02-05 | 2004-05-18 | Corline Systems Ab | Användning av ett koagulationsförebyggande ämne i samband med transplantation av insulinproducerande celler |
AU3703200A (en) * | 1999-02-22 | 2000-09-14 | Instrumentation Laboratory | Recombinant protein c activator and uses therefor |
JP2001211882A (ja) * | 2000-01-31 | 2001-08-07 | Shiyuuji Miyagawa | 移植関連タンパク質をコードするコドン改変型遺伝子 |
DE10033195A1 (de) * | 2000-07-07 | 2002-03-21 | Aventis Pharma Gmbh | Bifunktionale Fusionsproteine aus Hirudin und TAP |
CN100513548C (zh) | 2001-06-11 | 2009-07-15 | 应用超微系统股份有限公司 | 将AcmA型蛋白质锚融合体与微生物细胞壁材料进行结合的改良方法 |
EP1651050B1 (en) | 2003-07-21 | 2012-08-22 | Lifecell Corporation | Acellular tissue matrices made from galactose alpha-1,3-galactose -deficient tissue |
JP2007529278A (ja) | 2004-03-17 | 2007-10-25 | レビビコア, インコーポレイテッド | 機能的α1,3ガラクトシルトランスフェラーゼを欠く動物に由来する組織生成物 |
CA3079874C (en) | 2004-10-22 | 2023-01-03 | Revivicor, Inc. | Ungulates with genetically modified immune systems |
US20060148080A1 (en) * | 2004-12-30 | 2006-07-06 | Paul Diamond | Methods for supporting and producing human cells and tissues in non-human mammal hosts |
US7951384B2 (en) * | 2005-08-05 | 2011-05-31 | University Of Massachusetts | Virus-like particles as vaccines for paramyxovirus |
US9216212B2 (en) | 2005-08-05 | 2015-12-22 | University Of Massachusetts | Virus-like particles as vaccines for paramyxovirus |
WO2007035213A2 (en) | 2005-08-09 | 2007-03-29 | Revivicor, Inc. | Transgenic ungulates expressing ctla4-ig and uses thereof |
KR101112713B1 (ko) * | 2008-06-13 | 2012-02-24 | 인제대학교 산학협력단 | 인간 면역반응 조절인자(hDAF)와 인간 조직혈액응고 억제인자(TFPI) 기능부위와 CD4의 세포표면 부착부위와의 융합유전자(hTFPI/hCD4)를 조합 발현하는 단일 벡터 및 그 제조방법 |
JP2013501528A (ja) | 2009-08-14 | 2013-01-17 | レビビコア, インコーポレイテッド | 糖尿病の処置のためのマルチ・トランスジェニック・ブタ |
GB0915519D0 (en) | 2009-09-04 | 2009-10-07 | King S College London | Ntithrombotic compounds |
US9420770B2 (en) | 2009-12-01 | 2016-08-23 | Indiana University Research & Technology Corporation | Methods of modulating thrombocytopenia and modified transgenic pigs |
AU2011215685B2 (en) | 2010-02-12 | 2015-08-20 | Oncomed Pharmaceuticals, Inc. | Methods for identifying and isolating cells expressing a polypeptide |
MX2012010198A (es) | 2010-03-01 | 2012-10-03 | Bayer Healthcare Llc | Anticuerpos monoclonales optimizados contra el inhibidor de la via del factor tisular (tfpi). |
ES2680636T3 (es) * | 2011-02-14 | 2018-09-10 | Revivicor Inc. | Cerdos genéticamente modificados para xenotrasplante de xenoinjertos vascularizados y derivados de los mismos |
US20140115728A1 (en) | 2012-10-24 | 2014-04-24 | A. Joseph Tector | Double knockout (gt/cmah-ko) pigs, organs and tissues |
WO2015007880A1 (en) | 2013-07-19 | 2015-01-22 | Novo Nordisk A/S | Antibodies recognizing the n-terminal part of tissue factor pathway inhibitor capable of eliciting pro-coagulant activity |
CA2925332C (en) | 2013-11-04 | 2022-07-12 | Lifecell Corporation | Methods of removing alpha-galactose |
DE102014103706B4 (de) * | 2014-03-18 | 2018-05-30 | Pratap Banerjee | Vorrichtung zur Simulation gynäkologischer Operationen |
KR101939198B1 (ko) * | 2017-06-27 | 2019-01-16 | 고려대학교 산학협력단 | 돼지 및 인간 조직혈액응고 억제인자 융합 이뮤노글로불린 |
GB201804092D0 (en) * | 2018-03-14 | 2018-04-25 | Imperial Innovations Ltd | Methods and compositions |
CN114728173A (zh) * | 2019-09-24 | 2022-07-08 | 加利福尼亚大学董事会 | 用于配体依赖性转录调控的具有异源停止转移序列的新型受体 |
CN112083172B (zh) * | 2020-09-17 | 2024-01-26 | 鄂尔多斯市中心医院(内蒙古自治区超声影像研究所) | 一种从蜱cDNA文库中筛选具有抗凝血活性的蛋白质的方法 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5109113A (en) * | 1986-05-02 | 1992-04-28 | Genentech, Inc. | Membrane anchor fusion polypeptides |
NZ248153A (en) | 1989-10-12 | 1997-07-27 | Imutran Ltd | Performing animal tissue transplants involving use of homologous complement restriction factors (hcrf) to prevent rejection |
WO1992009685A1 (en) * | 1990-11-29 | 1992-06-11 | The Australian National University | Control of plant cell proliferation and growth |
US5223408A (en) * | 1991-07-11 | 1993-06-29 | Genentech, Inc. | Method for making variant secreted proteins with altered properties |
ZA941414B (en) * | 1993-03-02 | 1994-09-28 | Novo Nordisk A G | Non-glycosylated TFPI analogues |
US5891645A (en) * | 1994-06-01 | 1999-04-06 | Alexion Pharmaceuticals, Inc. | Porcine E-selectin |
US5589359A (en) * | 1994-08-05 | 1996-12-31 | Chiron Corporation | Chimeric proteins |
DE69528591T2 (de) * | 1994-08-05 | 2003-02-20 | Chiron Corp | Herstellung des inhibitors fuer die komplexbildung des gewebefaktors |
GB9517779D0 (en) | 1995-08-31 | 1995-11-01 | Roslin Inst Edinburgh | Biological manipulation |
AU733681B2 (en) | 1997-03-26 | 2001-05-24 | Imperial College Innovations Ltd. | Anticoagulant fusion protein anchored to cell membrane |
-
1998
- 1998-03-26 AU AU67383/98A patent/AU733681B2/en not_active Ceased
- 1998-03-26 CA CA2285702A patent/CA2285702C/en not_active Expired - Lifetime
- 1998-03-26 EP EP05077712.7A patent/EP1676920B1/en not_active Expired - Lifetime
- 1998-03-26 DE DE69833545T patent/DE69833545T2/de not_active Expired - Lifetime
- 1998-03-26 JP JP54522098A patent/JP4243355B2/ja not_active Expired - Lifetime
- 1998-03-26 NZ NZ500007A patent/NZ500007A/en unknown
- 1998-03-26 CN CNB988054531A patent/CN1192109C/zh not_active Expired - Fee Related
- 1998-03-26 EP EP98912600A patent/EP1000161B1/en not_active Expired - Lifetime
- 1998-03-26 AT AT98912600T patent/ATE318316T1/de not_active IP Right Cessation
- 1998-03-26 ES ES05077712.7T patent/ES2513043T3/es not_active Expired - Lifetime
- 1998-03-26 ES ES98912600T patent/ES2259206T3/es not_active Expired - Lifetime
- 1998-03-26 KR KR1019997008736A patent/KR100561055B1/ko not_active IP Right Cessation
- 1998-03-26 WO PCT/GB1998/000850 patent/WO1998042850A1/en active IP Right Grant
- 1998-03-26 US US09/402,515 patent/US6423316B1/en not_active Expired - Lifetime
-
2002
- 2002-03-18 US US10/101,523 patent/US20050118160A1/en not_active Abandoned
-
2008
- 2008-01-16 JP JP2008007332A patent/JP2008109939A/ja not_active Withdrawn
-
2009
- 2009-11-26 JP JP2009269347A patent/JP2010279348A/ja active Pending
-
2011
- 2011-03-17 US US13/050,120 patent/US9376684B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
EP1000161A1 (en) | 2000-05-17 |
US6423316B1 (en) | 2002-07-23 |
ES2259206T3 (es) | 2006-09-16 |
JP2010279348A (ja) | 2010-12-16 |
DE69833545D1 (de) | 2006-04-27 |
EP1000161B1 (en) | 2006-02-22 |
AU6738398A (en) | 1998-10-20 |
US20050118160A1 (en) | 2005-06-02 |
EP1676920A2 (en) | 2006-07-05 |
US20120017288A1 (en) | 2012-01-19 |
AU733681B2 (en) | 2001-05-24 |
KR20010005668A (ko) | 2001-01-15 |
WO1998042850A1 (en) | 1998-10-01 |
CA2285702C (en) | 2016-06-28 |
CN1192109C (zh) | 2005-03-09 |
US9376684B2 (en) | 2016-06-28 |
JP2001523094A (ja) | 2001-11-20 |
CN1265148A (zh) | 2000-08-30 |
EP1676920A3 (en) | 2007-07-25 |
NZ500007A (en) | 2001-08-31 |
ES2513043T3 (es) | 2014-10-24 |
KR100561055B1 (ko) | 2006-03-16 |
JP4243355B2 (ja) | 2009-03-25 |
EP1676920B1 (en) | 2014-07-09 |
ATE318316T1 (de) | 2006-03-15 |
DE69833545T2 (de) | 2006-12-14 |
CA2285702A1 (en) | 1998-10-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4243355B2 (ja) | 細胞膜に固定された抗凝固性融合タンパク質 | |
ES2315016T3 (es) | Moleculas llamadas b7l-1. | |
JP4426724B2 (ja) | Ldcamと称される分子 | |
JP2009213483A (ja) | 可溶性mhc複合体とその利用法 | |
US20070128198A1 (en) | Compositions comprising antibodies to human fgl2 | |
HRP20020767A2 (en) | Production of recombinant blood clotting factors in human cell lines | |
JPH08503368A (ja) | Elkリガンドと呼ばれる新規なサイトカイン | |
HU211503A9 (en) | Proteins with factor viii activity, process for their preparation and pharmaceutical compositions containing them | |
US20040192599A1 (en) | Gene therapy for hemophilia a | |
RU2128705C1 (ru) | Протеин, ингибирующий вызываемую коллагеном агрегацию тромбоцитов млекопитающих, рекомбинантный протеин, ингибирующий вызываемую коллагеном агрегацию тромбоцитов, фрагмент днк, кодирующий рекомбинантный протеин, вектор экспрессии (варианты), штамм культивируемых животных клеток внк - продуцент рекомбинантного протеина (варианты), способ получения рекомбинантного протеина, фармацевтическая композиция | |
US20060078550A1 (en) | Porcine fgl2 | |
US6419921B1 (en) | DNA-constructs of blood clotting factors and P-Selectin | |
EP1010762A1 (en) | DNA constructs of blood clotting factors and P-Selectin | |
JP2001286289A (ja) | トロンボスポンジンドメインを有する新規メタロプロテアーゼとこれをコードする核酸組成物 | |
AU2002317065A1 (en) | Gene therapy for hemophilia A |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20080411 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20080710 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20080716 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20081010 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090526 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20090820 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20090825 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20091023 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20091028 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20100203 |
|
A761 | Written withdrawal of application |
Free format text: JAPANESE INTERMEDIATE CODE: A761 Effective date: 20100210 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20101006 |