JP2023109987A - 抗ヒトgpvi抗体を用いた血小板凝集の阻害 - Google Patents
抗ヒトgpvi抗体を用いた血小板凝集の阻害 Download PDFInfo
- Publication number
- JP2023109987A JP2023109987A JP2023088912A JP2023088912A JP2023109987A JP 2023109987 A JP2023109987 A JP 2023109987A JP 2023088912 A JP2023088912 A JP 2023088912A JP 2023088912 A JP2023088912 A JP 2023088912A JP 2023109987 A JP2023109987 A JP 2023109987A
- Authority
- JP
- Japan
- Prior art keywords
- gpvi
- seq
- amino acid
- human
- antibody
- 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.)
- Pending
Links
- 102100038394 Platelet glycoprotein VI Human genes 0.000 title abstract description 3
- 101710194982 Platelet glycoprotein VI Proteins 0.000 title abstract 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 title description 43
- 230000005764 inhibitory process Effects 0.000 title description 9
- 108090000623 proteins and genes Proteins 0.000 abstract description 234
- 102000004169 proteins and genes Human genes 0.000 abstract description 228
- 108010064773 platelet membrane glycoprotein VI Proteins 0.000 abstract description 150
- 230000027455 binding Effects 0.000 abstract description 106
- 238000011282 treatment Methods 0.000 abstract description 44
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 9
- 239000005557 antagonist Substances 0.000 abstract description 8
- 241000282412 Homo Species 0.000 abstract description 7
- 230000002265 prevention Effects 0.000 abstract 1
- 235000018102 proteins Nutrition 0.000 description 225
- 125000000539 amino acid group Chemical group 0.000 description 138
- 239000012634 fragment Substances 0.000 description 76
- 125000003275 alpha amino acid group Chemical group 0.000 description 75
- 235000001014 amino acid Nutrition 0.000 description 74
- 238000000034 method Methods 0.000 description 72
- 239000000427 antigen Substances 0.000 description 67
- 102000036639 antigens Human genes 0.000 description 67
- 108091007433 antigens Proteins 0.000 description 67
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 66
- 229940024606 amino acid Drugs 0.000 description 61
- 201000010099 disease Diseases 0.000 description 61
- 150000001413 amino acids Chemical class 0.000 description 58
- 108010035532 Collagen Proteins 0.000 description 49
- 102000008186 Collagen Human genes 0.000 description 49
- 210000001772 blood platelet Anatomy 0.000 description 49
- 229920001436 collagen Polymers 0.000 description 49
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 48
- 102100033571 Tissue-type plasminogen activator Human genes 0.000 description 42
- 108050006955 Tissue-type plasminogen activator Proteins 0.000 description 41
- 210000004027 cell Anatomy 0.000 description 33
- 238000006467 substitution reaction Methods 0.000 description 32
- 239000000203 mixture Substances 0.000 description 31
- 210000004602 germ cell Anatomy 0.000 description 27
- 239000008194 pharmaceutical composition Substances 0.000 description 27
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 25
- 208000007536 Thrombosis Diseases 0.000 description 23
- 239000003814 drug Substances 0.000 description 23
- 230000000694 effects Effects 0.000 description 21
- 230000002401 inhibitory effect Effects 0.000 description 21
- 238000001802 infusion Methods 0.000 description 19
- 239000003446 ligand Substances 0.000 description 19
- 108060003951 Immunoglobulin Proteins 0.000 description 18
- 102000018358 immunoglobulin Human genes 0.000 description 18
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 17
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 16
- 239000004475 Arginine Substances 0.000 description 15
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 15
- 238000012217 deletion Methods 0.000 description 15
- 230000037430 deletion Effects 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 229940068196 placebo Drugs 0.000 description 15
- 239000000902 placebo Substances 0.000 description 15
- 108010073385 Fibrin Proteins 0.000 description 14
- 102000009123 Fibrin Human genes 0.000 description 14
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 14
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 14
- 235000009697 arginine Nutrition 0.000 description 14
- 229950003499 fibrin Drugs 0.000 description 14
- 230000006870 function Effects 0.000 description 14
- 239000013598 vector Substances 0.000 description 14
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 13
- 230000004048 modification Effects 0.000 description 13
- 238000012986 modification Methods 0.000 description 13
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 12
- 208000032843 Hemorrhage Diseases 0.000 description 12
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 12
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 12
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 12
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 12
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 12
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 12
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 12
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 12
- 235000009582 asparagine Nutrition 0.000 description 12
- 229960001230 asparagine Drugs 0.000 description 12
- 208000034158 bleeding Diseases 0.000 description 12
- 230000000740 bleeding effect Effects 0.000 description 12
- 150000007523 nucleic acids Chemical class 0.000 description 12
- 108090000765 processed proteins & peptides Proteins 0.000 description 12
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 11
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 11
- 241000282567 Macaca fascicularis Species 0.000 description 11
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 11
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 11
- 239000004473 Threonine Substances 0.000 description 11
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 11
- 230000008707 rearrangement Effects 0.000 description 11
- 235000004400 serine Nutrition 0.000 description 11
- 235000008521 threonine Nutrition 0.000 description 11
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 10
- 238000007792 addition Methods 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 10
- 235000004554 glutamine Nutrition 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- 108091033319 polynucleotide Proteins 0.000 description 10
- 102000040430 polynucleotide Human genes 0.000 description 10
- 239000002157 polynucleotide Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 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 9
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 9
- 239000004472 Lysine Substances 0.000 description 9
- 208000026106 cerebrovascular disease Diseases 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 235000013922 glutamic acid Nutrition 0.000 description 9
- 239000004220 glutamic acid Substances 0.000 description 9
- 230000001965 increasing effect Effects 0.000 description 9
- 235000018977 lysine Nutrition 0.000 description 9
- 102000039446 nucleic acids Human genes 0.000 description 9
- 108020004707 nucleic acids Proteins 0.000 description 9
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 8
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 8
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 8
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 8
- 230000002776 aggregation Effects 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 8
- 235000003704 aspartic acid Nutrition 0.000 description 8
- 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 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 8
- 229960000310 isoleucine Drugs 0.000 description 8
- 235000014705 isoleucine Nutrition 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 235000002374 tyrosine Nutrition 0.000 description 8
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 8
- 239000004474 valine Substances 0.000 description 8
- 235000014393 valine Nutrition 0.000 description 8
- 206010003178 Arterial thrombosis Diseases 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 206010047249 Venous thrombosis Diseases 0.000 description 7
- 239000003527 fibrinolytic agent Substances 0.000 description 7
- 108020001507 fusion proteins Proteins 0.000 description 7
- 102000037865 fusion proteins Human genes 0.000 description 7
- 230000000977 initiatory effect Effects 0.000 description 7
- 208000010125 myocardial infarction Diseases 0.000 description 7
- 230000010118 platelet activation Effects 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 229960000103 thrombolytic agent Drugs 0.000 description 7
- 201000001320 Atherosclerosis Diseases 0.000 description 6
- 239000004471 Glycine Substances 0.000 description 6
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 6
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 6
- 108010076504 Protein Sorting Signals Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000002255 enzymatic effect Effects 0.000 description 6
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 6
- 235000014304 histidine Nutrition 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 235000005772 leucine Nutrition 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 230000035772 mutation Effects 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
- 235000008729 phenylalanine Nutrition 0.000 description 6
- 210000004623 platelet-rich plasma Anatomy 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 208000037803 restenosis Diseases 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 241000282693 Cercopithecidae Species 0.000 description 5
- 108700022150 Designed Ankyrin Repeat Proteins Proteins 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 108091028043 Nucleic acid sequence Proteins 0.000 description 5
- 208000010378 Pulmonary Embolism Diseases 0.000 description 5
- 208000006011 Stroke Diseases 0.000 description 5
- 108090000190 Thrombin Proteins 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
- 208000024248 Vascular System injury Diseases 0.000 description 5
- 208000012339 Vascular injury Diseases 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 239000003146 anticoagulant agent Substances 0.000 description 5
- 208000029078 coronary artery disease Diseases 0.000 description 5
- 239000013604 expression vector Substances 0.000 description 5
- 230000003480 fibrinolytic effect Effects 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- 229960004072 thrombin Drugs 0.000 description 5
- 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 4
- 108010087819 Fc receptors Proteins 0.000 description 4
- 102000009109 Fc receptors Human genes 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 4
- 125000000998 L-alanino group Chemical group [H]N([*])[C@](C([H])([H])[H])([H])C(=O)O[H] 0.000 description 4
- 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 4
- 241000700159 Rattus Species 0.000 description 4
- 238000012300 Sequence Analysis Methods 0.000 description 4
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 4
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 4
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000010367 cloning Methods 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 230000007783 downstream signaling Effects 0.000 description 4
- 239000012636 effector Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 210000003292 kidney cell Anatomy 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000003472 neutralizing effect Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 4
- 238000013151 thrombectomy Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000032064 Chronic Limb-Threatening Ischemia Diseases 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 3
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 3
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 3
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 3
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 3
- 206010034576 Peripheral ischaemia Diseases 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 230000001594 aberrant effect Effects 0.000 description 3
- 238000001042 affinity chromatography Methods 0.000 description 3
- 238000002399 angioplasty Methods 0.000 description 3
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- -1 coatings Substances 0.000 description 3
- 238000004590 computer program Methods 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 230000005847 immunogenicity Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000003593 megakaryocyte Anatomy 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000007115 recruitment Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000012146 running buffer Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 206010043554 thrombocytopenia Diseases 0.000 description 3
- 238000002424 x-ray crystallography Methods 0.000 description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical class NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 2
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 2
- 208000002109 Argyria Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 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
- 206010048554 Endothelial dysfunction Diseases 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 description 2
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 2
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 2
- 108010085895 Laminin Proteins 0.000 description 2
- 102000007547 Laminin Human genes 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 102000002262 Thromboplastin Human genes 0.000 description 2
- 108010031318 Vitronectin Proteins 0.000 description 2
- 102100035140 Vitronectin Human genes 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000007214 atherothrombosis Effects 0.000 description 2
- 102000023732 binding proteins Human genes 0.000 description 2
- 108091008324 binding proteins Proteins 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000001720 carbohydrates Chemical group 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000007211 cardiovascular event Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000007887 coronary angioplasty Methods 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 230000009260 cross reactivity Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000008694 endothelial dysfunction Effects 0.000 description 2
- 230000005713 exacerbation Effects 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 102000006495 integrins Human genes 0.000 description 2
- 108010044426 integrins Proteins 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 238000005497 microtitration Methods 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 102000013415 peroxidase activity proteins Human genes 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 238000005498 polishing Methods 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 230000002947 procoagulating effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000012916 structural analysis Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001732 thrombotic effect Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- HQRHFUYMGCHHJS-UHFFFAOYSA-N 2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NCC(=O)NCC(=O)NC(C(O)=O)CCCN=C(N)N HQRHFUYMGCHHJS-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- BUQICHWNXBIBOG-LMVFSUKVSA-N Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)N BUQICHWNXBIBOG-LMVFSUKVSA-N 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 208000025494 Aortic disease Diseases 0.000 description 1
- WYBVBIHNJWOLCJ-IUCAKERBSA-N Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCNC(N)=N WYBVBIHNJWOLCJ-IUCAKERBSA-N 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000021910 Cerebral Arterial disease Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 108010048623 Collagen Receptors Proteins 0.000 description 1
- 206010056489 Coronary artery restenosis Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- AMRLSQGGERHDHJ-FXQIFTODSA-N Cys-Ala-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMRLSQGGERHDHJ-FXQIFTODSA-N 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- 102000012545 EGF-like domains Human genes 0.000 description 1
- 108050002150 EGF-like domains Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 229920003360 EVASIN® Polymers 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 238000012276 Endovascular treatment Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 108010021468 Fc gamma receptor IIA Proteins 0.000 description 1
- 108010008177 Fd immunoglobulins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101000746783 Homo sapiens Cytochrome b-c1 complex subunit 6, mitochondrial Proteins 0.000 description 1
- 101001057612 Homo sapiens Dual specificity protein phosphatase 5 Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- UWBDLNOCIDGPQE-GUBZILKMSA-N Ile-Lys Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN UWBDLNOCIDGPQE-GUBZILKMSA-N 0.000 description 1
- WMDZARSFSMZOQO-DRZSPHRISA-N Ile-Phe Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 WMDZARSFSMZOQO-DRZSPHRISA-N 0.000 description 1
- MUFXDFWAJSPHIQ-XDTLVQLUSA-N Ile-Tyr Chemical compound CC[C@H](C)[C@H]([NH3+])C(=O)N[C@H](C([O-])=O)CC1=CC=C(O)C=C1 MUFXDFWAJSPHIQ-XDTLVQLUSA-N 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 102100025305 Integrin alpha-2 Human genes 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 102000019298 Lipocalin Human genes 0.000 description 1
- 108050006654 Lipocalin Proteins 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- WYBVBIHNJWOLCJ-UHFFFAOYSA-N N-L-arginyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCCN=C(N)N WYBVBIHNJWOLCJ-UHFFFAOYSA-N 0.000 description 1
- 230000004988 N-glycosylation Effects 0.000 description 1
- 230000004989 O-glycosylation Effects 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102100037600 P2Y purinoceptor 1 Human genes 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102000013566 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 108010010336 Platelet Membrane Glycoproteins Proteins 0.000 description 1
- 102000015795 Platelet Membrane Glycoproteins Human genes 0.000 description 1
- 208000013544 Platelet disease Diseases 0.000 description 1
- 206010073391 Platelet dysfunction Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010085249 Purinergic P2 Receptors Proteins 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108010088160 Staphylococcal Protein A Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000034841 Thrombotic Microangiopathies Diseases 0.000 description 1
- 208000035134 Trousseau syndrome Diseases 0.000 description 1
- OHGNSVACHBZKSS-KWQFWETISA-N Trp-Ala Chemical compound C1=CC=C2C(C[C@H]([NH3+])C(=O)N[C@@H](C)C([O-])=O)=CNC2=C1 OHGNSVACHBZKSS-KWQFWETISA-N 0.000 description 1
- PITVQFJBUFDJDD-XEGUGMAKSA-N Trp-Ile Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)=CNC2=C1 PITVQFJBUFDJDD-XEGUGMAKSA-N 0.000 description 1
- YVXIAOOYAKBAAI-SZMVWBNQSA-N Trp-Leu-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 YVXIAOOYAKBAAI-SZMVWBNQSA-N 0.000 description 1
- ZHDQRPWESGUDST-JBACZVJFSA-N Trp-Phe-Gln Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C1=CC=CC=C1 ZHDQRPWESGUDST-JBACZVJFSA-N 0.000 description 1
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 0.000 description 1
- DVLHKUWLNKDINO-PMVMPFDFSA-N Trp-Tyr-Leu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O DVLHKUWLNKDINO-PMVMPFDFSA-N 0.000 description 1
- LWFWZRANSFAJDR-JSGCOSHPSA-N Trp-Val Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(O)=O)=CNC2=C1 LWFWZRANSFAJDR-JSGCOSHPSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 244000000188 Vaccinium ovalifolium Species 0.000 description 1
- VEYJKJORLPYVLO-RYUDHWBXSA-N Val-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 VEYJKJORLPYVLO-RYUDHWBXSA-N 0.000 description 1
- 208000032594 Vascular Remodeling Diseases 0.000 description 1
- 206010047097 Vascular purpura Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 102100023038 WD and tetratricopeptide repeats protein 1 Human genes 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940099983 activase Drugs 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229960003318 alteplase Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 102000025171 antigen binding proteins Human genes 0.000 description 1
- 108091000831 antigen binding proteins Proteins 0.000 description 1
- 230000006502 antiplatelets effects Effects 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- 208000007474 aortic aneurysm Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 125000001314 canonical amino-acid group Chemical group 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 108020001096 dihydrofolate reductase Proteins 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- CSVGEMRSDNSWRF-UHFFFAOYSA-L disodium;dihydrogen phosphate Chemical compound [Na+].[Na+].OP(O)([O-])=O.OP(O)([O-])=O CSVGEMRSDNSWRF-UHFFFAOYSA-L 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000001 effect on platelet aggregation Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000013156 embolectomy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 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 1
- 210000000245 forearm Anatomy 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 150000002337 glycosamines Chemical group 0.000 description 1
- 108010062266 glycyl-glycyl-argininal Proteins 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000043381 human DUSP5 Human genes 0.000 description 1
- 102000048638 human UQCRH Human genes 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000010729 leg swelling Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 1
- 239000012516 mab select resin Substances 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 238000013146 percutaneous coronary intervention Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000002885 thrombogenetic effect Effects 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 108010009962 valyltyrosine Proteins 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- 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
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
-
- 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
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6456—Plasminogen activators
- C12N9/6459—Plasminogen activators t-plasminogen activator (3.4.21.68), i.e. tPA
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21068—Tissue plasminogen activator (3.4.21.68), i.e. tPA
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- 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
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
-
- 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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Biomedical Technology (AREA)
- Mycology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Biotechnology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
- hGPVI(配列番号13)のアミノ酸残基114~142またはhGPVI(配列番号13)のアミノ酸残基114~142と少なくとも60%の同一性を共有する配列からの少なくとも1つのアミノ酸残基と、
- hGPVI(配列番号13)のアミノ酸残基165~187またはhGPVI(配列番号13)のアミノ酸残基165~187と少なくとも60%の同一性を共有する配列からの少なくとも1つのアミノ酸残基と
を含む立体構造エピトープに結合する。
- 重鎖の可変領域が以下のCDR:
VH-CDR1:GYTFTSYNMH(配列番号1)、
VH-CDR2:GIYPGNGDTSYNQKFQG(配列番号2)、および
VH-CDR3:GTVVGDWYFDV(配列番号3)
のうちの少なくとも1つまたは配列番号1~3と少なくとも60%の同一性を共有するアミノ酸配列を有する任意のCDRを含み、かつ
- 軽鎖の可変領域が以下のCDR:
VL-CDR1:RSSQSLENSNGNTYLN(配列番号4)、
VL-CDR2:RVSNRFS(配列番号5)、および
VL-CDR3:LQLTHVPWT(配列番号6)
のうちの少なくとも1つまたは配列番号4~6と少なくとも60%の同一性を共有するアミノ酸配列を有する任意のCDRを含む、
抗体分子である。
(配列番号13)
MSPSPTALFCLGLCLGRVPA(シグナルペプチド)
QSGPLPKPSLQALPSSLVPLEKPVTLRCQGPPGVDLYRLEKLSSSRYQDQAVLFIPAMKRSLAGRYRCSYQNGSLWSLPSDQLELVATGVFAKPSLSAQPGPAVSSGGDVTLQCQTRYGFDQFALYKEGDPAPYKNPERWYRASFPIITVTAAHSGTYRCYSFSSRDPYLWSAPSDPLELVVTGTSVTPSRLPTEPPSSVAEFSEATAELTVSFTNKVFTTETSRSITTSPKESDSPAGPARQYYTKGN(細胞外ドメイン)
LVRICLGAVILIILAGFLAEDWHSRRKRLRHRGRAVQRPLPPLPPLPQTRKSHGGQDGGRQDVHSRGLCS(膜貫通ドメインと細胞質ドメイン)
- CDR-L1:
開始-およそ残基24
前の残基は常にCys
後の残基は常にTrp。典型的にはTRP-TYR-GLNであるが、TRP-LEU-GLN、TRP-PHE-GLN、TRP-TYR-LEUであってもよい
長さは10~17残基
- CDR-L2:
開始-L1の終了後に常に16残基
前の残基は一般にILE-TYRであるが、VAL-TYR、ILE-LYS、ILE-PHEであってもよい
長さは常に7残基
- CDR-L3:
開始-L2の終了後に常に33残基
前の残基は常にCys
後の残基は常にPHE-GLY-XXX-GLY(配列番号21)
長さは7~11残基
- CDR-H1:
開始-およそ残基26(CYSの後に常に4残基)、[Chothia/AbM定義]Kabat定義は5残基後から開始
前の残基は常にCYS-XXX-XXX-XXX(配列番号22)
後の残基は常にTRP。典型的にはTRP-VALであるが、TRP-ILE、TRP-ALAであってもよい
長さは10~12残基(AbM定義)、Chothia定義は最後の4残基を除外する
- CDR-H2:
開始-CDR-H1の終了(Kabat/AbM定義)後に常に15残基
前の残基は典型的にLEU-GLU-TRP-ILE-GLY(配列番号23)であるが、多くの変形が可能である
後の残基はLYS/ARG-LEU/ILE/VAL/PHE/THR/ALA-THR/SER/ILE/ALA
長さはKabat定義の16~19残基(AbM定義は7残基前で終了)
- CDR-H3:
開始-CDR-H2の終了後に常に33残基(常にCYSの後に2残基)
前の残基は常にCYS-XXX-XXX(典型的にはCYS-ALA-ARG)
後の残基は常にTRP-GLY-XXX-GLY(配列番号24)
長さは3~25残基
- ヒトGPVI(配列番号13)のアミノ酸残基114~142、好ましくは115~141、より好ましくは116~140、より好ましくは117~139、より好ましくは118~138、より好ましくは119~137、より好ましくは120~136、さらにより好ましくは121~135もしくは121~136、またはヒトGPVI(配列番号13)のアミノ酸残基114~142、好ましくは115~141、より好ましくは116~140、より好ましくは117~139、より好ましくは118~138、より好ましくは119~137、より好ましくは120~136、さらにより好ましくは121~135もしくは121~136と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列からの少なくとも1つのアミノ酸残基と、
- ヒトGPVI(配列番号13)のアミノ酸残基165~187、好ましくは166~186、より好ましくは167~185、より好ましくは168~184、さらにより好ましくは169~183、またはヒトGPVI(配列番号13)のアミノ酸残基165~187、好ましくは166~186、より好ましくは167~185、より好ましくは168~184、さらにより好ましくは169~183と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列からの少なくとも1つのアミノ酸残基と
を含む。
- ヒトGPVI(配列番号13)のアミノ酸残基114~142、好ましくは115~141、より好ましくは116~140、より好ましくは117~139、より好ましくは118~138、より好ましくは119~137、より好ましくは120~136、さらにより好ましくは121~135もしくは121~136、またはヒトGPVI(配列番号13)のアミノ酸残基114~142、好ましくは115~141、より好ましくは116~140、より好ましくは117~139、より好ましくは118~138、より好ましくは119~137、より好ましくは120~136、さらにより好ましくは121~135もしくは121~136と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列からの少なくとも1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28個のアミノ酸残基と、
- ヒトGPVI(配列番号13)のアミノ酸残基165~187、好ましくは166~186、より好ましくは167~185、より好ましくは168~184、さらにより好ましくは169~183、またはヒトGPVI(配列番号13)のアミノ酸残基165~187、好ましくは166~186、より好ましくは167~185、より好ましくは168~184、さらにより好ましくは169~183と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列からの少なくとも1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22個のアミノ酸残基と
を含む。
- ヒトGPVI(配列番号13)のアミノ酸残基114~135、好ましくは115~135、より好ましくは116~135、より好ましくは117~135、より好ましくは118~135、より好ましくは119~135、より好ましくは120~135、さらにより好ましくは121~135もしくは121~136、またはヒトGPVI(配列番号13)のアミノ酸残基114~135、好ましくは115~135、より好ましくは116~135、より好ましくは117~135、より好ましくは118~135、より好ましくは119~135、より好ましくは120~135、さらにより好ましくは121~135もしくは121~136と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列からの少なくとも1つのアミノ酸残基と、
- ヒトGPVI(配列番号13)のアミノ酸残基165~187、好ましくは166~186、より好ましくは167~185、より好ましくは168~184、さらにより好ましくは169~183、またはヒトGPVI(配列番号13)のアミノ酸残基165~187、好ましくは166~186、より好ましくは167~185、より好ましくは168~184、さらにより好ましくは169~183と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列からの少なくとも1つのアミノ酸残基と
を含む。
- ヒトGPVI(配列番号13)のアミノ酸残基114~135、好ましくは115~135、より好ましくは116~135、より好ましくは117~135、より好ましくは118~135、より好ましくは119~135、より好ましくは120~135、さらにより好ましくは121~135もしくは121~136、またはヒトGPVI(配列番号13)のアミノ酸残基114~135、好ましくは115~135、より好ましくは116~135、より好ましくは117~135、より好ましくは118~135、より好ましくは119~135、より好ましくは120~135、さらにより好ましくは121~135もしくは121~136と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列からの少なくとも1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21個のアミノ酸残基と、
- ヒトGPVI(配列番号13)のアミノ酸残基165~187、好ましくは166~186、より好ましくは167~185、より好ましくは168~184、さらにより好ましくは169~183、またはヒトGPVI(配列番号13)のアミノ酸残基165~187、好ましくは166~186、より好ましくは167~185、より好ましくは168~184、さらにより好ましくは169~183と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列からの少なくとも1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22個のアミノ酸残基と
を含む。
- GPVI配列(配列番号13)中の以下の残基:125S、126S、128G、133Qおよび/または136Tのうちの少なくとも1つ(例えば、1、2、3、4または5つ)と、
- GPVI配列(配列番号13)中の以下の残基:171T、172Aおよび/または174Hのうちの少なくとも1つ(例えば、1、2または3つ)と
を含む。
- GPVI配列(配列番号13)中の以下の残基:125S、126S、128Gおよび/または133Qのうちの少なくとも1つ(例えば、1、2、3または4つ)と、
- GPVI配列(配列番号13)中の以下の残基:171T、172Aおよび/または174Hのうちの少なくとも1つ(例えば、1、2または3つ)と
を含む。
- GPVI配列(配列番号13)中の以下の残基:125S、126S、128G、133Qおよび136Tと、
- GPVI配列(配列番号13)中の以下の残基:171T、172Aおよび174Hと
を含む。
- GPVI配列(配列番号13)中の以下の残基:125S、126S、128Gおよび133Qと、
- GPVI配列(配列番号13)中の以下の残基:171T、172Aおよび174Hと
を含む。
- ヒトGPVI(配列番号13)のアミノ酸残基121~135もしくは121~136、またはヒトGPVI(配列番号13)のアミノ酸残基121~135もしくは121~136と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列、および
- ヒトGPVI(配列番号13)のアミノ酸残基169~183またはヒトGPVI(配列番号13)のアミノ酸残基169~183と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列
からなる。
- ヒトGPVI(配列番号13)のアミノ酸残基121~135もしくは121~136、またはヒトGPVI(配列番号13)のアミノ酸残基121~135もしくは121~136と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列、および
- ヒトGPVI(配列番号13)のアミノ酸残基169~183またはヒトGPVI(配列番号13)のアミノ酸残基169~183と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列
からなる立体構造エピトープに結合する。
- ヒトGPVI(配列番号13)のアミノ酸残基121~135もしくは121~136、またはヒトGPVI(配列番号13)のアミノ酸残基121~135もしくは121~136と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列、および
- ヒトGPVI(配列番号13)のアミノ酸残基169~180またはヒトGPVI(配列番号13)のアミノ酸残基169~180と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列
からなる。
- ヒトGPVI(配列番号13)のアミノ酸残基121~135もしくは121~136、またはヒトGPVI(配列番号13)のアミノ酸残基121~135もしくは121~136と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列、および
- ヒトGPVI(配列番号13)のアミノ酸残基169~180またはヒトGPVI(配列番号13)のアミノ酸残基169~180と少なくとも60%、70%、75%、80%、90%、95%、96%、97%、98%、99%の同一性を共有する配列
からなる立体構造エピトープに結合する。
VH-CDR1:GYTFTSYNMH(配列番号1)、
VH-CDR2:GIYPGNGDTSYNQKFQG(配列番号2)、および
VH-CDR3:GTVVGDWYFDV(配列番号3)
のうちの少なくとも1つを含む。
VL-CDR1:RSSQSLENSNGNTYLN(配列番号4)、
VL-CDR2:RVSNRFS(配列番号5)、および
VL-CDR3:LQLTHVPWT(配列番号6)
のうちの少なくとも1つを含む。
- 重鎖にGYTFTSYNMH(配列番号1)、GIYPGNGDTSYNQKFQG(配列番号2)およびGTVVGDWYFDV(配列番号3)のうちの少なくとも1つのCDR、および/または
- 軽鎖にRSSQSLENSNGNTYLN(配列番号4)、RVSNRFS(配列番号5)およびLQLTHVPWT(配列番号6)のうちの少なくとも1つのCDR
を含む。
(i)配列番号1、2および3にそれぞれ示されている重鎖CDR1、CDR2およびCDR3(VH-CDR1、VH-CDR2、VH-CDR3)アミノ酸配列と、
(ii)配列番号4、5および6にそれぞれ示されている軽鎖CDR1、CDR2およびCDR3(VL-CDR1、VL-CDR2、VL-CDR3)アミノ酸配列と
を有する抗体であり、任意で前記配列のいずれかにおけるアミノ酸の1つ、2つ、3つまたはそれ以上は異なるアミノ酸で置換されていてもよい。
(配列番号7)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEWMGGIYPGNGDTSYNQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGTVVGDWYFDVWGQGTLVTVSS
(配列番号8)
DIQMTQSPSSLSASVGDRVTITCRSSQSLENSNGNTYLNWYQQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCLQLTHVPWTFGQGTKVEITR
(配列番号9)
DIQMTQSPSSLSASVGDRVTITCSASQSLENSNGNTYLNWYQQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQLTHVPWTFGQGTKVEIKR
(配列番号10)
CAGGTTCAGCTGGTTCAGTCAGGGGCTGAGGTGAAGAAGCCTGGAGCCTCAGTGAAGGTGTCCTGCAAGGCTTCTGGCTACACATTTACCAGTTACAATATGCACTGGGTAAGACAGGCTCCTGGACAGGGCCTGGAATGGATGGGAGGTATTTATCCAGGAAATGGTGATACTTCCTACAATCAGAAGTTCCAGGGCCGAGTTACTATGACTCGGGACACTTCCACCTCTACAGTGTACATGGAGCTCAGCAGCCTGAGATCTGAGGACACCGCGGTCTATTACTGTGCAAGAGGCACCGTGGTCGGCGACTGGTACTTCGATGTGTGGGGCCAAGGCACCCTGGTCACCGTGAGCAGT
(配列番号11)
GACATCCAGATGACCCAGAGCCCAAGCAGCCTGAGCGCCAGCGTGGGTGACAGAGTGACCATCACCTGTAGAAGTAGTCAGAGCCTTGAGAACAGCAACGGAAACACCTACCTGAATTGGTACCAGCAGAAGCCAGGTAAGGCTCCAAAGCTGCTGATCTACAGAGTTTCCAACCGATTCTCTGGTGTGCCAAGCAGATTCAGCGGTAGCGGTAGCGGTACCGACTTCACCTTCACCATCAGCAGCCTCCAGCCAGAGGACATCGCCACCTACTACTGCCTCCAGCTGACTCATGTCCCATGGACCTTCGGTCAGGGCACCAAGGTGGAGATCACCCGG
(配列番号12)
GACATCCAGATGACCCAGAGCCCAAGCAGCCTGAGCGCCAGCGTGGGTGACAGAGTGACCATCACCTGTAGTGCCAGTCAGAGCCTTGAGAACAGCAACGGAAACACCTACCTGAATTGGTACCAGCAGAAGCCAGGTAAGGCTCCAAAGCTGCTGATCTACAGAGTTTCCAACCGATTCTCTGGTGTGCCAAGCAGATTCAGCGGTAGCGGTAGCGGTACCGACTTCACCCTCACCATCAGCAGCCTCCAGCCAGAGGACTTCGCCACCTACTACTGCCTCCAGCTGACTCATGTCCCATGGACCTTCGGTCAGGGCACCAAGGTGGAGATCAAACGC
(配列番号14)
GCCTCCACCAAGGGTCCCTCAGTCTTCCCACTGGCACCCTCCTCCAAGAGCACCTCTGGTGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCAGAACCAGTGACTGTGTCATGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCTGCTGTCTTGCAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTCGAGCCTAAGTCATGCGACAAGACTCAC。
(配列番号15)
ACTGTGGCTGCACCAAGTGTGTTCATCTTCCCACCTAGCGATGAGCAGTTGAAATCTGGAACTGCCTCTGTCGTGTGCCTCCTGAACAACTTCTACCCACGGGAGGCCAAGGTACAGTGGAAGGTGGATAACGCCCTCCAATCCGGTAACTCCCAGGAGAGTGTCACAGAGCAAGATAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACTCTGAGCAAAGCAGACTACGAGAAGCACAAGGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCCCCTGTCACAAAGAGCTTCAACCGGGGAGAGTGT
(配列番号16)
ATGGATATGCGTGTACCAGCTCAACTACTTGGACTTCTATTGCTTTGGCTTCGTGGTGCTAGATGT
(配列番号17)
ATGGACTGGACTTGGAGAATCCTATTCTTGGTTGCTGCAGCTACAGGTGCTCATTCA
(配列番号18)
GCGGCCGCCACCATGGACTGGACTTGGAGAATCCTATTCTTGGTTGCTGCAGCTACAGGTGCTCATTCACAGGTTCAGCTGGTTCAGTCAGGGGCTGAGGTGAAGAAGCCTGGAGCCTCAGTGAAGGTGTCCTGCAAGGCTTCTGGCTACACATTTACCAGTTACAATATGCACTGGGTAAGACAGGCTCCTGGACAGGGCCTGGAATGGATGGGAGGTATTTATCCAGGAAATGGTGATACTTCCTACAATCAGAAGTTCCAGGGCCGAGTTACTATGACTCGGGACACTTCCACCTCTACAGTGTACATGGAGCTCAGCAGCCTGAGATCTGAGGACACCGCGGTCTATTACTGTGCAAGAGGCACCGTGGTCGGCGACTGGTACTTCGATGTGTGGGGCCAAGGCACCCTGGTCACCGTGAGCAGTGCCTCCACCAAGGGTCCCTCAGTCTTCCCACTGGCACCCTCCTCCAAGAGCACCTCTGGTGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCAGAACCAGTGACTGTGTCATGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCTGCTGTCTTGCAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTCGAGCCTAAGTCATGCGACAAGACTCACTGATGAGGATCC
(配列番号19)
GACGTCACCATGGATATGCGTGTACCAGCTCAACTACTTGGACTTCTATTGCTTTGGCTTCGTGGTGCTAGATGTGACATCCAGATGACCCAGAGCCCAAGCAGCCTGAGCGCCAGCGTGGGTGACAGAGTGACCATCACCTGTAGAAGTAGTCAGAGCCTTGAGAACAGCAACGGAAACACCTACCTGAATTGGTACCAGCAGAAGCCAGGTAAGGCTCCAAAGCTGCTGATCTACAGAGTTTCCAACCGATTCTCTGGTGTGCCAAGCAGATTCAGCGGTAGCGGTAGCGGTACCGACTTCACCTTCACCATCAGCAGCCTCCAGCCAGAGGACATCGCCACCTACTACTGCCTCCAGCTGACTCATGTCCCATGGACCTTCGGTCAGGGCACCAAGGTGGAGATCACCCGGACTGTGGCTGCACCAAGTGTGTTCATCTTCCCACCTAGCGATGAGCAGTTGAAATCTGGAACTGCCTCTGTCGTGTGCCTCCTGAACAACTTCTACCCACGGGAGGCCAAGGTACAGTGGAAGGTGGATAACGCCCTCCAATCCGGTAACTCCCAGGAGAGTGTCACAGAGCAAGATAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACTCTGAGCAAAGCAGACTACGAGAAGCACAAGGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCCCCTGTCACAAAGAGCTTCAACCGGGGAGAGTGTTGATGATATC
(配列番号20)
GACGTCACCATGGATATGCGTGTACCAGCTCAACTACTTGGACTTCTATTGCTTTGGCTTCGTGGTGCTAGATGTGACATCCAGATGACCCAGAGCCCAAGCAGCCTGAGCGCCAGCGTGGGTGACAGAGTGACCATCACCTGTAGTGCCAGTCAGAGCCTTGAGAACAGCAACGGAAACACCTACCTGAATTGGTACCAGCAGAAGCCAGGTAAGGCTCCAAAGCTGCTGATCTACAGAGTTTCCAACCGATTCTCTGGTGTGCCAAGCAGATTCAGCGGTAGCGGTAGCGGTACCGACTTCACCCTCACCATCAGCAGCCTCCAGCCAGAGGACTTCGCCACCTACTACTGCCTCCAGCTGACTCATGTCCCATGGACCTTCGGTCAGGGCACCAAGGTGGAGATCAAACGCACTGTGGCTGCACCAAGTGTGTTCATCTTCCCACCTAGCGATGAGCAGTTGAAATCTGGAACTGCCTCTGTCGTGTGCCTCCTGAACAACTTCTACCCACGGGAGGCCAAGGTACAGTGGAAGGTGGATAACGCCCTCCAATCCGGTAACTCCCAGGAGAGTGTCACAGAGCAAGATAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACTCTGAGCAAAGCAGACTACGAGAAGCACAAGGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCCCCTGTCACAAAGAGCTTCAACCGGGGAGAGTGTTGATGATATC
- アルギニンによる配列番号25または配列番号26の125位のプロリンの再配置、
- N末端におけるフィンガードメインの欠失および/または配列番号25または配列番号26におけるEGF様ドメインの欠失および/またはグルタミンによる配列番号25または配列番号26の117位のアスパラギンの再配置、
- アスパラギンによる配列番号25または配列番号26の103位のトレオニンの再配置および/またはグルタミンによる配列番号25または配列番号26の117位のアスパラギンの再配置および/またはアラニン-アラニン-アラニン-アラニン(AAAA)による配列番号25の296~299位のリジン-ヒスチジン-アルギニン-アルギニン(KHRR)の再配置、
- セリンによる配列番号25または配列番号26の84位のシステインの再配置、
- グルタミン酸またはグリシンによる配列番号25または配列番号26の275位のアルギニンの再配置および/または配列番号25または配列番号26におけるクリングル1ドメインの欠失
のうちの少なくとも1つをさらに含む。
動物
本研究ではどんな治療も過去に受けたことのない28匹のカニクイザルを使用した。
最初に、増加用量のACT017(1、2、4、8mg/kg)またはそのビヒクルを15分間にわたって静脈内投与した(n=4~8)。投与から30分後および2時間後の時点で血液を採取した。
血小板凝集:遠心分離(120×g、15分、20℃)後に多血小板血漿(PRP)をサルから得て、即座に使用した。その凝集の速度および強度をAPACT(登録商標)血小板凝集計および各種濃度の本発明のFabを含むPRPに対して2.5mg.mL-1のコラーゲン(Hormコラーゲン、Nycomed社、DE)濃度を用いて測定し、連続的に記録した。血小板凝集の強度を光透過における増加率(%)として測定した。注射の開始後の指示された時間における平均±SDが提示されている。
ACT017投与の効果を非ヒト霊長類において特徴づけた。8匹のカニクイザルがこの研究に参加した。
本研究は、健康な志願者におけるACT017の安全性、忍容性、薬物動態および薬力学に対する無作為化、二重盲検、プラセボ対照漸増単回投与研究である。
本研究に含めた対象は、30~60歳の年齢(両端の値を含む)のBMI≧18kg/m2かつ≦30kg/m2の健康な男性対象または妊娠しておらず授乳中でない女性対象であった。計48人の対象を6つの漸増用量レベルコホートに登録し、各コホートは8人の対象(6人が有効成分、2人がプラセボ)からなっていた。各コホートを2つのサブコホートに分け、すなわち1つのコホート(1人は有効成分、1人はプラセボ)には最初に投薬し、それ以外のコホート(5人は有効成分、1人はプラセボ)にはその48時間後に投薬した。
治験薬は500mgのACT017および適合プラセボ溶液を含む50mLバイアルであった。6時間の注入の間に治療が行われた。
コホート1:治療A:62.5mgのACT017(n=6)、治療B:適合プラセボ(n=2)。
コホート2:治療A:125mgのACT017(n=6)、治療B:適合プラセボ(n=2)。
コホート3:治療A:250mgのACT017(n=6)、治療B:適合プラセボ(n=2)。
コホート4:治療A:500mgのACT017(n=6)、治療B:適合プラセボ(n=2)。
コホート5:治療A:1000mgのACT017(n=6)、治療B:適合プラセボ(n=2)。
コホート6:治療A:2000mgのACT017(n=6)、治療B:適合プラセボ(n=2)。
ACT017のための薬物動態採血は対象ごとに15個の試料を必要とした。
・有害事象:本研究の最初から最後まで
・バイタルサイン:頻繁
・ECG(心電図):バイタルサインよりも少ない頻度
・血液検査を含む臨床検査:2回
・凝固パラメータ:5回
・出血時間:4回
・血小板数:7回
・血小板凝集(コラーゲン):6回
・免疫原性/ADA:3回
図9に示すように、対象2における血小板凝集率(%)は、投与の開始から15分後にのみ、ベースラインのパーセンテージと比較して約70%減少し、その後の8時間にわたって約10%に維持され、次いで再び上昇して24時間後に約70%の凝集に達し、次いで投与から48時間後にベースラインに戻る。投与から168時間後に血小板凝集に対する効果は認められない。従って対象2において観察された効果は可逆的である。対象1では、血小板凝集率(%)は当該経験の168時間の間に変化しないようである。
以下のように可溶性GPVI-Fcを作製した:トリペプチドGGRを介してヒトIgG1 Fcドメインに融合された最初のメチオニンからアスパラギン269までのヒトGPVIの外部ドメインをコードする遺伝子をコドンの最適化後に合成した。この遺伝子をpTT5ベクターにクローニングした後、HEK293-6E細胞
にトランスフェクトした。分泌されたGPVI-Fcを、MAbselect matrix(GE Healthcare社、17519901)を用いた親和性クロマトグラフィー、およびその後のNuvia(商標)HR-S陽イオン交換樹脂(BioRad社、156051)上でのポリッシングクロマトグラフィー(polishing chromatography)によって、上記細胞の馴化培地から精製した。
450nmでの吸光度をFlustar Optimaで測定する。
図7に示すように、GPVI-Fcの二重変異体は依然として、用量依存的にコラーゲンに結合することができ、これはコラーゲンに対するGPVIの親和性がこれらの変異体の存在下で主に保存されていることを示す。但し図8に示すように、ACT017は野生型GPVI-Fcに結合することができるが、高濃度であっても二重変異体には結合することはできない。従って、これらの結果により、GPVI配列上のACT017のエピトープの位置が確認された。
Claims (1)
- 本出願の明細書または図面に記載される発明。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17154658.3 | 2017-02-03 | ||
EP17154658 | 2017-02-03 | ||
JP2019542193A JP7360945B2 (ja) | 2017-02-03 | 2018-02-02 | 抗ヒトgpvi抗体を用いた血小板凝集の阻害 |
PCT/EP2018/052664 WO2018141909A1 (en) | 2017-02-03 | 2018-02-02 | Inhibition of platelet aggregation using anti-human gpvi antibodies |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019542193A Division JP7360945B2 (ja) | 2017-02-03 | 2018-02-02 | 抗ヒトgpvi抗体を用いた血小板凝集の阻害 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2023109987A true JP2023109987A (ja) | 2023-08-08 |
JP2023109987A5 JP2023109987A5 (ja) | 2023-11-20 |
Family
ID=57963133
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019542193A Active JP7360945B2 (ja) | 2017-02-03 | 2018-02-02 | 抗ヒトgpvi抗体を用いた血小板凝集の阻害 |
JP2023088912A Pending JP2023109987A (ja) | 2017-02-03 | 2023-05-30 | 抗ヒトgpvi抗体を用いた血小板凝集の阻害 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019542193A Active JP7360945B2 (ja) | 2017-02-03 | 2018-02-02 | 抗ヒトgpvi抗体を用いた血小板凝集の阻害 |
Country Status (14)
Country | Link |
---|---|
US (2) | US11692033B2 (ja) |
EP (1) | EP3577136A1 (ja) |
JP (2) | JP7360945B2 (ja) |
KR (2) | KR20240046168A (ja) |
CN (1) | CN110494447B (ja) |
AU (2) | AU2018214222C1 (ja) |
BR (1) | BR112019016065A8 (ja) |
CA (1) | CA3051169A1 (ja) |
IL (1) | IL268299B1 (ja) |
MA (1) | MA47415A (ja) |
MX (1) | MX2019009137A (ja) |
SG (1) | SG11201906530TA (ja) |
TW (2) | TWI810173B (ja) |
WO (1) | WO2018141909A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021250026A1 (en) * | 2020-06-08 | 2021-12-16 | Acticor Biotech | Use of anti-gpvi antibodies for the treatment of acute respiratory distress syndrome |
EP4399228A1 (en) * | 2021-09-07 | 2024-07-17 | Etablissement Français du Sang | Targeted regulation of platelet and megakaryocyte activation by heteroreceptor co-clustering |
WO2023156683A1 (en) * | 2022-02-21 | 2023-08-24 | Acticor Biotech | Treatment of cardiovascular diseases using anti-human gpvi antibodies |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5892019A (en) | 1987-07-15 | 1999-04-06 | The United States Of America, As Represented By The Department Of Health And Human Services | Production of a single-gene-encoded immunoglobulin |
IE69054B1 (en) | 1988-07-20 | 1996-08-07 | Schering Ag | Vampire bat salivary plasminogen activators |
DE3903581A1 (de) | 1989-02-07 | 1990-08-16 | Boehringer Mannheim Gmbh | Gewebs-plasminogenaktivator-derivat |
DE3920358A1 (de) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung |
GB9114948D0 (en) | 1991-07-11 | 1991-08-28 | Pfizer Ltd | Process for preparing sertraline intermediates |
EP1136556B1 (en) | 1991-11-25 | 2005-06-08 | Enzon, Inc. | Method of producing multivalent antigen-binding proteins |
DK0643772T3 (da) | 1992-06-03 | 1998-02-02 | Genentech Inc | Glycosyleringsvarianter af vævsplasminogenaktivator med forbedrede terapeutiske egenskaber |
US7291714B1 (en) | 1999-06-30 | 2007-11-06 | Millennium Pharmaceuticals, Inc. | Glycoprotein VI and uses thereof |
US20040001826A1 (en) * | 1999-06-30 | 2004-01-01 | Millennium Pharmaceuticals, Inc. | Glycoprotein VI and uses thereof |
US6245527B1 (en) * | 1999-06-30 | 2001-06-12 | Millennium Pharmaceuticals, Inc. | Nucleic acid molecules encoding glycoprotein VI and recombinant uses thereof |
WO2001016321A1 (en) * | 1999-09-01 | 2001-03-08 | Otsuka Pharmaceutical Co., Ltd. | Platelet membrane glycoprotein vi (gpvi) dna and protein sequences, and uses thereof |
EP1224942A1 (en) | 2001-01-23 | 2002-07-24 | Bernhard Dr. Nieswandt | Use of JAQ1 (monoclonal antibody anti GPVI) as a medicament for the protection against thrombotic diseases |
AU2002333241B2 (en) | 2001-07-18 | 2008-09-18 | Merck Patent Gmbh | Glycoprotein VI fusion proteins |
GB0130543D0 (en) | 2001-12-20 | 2002-02-06 | Univ Cambridge Tech | Human antibodies and their use |
EP1538165A1 (en) | 2003-12-03 | 2005-06-08 | Procorde GmbH | Inhibitors of glycoprotein VI based on monoclonal antibody hgp 5c4 |
US20070071744A1 (en) | 2002-06-07 | 2007-03-29 | Gotz Munch | Agents which bind to epitopes of glycoprotein VI |
GB0511590D0 (en) | 2005-06-07 | 2005-07-13 | Procorde Gmbh | Anti-thrombotic agents |
CN100558895C (zh) * | 2003-07-18 | 2009-11-11 | 持田制药株式会社 | 抗血小板膜糖蛋白vi单克隆抗体 |
EP1745076B1 (en) | 2004-04-29 | 2012-06-13 | Otsuka Pharmaceutical Co., Ltd. | Antibodies specific for glycoprotein vi and methods of producing these antibodies |
US20090041783A1 (en) | 2005-04-28 | 2009-02-12 | Mochida Pharmaceutical Co., Ltd. | Anti-platelet membrane glycoprotein vi monoclonal antibody |
CA2606450A1 (en) | 2005-04-28 | 2006-11-09 | Mochida Pharmaceutical Co., Ltd. | Anti-platelet membrane glycoprotein vi monoclonal antibody |
EP1916259A1 (en) | 2006-10-26 | 2008-04-30 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Anti-glycoprotein VI SCFV fragment for treatment of thrombosis |
UY33115A (es) | 2009-12-18 | 2011-07-29 | Sanofi Aventis | NUEVOS ANTICUERPOS ANTAGONISTAS Y SUS FRAGMENTOS Fab CONTRA GPVI Y SUS USOS |
AR087749A1 (es) | 2011-09-01 | 2014-04-16 | Eisai R&D Man Co Ltd | Anticuerpos anti-xcr1 humano |
ES2823998T3 (es) | 2011-09-08 | 2021-05-11 | Inst Nat Sante Rech Med | Nuevos activadores de plasminógeno tisular mutados y usos de los mismos |
EP3331553B1 (en) * | 2015-08-05 | 2022-06-29 | Acticor Biotech | Novel anti-human gpvi antibodies and uses thereof |
-
2018
- 2018-02-02 WO PCT/EP2018/052664 patent/WO2018141909A1/en unknown
- 2018-02-02 SG SG11201906530TA patent/SG11201906530TA/en unknown
- 2018-02-02 TW TW107103804A patent/TWI810173B/zh active
- 2018-02-02 TW TW112116638A patent/TW202339799A/zh unknown
- 2018-02-02 US US16/477,327 patent/US11692033B2/en active Active
- 2018-02-02 KR KR1020247003757A patent/KR20240046168A/ko active Search and Examination
- 2018-02-02 CN CN201880010227.0A patent/CN110494447B/zh active Active
- 2018-02-02 MX MX2019009137A patent/MX2019009137A/es unknown
- 2018-02-02 CA CA3051169A patent/CA3051169A1/en active Pending
- 2018-02-02 KR KR1020197024528A patent/KR102633644B1/ko active IP Right Grant
- 2018-02-02 AU AU2018214222A patent/AU2018214222C1/en active Active
- 2018-02-02 JP JP2019542193A patent/JP7360945B2/ja active Active
- 2018-02-02 IL IL268299A patent/IL268299B1/en unknown
- 2018-02-02 EP EP18704492.0A patent/EP3577136A1/en active Pending
- 2018-02-02 BR BR112019016065A patent/BR112019016065A8/pt unknown
- 2018-02-02 MA MA047415A patent/MA47415A/fr unknown
-
2021
- 2021-04-28 AU AU2021202612A patent/AU2021202612B2/en active Active
-
2023
- 2023-05-12 US US18/316,564 patent/US20230391869A1/en active Pending
- 2023-05-30 JP JP2023088912A patent/JP2023109987A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
MX2019009137A (es) | 2019-12-19 |
MA47415A (fr) | 2019-12-11 |
CN110494447B (zh) | 2024-06-04 |
BR112019016065A8 (pt) | 2022-11-08 |
JP7360945B2 (ja) | 2023-10-13 |
KR20240046168A (ko) | 2024-04-08 |
KR102633644B1 (ko) | 2024-02-05 |
BR112019016065A2 (pt) | 2020-05-26 |
US11692033B2 (en) | 2023-07-04 |
AU2018214222C1 (en) | 2021-08-05 |
US20190367608A1 (en) | 2019-12-05 |
AU2018214222B2 (en) | 2021-01-28 |
TW202339799A (zh) | 2023-10-16 |
US20230391869A1 (en) | 2023-12-07 |
CN110494447A (zh) | 2019-11-22 |
TWI810173B (zh) | 2023-08-01 |
JP2020507317A (ja) | 2020-03-12 |
WO2018141909A1 (en) | 2018-08-09 |
RU2019127768A (ru) | 2021-03-03 |
CA3051169A1 (en) | 2018-08-09 |
AU2021202612B2 (en) | 2024-03-14 |
EP3577136A1 (en) | 2019-12-11 |
TW201839009A (zh) | 2018-11-01 |
AU2021202612A1 (en) | 2021-05-27 |
KR20190121767A (ko) | 2019-10-28 |
SG11201906530TA (en) | 2019-08-27 |
RU2019127768A3 (ja) | 2021-05-28 |
AU2018214222A1 (en) | 2019-08-01 |
IL268299A (en) | 2019-09-26 |
IL268299B1 (en) | 2024-06-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7277689B2 (ja) | 新規な抗ヒトgpvi抗体およびその使用 | |
KR101852915B1 (ko) | 과립구-대식세포 콜로니 자극 인자에 대한 항체 | |
AU2021202612B2 (en) | Inhibition of platelet aggregation using anti-human GPVI antibodies | |
CA3004830A1 (en) | Composition and methods for anti-tnfr2 antibodies | |
RU2778884C2 (ru) | Выделенный гуманизированный белок, связывающийся с гликопротеином VI человека, выделенное антитело, связывающееся с гликопротеином VI человека | |
WO2023156683A1 (en) | Treatment of cardiovascular diseases using anti-human gpvi antibodies | |
RU2773819C2 (ru) | Белок, связанный с гликопротеином человека, композиция, фармацевтическая композиция, вектор экспрессии | |
WO2023225197A2 (en) | Klrb1 binding agents and methods of use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230627 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20230627 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231110 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20240521 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20240815 |