CN110234353B - 用于FXIa抗体的新型稳定制剂 - Google Patents
用于FXIa抗体的新型稳定制剂 Download PDFInfo
- Publication number
- CN110234353B CN110234353B CN201880007721.1A CN201880007721A CN110234353B CN 110234353 B CN110234353 B CN 110234353B CN 201880007721 A CN201880007721 A CN 201880007721A CN 110234353 B CN110234353 B CN 110234353B
- Authority
- CN
- China
- Prior art keywords
- liquid pharmaceutical
- pharmaceutical formulation
- ser
- val
- gly
- 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.)
- Active
Links
- 239000000203 mixture Substances 0.000 title claims description 62
- 238000009472 formulation Methods 0.000 title claims description 50
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 64
- 239000007788 liquid Substances 0.000 claims abstract description 62
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 230000009424 thromboembolic effect Effects 0.000 claims abstract description 11
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 10
- 230000002265 prevention Effects 0.000 claims abstract description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 59
- 239000004471 Glycine Substances 0.000 claims description 29
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 29
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 24
- 229920000053 polysorbate 80 Polymers 0.000 claims description 24
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 23
- DPVHGFAJLZWDOC-PVXXTIHASA-N (2r,3s,4s,5r,6r)-2-(hydroxymethyl)-6-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxane-3,4,5-triol;dihydrate Chemical compound O.O.O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DPVHGFAJLZWDOC-PVXXTIHASA-N 0.000 claims description 22
- 229940068968 polysorbate 80 Drugs 0.000 claims description 22
- 229940074409 trehalose dihydrate Drugs 0.000 claims description 22
- 239000003381 stabilizer Substances 0.000 claims description 16
- 239000000080 wetting agent Substances 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000000969 carrier Substances 0.000 claims description 7
- 238000004108 freeze drying Methods 0.000 claims description 7
- 239000003755 preservative agent Substances 0.000 claims description 7
- 239000004615 ingredient Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 1
- 239000012669 liquid formulation Substances 0.000 abstract description 7
- 239000004480 active ingredient Substances 0.000 abstract description 5
- 108010039209 Blood Coagulation Factors Proteins 0.000 abstract description 3
- 102000015081 Blood Coagulation Factors Human genes 0.000 abstract description 3
- 239000003114 blood coagulation factor Substances 0.000 abstract description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 30
- 229960002885 histidine Drugs 0.000 description 29
- 238000002296 dynamic light scattering Methods 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 20
- 108090000623 proteins and genes Proteins 0.000 description 20
- 208000035475 disorder Diseases 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 201000010099 disease Diseases 0.000 description 17
- 239000000178 monomer Substances 0.000 description 15
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 14
- 229930006000 Sucrose Natural products 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 239000005720 sucrose Substances 0.000 description 14
- 239000000872 buffer Substances 0.000 description 13
- 208000002815 pulmonary hypertension Diseases 0.000 description 12
- 230000015271 coagulation Effects 0.000 description 11
- 238000005345 coagulation Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000011084 recovery Methods 0.000 description 11
- 238000001542 size-exclusion chromatography Methods 0.000 description 11
- 238000005259 measurement Methods 0.000 description 10
- 238000011321 prophylaxis Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 108010080805 Factor XIa Proteins 0.000 description 8
- 230000035882 stress Effects 0.000 description 8
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 7
- 239000007853 buffer solution Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000012905 visible particle Substances 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 208000001435 Thromboembolism Diseases 0.000 description 5
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 5
- 230000009878 intermolecular interaction Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000001732 thrombotic effect Effects 0.000 description 5
- 230000000007 visual effect Effects 0.000 description 5
- 208000005189 Embolism Diseases 0.000 description 4
- 241000880493 Leptailurus serval Species 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 230000003204 osmotic effect Effects 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 3
- 206010053159 Organ failure Diseases 0.000 description 3
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000003599 detergent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000009662 stress testing Methods 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 208000026151 Chronic thromboembolic pulmonary hypertension Diseases 0.000 description 2
- 206010053567 Coagulopathies Diseases 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- 206010014522 Embolism venous Diseases 0.000 description 2
- 108010062466 Enzyme Precursors Proteins 0.000 description 2
- 102000010911 Enzyme Precursors Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108010048049 Factor IXa Proteins 0.000 description 2
- 108010014173 Factor X Proteins 0.000 description 2
- 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- OJNZVYSGVYLQIN-BQBZGAKWSA-N Gly-Met-Asp Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(O)=O OJNZVYSGVYLQIN-BQBZGAKWSA-N 0.000 description 2
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 208000021124 Heritable pulmonary arterial hypertension Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 208000020875 Idiopathic pulmonary arterial hypertension Diseases 0.000 description 2
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 2
- 208000019693 Lung disease Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 208000034486 Multi-organ failure Diseases 0.000 description 2
- 208000010718 Multiple Organ Failure Diseases 0.000 description 2
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 2
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 2
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 2
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 206010069351 acute lung injury Diseases 0.000 description 2
- 206010000891 acute myocardial infarction Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 238000000149 argon plasma sintering Methods 0.000 description 2
- -1 aromatic alcohols Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000008366 buffered solution Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000035602 clotting Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- 108010015792 glycyllysine Proteins 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 210000003709 heart valve Anatomy 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000000644 isotonic solution Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000004768 organ dysfunction Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108010053725 prolylvaline Proteins 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 230000008728 vascular permeability Effects 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 1
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 1
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 1
- WCBVQNZTOKJWJS-ACZMJKKPSA-N Ala-Cys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O WCBVQNZTOKJWJS-ACZMJKKPSA-N 0.000 description 1
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 1
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 1
- WQLDNOCHHRISMS-NAKRPEOUSA-N Ala-Pro-Ile Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WQLDNOCHHRISMS-NAKRPEOUSA-N 0.000 description 1
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 1
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 1
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 1
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 1
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 1
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 1
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 1
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 1
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 1
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- PDECQIHABNQRHN-GUBZILKMSA-N Asp-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O PDECQIHABNQRHN-GUBZILKMSA-N 0.000 description 1
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 1
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 1
- NVFSJIXJZCDICF-SRVKXCTJSA-N Asp-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N NVFSJIXJZCDICF-SRVKXCTJSA-N 0.000 description 1
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 1
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 1
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 1
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 1
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 208000015121 Cardiac valve disease Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 102100022641 Coagulation factor IX Human genes 0.000 description 1
- 208000027932 Collagen disease Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- BVFQOPGFOQVZTE-ACZMJKKPSA-N Cys-Gln-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O BVFQOPGFOQVZTE-ACZMJKKPSA-N 0.000 description 1
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010014498 Embolic stroke Diseases 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010014172 Factor V Proteins 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 108010061932 Factor VIIIa Proteins 0.000 description 1
- 108010074864 Factor XI Proteins 0.000 description 1
- 208000015872 Gaucher disease Diseases 0.000 description 1
- REJJNXODKSHOKA-ACZMJKKPSA-N Gln-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N REJJNXODKSHOKA-ACZMJKKPSA-N 0.000 description 1
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 1
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 1
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 1
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 1
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 1
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 1
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- IESFZVCAVACGPH-PEFMBERDSA-N Glu-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O IESFZVCAVACGPH-PEFMBERDSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 1
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- GPSHCSTUYOQPAI-JHEQGTHGSA-N Glu-Thr-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O GPSHCSTUYOQPAI-JHEQGTHGSA-N 0.000 description 1
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 1
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 1
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 1
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 1
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 1
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 1
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 1
- JNGHLWWFPGIJER-STQMWFEESA-N Gly-Pro-Tyr Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 JNGHLWWFPGIJER-STQMWFEESA-N 0.000 description 1
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 1
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 1
- TVTZEOHWHUVYCG-KYNKHSRBSA-N Gly-Thr-Thr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O TVTZEOHWHUVYCG-KYNKHSRBSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- 101001062768 Homo sapiens Coagulation factor XI Proteins 0.000 description 1
- 206010021133 Hypoventilation Diseases 0.000 description 1
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 1
- FADXGVVLSPPEQY-GHCJXIJMSA-N Ile-Cys-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N FADXGVVLSPPEQY-GHCJXIJMSA-N 0.000 description 1
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 1
- JODPUDMBQBIWCK-GHCJXIJMSA-N Ile-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O JODPUDMBQBIWCK-GHCJXIJMSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 1
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 1
- 201000005099 Langerhans cell histiocytosis Diseases 0.000 description 1
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 1
- USTCFDAQCLDPBD-XIRDDKMYSA-N Leu-Asn-Trp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N USTCFDAQCLDPBD-XIRDDKMYSA-N 0.000 description 1
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 1
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 1
- CQGSYZCULZMEDE-UHFFFAOYSA-N Leu-Gln-Pro Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)N1CCCC1C(O)=O CQGSYZCULZMEDE-UHFFFAOYSA-N 0.000 description 1
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 1
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 1
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 1
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 1
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 1
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 1
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 1
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 1
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 1
- IXHKPDJKKCUKHS-GARJFASQSA-N Lys-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IXHKPDJKKCUKHS-GARJFASQSA-N 0.000 description 1
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 1
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 1
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 1
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 1
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- CTJUSALVKAWFFU-CIUDSAMLSA-N Lys-Ser-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N CTJUSALVKAWFFU-CIUDSAMLSA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 1
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 1
- XABXVVSWUVCZST-GVXVVHGQSA-N Lys-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN XABXVVSWUVCZST-GVXVVHGQSA-N 0.000 description 1
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- BACYUWVYYTXETD-UHFFFAOYSA-N N-Lauroylsarcosine Chemical compound CCCCCCCCCCCC(=O)N(C)CC(O)=O BACYUWVYYTXETD-UHFFFAOYSA-N 0.000 description 1
- HXSUFWQYLPKEHF-IHRRRGAJSA-N Phe-Asn-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HXSUFWQYLPKEHF-IHRRRGAJSA-N 0.000 description 1
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 1
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 1
- JLLJTMHNXQTMCK-UBHSHLNASA-N Phe-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 JLLJTMHNXQTMCK-UBHSHLNASA-N 0.000 description 1
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 1
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 1
- HBXAOEBRGLCLIW-AVGNSLFASA-N Phe-Ser-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N HBXAOEBRGLCLIW-AVGNSLFASA-N 0.000 description 1
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 1
- BPIMVBKDLSBKIJ-FCLVOEFKSA-N Phe-Thr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BPIMVBKDLSBKIJ-FCLVOEFKSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 1
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 1
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 1
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 1
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 1
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 1
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 1
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 206010068690 Pulmonary vein occlusion Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038563 Reocclusion Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 208000006117 ST-elevation myocardial infarction Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 1
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 1
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 1
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 1
- ULVMNZOKDBHKKI-ACZMJKKPSA-N Ser-Gln-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ULVMNZOKDBHKKI-ACZMJKKPSA-N 0.000 description 1
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 1
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-N 0.000 description 1
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 1
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 1
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 1
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-CIUDSAMLSA-N 0.000 description 1
- RWDVVSKYZBNDCO-MELADBBJSA-N Ser-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CO)N)C(=O)O RWDVVSKYZBNDCO-MELADBBJSA-N 0.000 description 1
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 1
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 1
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 1
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 1
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 1
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 1
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 1
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 1
- TWLMXDWFVNEFFK-FJXKBIBVSA-N Thr-Arg-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O TWLMXDWFVNEFFK-FJXKBIBVSA-N 0.000 description 1
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 1
- KWQBJOUOSNJDRR-XAVMHZPKSA-N Thr-Cys-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N)O KWQBJOUOSNJDRR-XAVMHZPKSA-N 0.000 description 1
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 1
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 1
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 1
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 1
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 1
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 1
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 1
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 1
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 1
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 1
- BPGDJSUFQKWUBK-KJEVXHAQSA-N Thr-Val-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BPGDJSUFQKWUBK-KJEVXHAQSA-N 0.000 description 1
- 206010043647 Thrombotic Stroke Diseases 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 1
- DQDXHYIEITXNJY-BPUTZDHNSA-N Trp-Gln-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N DQDXHYIEITXNJY-BPUTZDHNSA-N 0.000 description 1
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 1
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 1
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 1
- GAYLGYUVTDMLKC-UWJYBYFXSA-N Tyr-Asp-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GAYLGYUVTDMLKC-UWJYBYFXSA-N 0.000 description 1
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 1
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 1
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 1
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 1
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 1
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- RMRFSFXLFWWAJZ-HJOGWXRNSA-N Tyr-Tyr-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 RMRFSFXLFWWAJZ-HJOGWXRNSA-N 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- GNWUWQAVVJQREM-NHCYSSNCSA-N Val-Asn-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N GNWUWQAVVJQREM-NHCYSSNCSA-N 0.000 description 1
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 1
- WDIGUPHXPBMODF-UMNHJUIQSA-N Val-Glu-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N WDIGUPHXPBMODF-UMNHJUIQSA-N 0.000 description 1
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 1
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- HPANGHISDXDUQY-ULQDDVLXSA-N Val-Lys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N HPANGHISDXDUQY-ULQDDVLXSA-N 0.000 description 1
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 1
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 1
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 1
- QHSSPPHOHJSTML-HOCLYGCPSA-N Val-Trp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N QHSSPPHOHJSTML-HOCLYGCPSA-N 0.000 description 1
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 1
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 1
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000030451 Vascular dementia disease Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 1
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000012443 analytical study Methods 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 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
- 210000001765 aortic valve Anatomy 0.000 description 1
- 108010008355 arginyl-glutamine Proteins 0.000 description 1
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
- 229940090047 auto-injector Drugs 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000013194 cardioversion Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002618 extracorporeal membrane oxygenation Methods 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 229940012426 factor x Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000012537 formulation buffer Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- 101150089730 gly-10 gene Proteins 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 108010037850 glycylvaline Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 208000034737 hemoglobinopathy Diseases 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 208000018337 inherited hemoglobinopathy Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 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
- 201000006370 kidney failure Diseases 0.000 description 1
- 210000005246 left atrium Anatomy 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 108010064235 lysylglycine Proteins 0.000 description 1
- 108010017391 lysylvaline Proteins 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 206010062198 microangiopathy Diseases 0.000 description 1
- 210000004115 mitral valve Anatomy 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000002071 myeloproliferative effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002840 non-reducing disaccharides Chemical group 0.000 description 1
- 230000001453 nonthrombogenic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 1
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 201000008312 primary pulmonary hypertension Diseases 0.000 description 1
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000009979 protective mechanism Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 210000002796 renal vein Anatomy 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 238000010911 splenectomy Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000001370 static light scattering Methods 0.000 description 1
- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 108010044292 tryptophyltyrosine Proteins 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 108010027345 wheylin-1 peptide Proteins 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- 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
- C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Dermatology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及包含针对凝血因子FXIa的人抗体作为活性成分的新型液体药物制剂。本发明还涉及特定液体制剂的冻干物,且还涉及其在治疗和预防血栓形成或血栓栓塞性病症中的用途。
Description
引言
本发明涉及包含作为活性成分的针对凝血因子FXIa的人抗体、尤其是WO2013167669A1中描述的那些的新型液体药物制剂。本发明还涉及特定液体制剂的冻干物,且还涉及其在治疗和预防血栓形成或血栓栓塞性病症中的用途。
凝血是生物体的保护机制,其有助于能够迅速地和可靠地“封闭”血管壁中的缺陷。因此,可以避免失血或者保持最小限度失血。血管损伤后的止血主要受凝血系统影响,其中触发血浆蛋白的复杂反应的酶促级联。许多凝血因子参与该过程,每种因子在活化后将各自下一个非活性的前体转化为其活性形式。在级联结束时出现可溶解的纤维蛋白原转化为不溶性纤维蛋白,导致血块的形成。在凝血中,传统上区分内源性和外源性系统,其结束于最终联合反应途径。
凝血因子FXIa是由起始至凝血的放大和蔓延的过渡的中心组分:在正反馈回路中,除了因子V和因子VIII之外,凝血酶还将因子XI活化为因子XIa,藉此因子IX被转化为因子IXa,并且,经由以这种方式产生的因子IXa/因子VIIIa复合物,因子X被活化并进而因此高度刺激凝血酶形成,从而导致强血栓生长并稳定血栓。抗FXIa抗体在现有技术中已知为抗凝血剂,即用于抑制或预防凝血的物质(参见WO2013167669A1)。BAY1213790是抗FXIa抗体,其包含根据SEQ ID NO:1的重链和根据SEQ ID NO:2的轻链的序列。
治疗性蛋白诸如例如人单克隆抗体,由于其特性,通常作为液体药物制剂而通过注射来施用。由于许多治疗有效的人单克隆抗体具有不利的特性,诸如低稳定性或聚集倾向,所以必需通过合适的药物制剂调节这些不利的特性。聚集体或变性的抗体可以具有例如低治疗效力。聚集体或变性的抗体也可以引发不期望的免疫反应。稳定的蛋白药物制剂也应当适合于防止化学不稳定。蛋白的化学不稳定性可以导致降解或片段化,且因此降低效力,或者甚至导致毒性副作用。因此,应当避免或至少最小化所有类型的低分子量片段的形成或产生。这些都是可能影响制备物的安全性的因素,且因此必须受影响。此外,当使用注射器或泵时,低粘度是有利的,因为这使得所需的力保持较低并因此增加可注射性。低粘度在生产期间也是有利的,例如,使得能够精确填充制备物。然而,人单克隆抗体的治疗用途经常需要使用高抗体浓度,其经常导致高粘度的问题。在他们的概述文章中,Daugherty和Mrsny(Adv Drug Deliv Rev.2006;58(5-6):686-706)讨论了该问题和在单克隆抗体的液体药物制剂中可能存在的其他问题。
液体制剂应当稳定抗体尽可能最长时间并且还使得能够冻干。因此,合适的液体药物制剂必须稳定抗体的生物效力和人单克隆抗体的生物物理特性。因此,需要单克隆抗体的浓缩液体制剂,其包含低比例的聚集体和降解产物,经长时段是稳定的,可以冻干并且具有最小的粘度。
本发明解决了上述需求,并提供了包含抗FXIa抗体和少量聚集体和降解产物的液体药物制剂,并且还可以由此生产稳定的冻干物。这些制剂还具有低粘度,且因此可以简单地施用于患者,例如通过注射器或自动注射器的方式。
本发明提供了包含抗FXIa抗体和组氨酸-甘氨酸缓冲系统的液体药物制剂。
发明描述
在一个实施方案中,所述液体药物制剂包含5-30mM组氨酸和100-200mM甘氨酸。在一个优选实施方案中,所述液体药物制剂包含5-10mM组氨酸和130-200mM甘氨酸。在一个特别优选的实施方案中,所述液体药物制剂包含10mM组氨酸和130mM甘氨酸。此外,所述液体药物制剂具有5.5-7.5的pH。在一个优选实施方案中,所述液体药物制剂具有5.7-6.3的pH。在一个特别优选的实施方案中,所述液体药物制剂具有6的pH。根据本发明的液体药物制剂包含浓度为5-50mg/ml的抗FXIa抗体。在一个优选实施方案中,所述抗FXIa抗体以10-40mg/ml的浓度存在。在一个特别优选的实施方案中,所述抗FXIa抗体具有25mg/ml的浓度。在所有实施方案中,所述抗FXIa抗体特别优选为BAY1213790。所述液体药物制剂还可以包含稳定剂。例如,稳定剂是糖。“糖”是指一组有机化合物,其为水溶性的,并且分为单糖、二糖和多元醇。优选的糖是非还原性二糖,特别优选蔗糖或海藻糖二水合物。在一个实施方案中,所述稳定剂存在至1-10%重量/体积(w/v)的程度,优选至3-7%(w/v)的程度,且特别优选至5%(w/v)的程度。在一个优选实施方案中,海藻糖二水合物存在至1-10%重量/体积(w/v)的程度,优选至3-7%(w/v)的程度,且特别优选至5%(w/v)的程度。所述液体药物制剂还可以包含润湿剂。术语“润湿剂”是指任何具有亲水区和疏水区的去污剂且包括非离子型、阳离子型、阴离子型和两性离子型去污剂。优选的去污剂可以选自聚氧乙烯山梨聚糖单油酸酯(也已知为聚山梨醇酯80或TWEEN 80)、聚氧乙烯山梨聚糖单月桂酸酯(也已知为聚山梨醇酯20或TWEEN 20)和N-月桂基肌氨酸。对于公开的组合物,优选非离子型润湿剂。对于本发明的组合物,尤其优选使用聚山梨醇酯80。所述润湿剂可以以0.001%至0.5%(w/v)的浓度使用,优选0.005%至0.1%(w/v)的浓度范围。特别优选使用0.01%(w/v)的润湿剂浓度。
可以任选地将防腐剂或其他添加剂、填充剂、稳定剂或载体添加至根据本发明的液体药物制剂中。合适的防腐剂是,例如,十八烷基二甲基苄基氯化铵,六甲基氯化铵,和芳族醇,诸如苯酚、对羟基苯甲酸酯或间甲酚。另外的药学上可接受的添加剂、稳定剂或载体描述于例如Remington’s Science And Practice of Pharmacy(第22版,Loyd V.Allen,Jr,编辑Philadelphia,PA:Pharmaceutical Press.2012)。
因此,本发明提供了包含抗FXIa抗体BAY1213790和组氨酸-甘氨酸缓冲系统的液体药物制剂,其中所述制剂包含5-30mM组氨酸和100-200mM甘氨酸,优选5-10mM组氨酸和130-200mM甘氨酸,且具有5.5-6.5、优选5.7-6.3的pH。这在低粘度下产生抗体BAY1213790的足够的稳定性和低聚集,并且还使得能够任选地冻干制剂。
根据本发明的一个实施方案是液体药物制剂,其包含
抗FXIa抗体BAY1213790,浓度为5-50mg/ml,优选10-40mg/ml,
5-30mM组氨酸和100-200mM甘氨酸,优选5-10mM组氨酸和130-200mM甘氨酸,
其中所述制剂具有5.5-6.5、优选5.7-6.3的pH。所述制剂任选地包含选自润湿剂、防腐剂、载体和稳定剂的另外的成分。
根据本发明的一个实施方案是液体药物制剂,其包含
抗FXIa抗体BAY1213790,浓度为5-50mg/ml,优选10-40mg/ml,
5-30mM组氨酸和100-200mM甘氨酸,优选5-10mM组氨酸和130-200mM甘氨酸,
1-10%(w/v)稳定剂,优选3-7%(w/v)海藻糖二水合物,
其中所述制剂具有5.5-6.5、优选5.7-6.3的pH。所述制剂任选地包含选自润湿剂、防腐剂、载体和稳定剂的另外的成分。
在一个实施方案中,所述液体药物制剂包含聚山梨醇酯80作为润湿剂,浓度为0.001%至0.5%(w/v),优选0.005%至0.1%(w/v)。
一个优选实施方案是液体药物制剂,其包含
抗FXIa抗体BAY1213790,浓度为10–40mg/ml,
5-10mM组氨酸和130-200mM甘氨酸,
3-7%(w/v)海藻糖二水合物,和
聚山梨醇酯80,浓度为0.005%至0.1%(w/v),
其中所述制剂具有5.7-6.3的pH。所述制剂任选地包含选自防腐剂、载体和稳定剂的另外的成分。
一个特别优选的实施方案是液体药物制剂,其包含
抗FXIa抗体BAY1213790,浓度为25mg/ml,
10mM组氨酸和130mM甘氨酸,
5%(w/v)海藻糖二水合物,和
聚山梨醇酯80,浓度为0.05%(w/v),
其中所述制剂具有6的pH。所述制剂任选地包含选自防腐剂、载体和稳定剂的另外的成分。
术语“缓冲剂”在本文中描述缓冲的溶液,在添加酸性或碱性物质后其pH仅略微改变。缓冲的溶液含有弱酸和其对应碱或弱碱和其对应酸的混合物。
术语“患者”是指接受预防性或治疗性治疗的人或动物个体。
术语“治疗”在本文中是指使用或施用治疗性物质至患者上/于患者,或使用或施用治疗性物质至患者的分离组织/于患者的分离组织,或至患者的细胞系/于患者的细胞系,所述患者正患有疾病,正显示疾病的症状,或具有疾病的易患性,其中目标在于治愈、改善、影响、中止或减轻疾病、其症状或疾病的易患性。
“有效剂量”在本文中描述活性成分量,以该量可至少部分地实现期望效果。因此“治疗有效剂量”定义为足以至少部分地治愈疾病,或至少部分地在患者体内消除由疾病引起的不良作用的活性成分量。对于该目的实际所需的量取决于疾病严重程度和患者的总体免疫状态。
“等张溶液”具有与人血液基本上相同的渗透压。等张溶液因此具有通常约250至350mOsm的渗透压。术语“低张”描述具有低于人血液的渗透压的渗透压的组合物,而“高张”组合物具有高于人血液的渗透压的渗透压。
术语“高分子量聚集体”(同义字:“HMW”)描述由至少两个蛋白单体构成的聚集体。
本发明进一步提供包含根据本发明的药物制剂之一和优选还包含使用说明的产品。在一个实施方案中,该产品包含含有根据本发明的液体制剂或冻干物的容器。可用的容器是,例如,瓶、小瓶、管或注射器。容器可以,例如,由玻璃或塑料制成。注射器可包含注射针头,其由,例如,金属制成。本发明进一步提供了试剂盒,其包含前述药物制剂。
在一个实施方案中,该容器是注射器。在一个进一步实施方案中,该注射器包含在注射装置中。优选在用标准输注溶液诸如0.9%NaCl溶液稀释之后经由静脉内(快速)输注来施用。
根据本发明的组合物相比于现有技术中可用的抗FXIa抗体的制剂表现出稳定性增加。优选的制剂适合作为液体制剂,但对于更严格的要求也可以是冻干的。因此,根据本发明的液体药物制剂也可以是重构的冻干物。由于该特性概况,根据本发明的液体药物制剂尤其适用于肠胃外施用。肠胃外施用尤其包括静脉内注射或输注、动脉内注射或输注(至动脉中)、肌肉内注射、鞘内注射、皮下注射、腹膜内注射或输注、骨内施用或注射至组织中。根据本发明的组合物尤其适用于静脉内或皮下施用。
根据本发明的液体药物制剂在长期测试中表现出高稳定性,甚至作为冻干物。它们还表现出优异的重构性,同时维持生物活性。根据本发明的液体药物制剂也可以是冷冻-干燥的,使得它们包含至多2%的残余水分。因此,本发明的一个进一步实施方案是通过冷冻-干燥根据本发明的液体制剂可获得的冻干物。优选包含至多2%残余水的冻干物。特别优选包含至多1%残余水的冻干物。
根据本发明的液体药物制剂具有有价值的药理学特性且可用于预防和治疗人和动物中的疾病。可用于疾病和其治疗的根据本发明的液体药物制剂尤其包括血栓形成或血栓栓塞性疾病的组。因此,根据本发明的液体药物制剂适用于治疗和/或预防可能由凝块形成产生的疾病或并发症。
在本发明的上下文中,“血栓形成或血栓栓塞性疾病”包括在动脉和静脉血管系统中发生并可用根据本发明的液体药物制剂治疗的疾病,特别是在心脏的冠状动脉中的疾病,诸如急性冠状动脉综合征(ACS)、存在ST段抬高(STEMI)和无ST段抬高(非STEMI)的心肌梗死、稳定型心绞痛、不稳定型心绞痛、在冠状动脉介入术诸如血管成形术、支架植入或主动脉冠状动脉搭桥术后的再闭塞和再狭窄,以及其他血管中的血栓形成或血栓栓塞性疾病,其导致外周动脉闭塞性病症、肺栓塞、静脉血栓栓塞、静脉血栓形成,特别是在下肢深静脉和肾静脉中,短暂性缺血发作以及血栓形成性中风和血栓栓塞性中风。
凝血系统的刺激可由各种原因或相关病症发生。尤其在外科手术、不能活动、卧床、感染、炎症或癌症或癌症治疗的背景中,可高度活化凝血系统,并可能存在血栓形成并发症,特别是静脉血栓形成。根据本发明的液体药物制剂因此适用于在患有癌症的患者中的外科手术的背景中预防血栓形成。根据本发明的液体药物制剂因此还适用于预防具有活化的凝血系统的患者中,例如在所述刺激情形中的血栓形成。
因此,根据本发明的液体药物制剂也适用于预防和治疗具有急性、间歇性或持续性心律失常,例如心房纤颤的患者和经受心脏复律的患者,以及具有心瓣膜病症或具有人工心瓣膜的患者中的心源性血栓栓塞,例如脑缺血、中风和系统性血栓栓塞和缺血。
此外,根据本发明的液体药物制剂适用于治疗和预防弥漫性血管内凝血(DIC),其尤其与败血症关联发生,但也由于外科手术、肿瘤病症、烧伤或其他损伤发生并可通过微血栓形成导致严重器官损伤。
此外,在微血管病性溶血性贫血中发生血栓栓塞并发症,和在体外循环的背景中,例如血液透析、ECMO(“体外膜氧合”)、LVAD(“左心室辅助装置”)和类似方法、AV瘘管、人造血管和人工心脏瓣膜中,通过血液与外来表面的接触发生血栓栓塞并发症。
此外,根据本发明的液体药物制剂适用于治疗和/或预防疾病,该疾病涉及微凝块形成或脑血管中的纤维蛋白沉积物,这可能导致痴呆病症,诸如血管性痴呆或阿尔茨海默症。在此,凝块可经由闭塞和通过结合其他疾病相关因子来造成该病症。
此外,根据本发明的液体药物制剂可用于抑制肿瘤生长和转移形成,以及用于预防和/或治疗肿瘤患者,特别是经历大型外科手术或化疗或放疗的患者的血栓栓塞并发症,例如静脉血栓栓塞。
此外,根据本发明的液体药物制剂也适用于预防和/或治疗肺高压。
在本发明的上下文中,术语“肺高压”包括肺动脉高压、与左心病症相关的肺高压、与肺部病症和/或缺氧相关的肺高压和由于慢性血栓栓塞的肺高压(CTEPH)。
“肺动脉高压”包括特发性肺动脉高压(IPAH,以前也称作原发性肺高压)、家族性肺动脉高压(FPAH)和相关性肺动脉高压(APAH),其与胶原病、先天系统性肺分流缺陷、门脉高压、HIV感染、特定药物和药剂的摄入、与其他病症(甲状腺病症、糖原贮积病症、高雪氏病、遗传性毛细管扩张、血红蛋白病、骨髓增生病症、脾切除)、与具有显著静脉/毛细管影响的病症,诸如肺静脉闭塞病症和肺毛细血管瘤以及新生儿的持续性肺高压相关。
与左心病症相关的肺高压包括患病的左心房或心室和二尖瓣或主动脉瓣缺陷。
与肺部病症和/或缺氧相关的肺高压包括慢性阻塞性肺病、间质性肺病、睡眠呼吸暂停综合征、肺泡通气不足、慢性高空病和先天畸形。
由于慢性血栓栓塞的肺高压(CTEPH)包括近端肺动脉的血栓栓塞性闭塞、远端肺动脉的血栓栓塞性闭塞和非血栓形成性肺栓塞(肿瘤、寄生虫、异物)。
本发明进一步提供了根据本发明的液体药物制剂用于生产用于治疗和/或预防与类肉瘤病、组织细胞增生症X和淋巴管瘤病相关的肺高压的药物的用途。
此外,根据本发明的液体药物制剂也适用于治疗和/或预防在传染病和/或全身炎性综合征(SIRS)、败血性器官功能障碍、败血性器官衰竭和多器官衰竭、急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、败血性休克和/或败血性器官衰竭背景中的弥漫性血管内凝血。
在感染过程中,可能存在凝血系统的泛发性活化(弥漫性血管内凝血或消耗性凝血病,下文称作“DIC”),伴随着各种器官中的微血栓形成和继发性出血并发症。此外,可能存在内皮损伤,伴有增加的血管通透性,并且体液和蛋白扩散到血管外空间中。随着感染的进展,可能存在器官衰竭(例如肾衰竭、肝衰竭、呼吸衰竭、中枢神经缺陷和心血管衰竭)或多器官衰竭。
在DIC的情况中,在受损内皮细胞的表面、异物表面或交联血管外组织的表面存在凝血系统的大规模活化。因此,凝血存在于各种器官的小血管中,伴随着缺氧和后续器官功能障碍。继发效应是凝血因子(例如因子X、凝血酶原和纤维蛋白原)和血小板的消耗,这降低血液的凝血能力并可能导致大出血。
根据本发明的液体药物制剂也适用于在基因突变导致提高的酶活性或提高的酶原水平并通过酶活性或酶原浓度的相关测试/测量确定这些的患者中初始预防血栓形成或血栓栓塞性病症和/或炎性病症和/或具有提高的血管通透性的病症。
本发明进一步提供了根据本发明的液体药物制剂用于治疗和/或预防病症、特别是上述病症的用途。
本发明进一步提供了根据本发明的液体药物制剂用于生产治疗和/或预防病症、特别是上述病症的药物的用途。
本发明进一步提供了使用治疗有效量的本发明的化合物治疗和/或预防病症、特别是上述病症的方法。
本发明进一步提供了根据本发明的液体药物制剂,其用于使用治疗有效量的根据本发明的化合物治疗和/或预防病症、特别是上述病症的方法。
这些在人中充分描述的疾病在其他哺乳动物中也可出现相当的病因学且可使用本发明的液体药物制剂治疗。
在本发明的背景下,术语“治疗(treatment)”或“治疗(treat)”在常规意义上使用并意指目的在于对抗、降低、减弱或减轻疾病或健康异常,和改善由该疾病损害的生活条件来照料、照顾和护理患者。
因此,本发明进一步提供了根据本发明的液体药物制剂用于治疗和/或预防病症、特别是上述病症的用途。
本发明进一步提供了根据本发明的液体药物制剂用于生产用于治疗和/或预防病症、特别是上述病症的药物的用途。
本发明进一步提供了根据本发明的液体药物制剂在用于治疗和/或预防病症、特别是前述病症的方法中的用途。
本发明进一步提供用于使用有效量的根据本发明的液体药物制剂之一治疗和/或预防疾病、更具体地前述疾病的方法。
在一个优选的实施方案中,治疗和/或预防是肠胃外施用根据本发明的液体药物制剂。特别优选静脉内或皮下施用。
根据本发明的药物制剂可单独使用,或者如果需要,与一种或多种其他药理活性物质组合使用,条件是该组合不导致不期望和不可接受的副作用。因此,本发明进一步提供了包含根据本发明的组合物中的至少一种和一种或多种另外的活性成分的药物,其特别用于治疗和/或预防前述疾病。
根据本发明的液体可以作为单一治疗施用,但也可以依次重复施用,或者可以在诊断后长期施用。
实施例
分析方法的描述
蛋白浓度(UV/VIS光谱学):
蛋白浓度通过280nm处的吸光度来测定。对于可能的光散射,还在320nm处校正测试。
缓冲液筛选:
制剂缓冲液测试遵循以下原则:
通过DSC方法(DSC:差示扫描量热法)通过温度曲线(T:15至105℃)的方式测定抗体的热稳定性(解折叠)。所谓的热解折叠(TM1)是用于比较各种缓冲系统的量度:随着TM1值增加,所述蛋白的热稳定性增加。因此,“更高”的TM1表明抗体在相关缓冲系统中的良好稳定性。
视觉图像:
受保护人员目视评价样品的可见颗粒的存在及其外观(薄片/纤维)(目视检查)。溶液应当尽可能不含可见颗粒。
蛋白回收率(C280):
pH测量:
测量总是在相同温度(20-25℃)下进行。每天用2种标准溶液校准仪器,其后测量对照,其偏差必须不超过0.05个pH单位。
SEC(HMW,单体,LMW)与UV检测器(280nm)的组合:
SEC(大小排阻色谱法)将单体与片段(低分子量LMW)和寡聚物(高分子量HMW)基于其空间大小分离。在这里,单体级分应当尽可能高。
DLS(中值):
药物抗体溶液的另外的质量标准可以通过动态光散射(DLS)确定。在这里,分子的光散射用于测定它们的流体动力学半径。抗体的流体动力学半径尤其取决于其构象。在应激测试期间,所述抗体的构象可以由于解折叠或自我缔合而改变-所述改变可通过DLS检测:
1)随着溶液中抗体浓度增加,分子间相互作用增加。如果力在这里具有吸引效应,则所述抗体倾向于所谓的寡聚体形成,即先前存在的单个单体现在形成几个抗体的实体。由于抗体实体看起来“更大”,所以测量的流体动力学半径增加。
2)周围培养基可能具有对所述抗体有利/不利的电荷;在这种情况下,其可以导致单个单体变性(解折叠);因此,测量的流体动力学半径同样看起来“放大”。
当考虑DLS结果时,应当考虑到在开发期间,两种不同的仪器用于DLS测量。在柏林,使用来自HORIBA Instruments的LB-550。在伍珀塔尔,使用来自Malvern的ZetasizerNano-ZS。组成和样品测量的差异可以导致略微不同的值。由于该原因,不应当比较结果!然而,可以再现用两种仪器的值的趋势。下面每个表描述用何种仪器测量获得的值。
A2值:
在第二维里系数(A2值)的测量中,通过静态光散射记录分子量的发展。在这种情况下,可以监测分子间相互作用,类似于动态光散射的测量。如果分子量随着浓度增加而超成比例地(super-proportionately)增加,则所述抗体倾向于聚集——制剂中的主要条件被称为“有吸引力的”。相反,如果分子量低于成比例地(sub-proportionately)发展,则“排斥”条件在系统中占优势。聚集的趋势受限。
CGE:
毛细管电泳是用于在电场中由于其电荷而分离分子的分析方法。分子的形状和大小也在通过凝胶样介质的分离中起作用,所得在这里也-类似于大小排阻色谱法,分离抗体及其片段或聚集体。
浑浊度:
借助于浊度测量实施溶液的浑浊度。在这种情况下,定义光度的光通过溶液,且然后可以在溶液的相对侧上检测和记录多少能量被并入。如果浑浊度增加,则浊度同样增加-更多的光被溶液“扣留”。
生物测定:
BAY 1213790(抗hFXIa单克隆抗体)的生物化学测试测定所述抗体对活化的人凝血因子XI(hFXIa)的抑制活性。在这种情况下,使用荧光酶活性测定法测定BAY1213790对人FXIa的功能中和作用。将测试样品的EC50值与BAY 1213790参考标准品进行比较。该标准品已通过相当的生产方法生产,并在<-60℃下储存在pH 6的10mM组氨酸/130mM甘氨酸缓冲液中。
Biacore:
通过表面等离子体共振光谱法(SPR,Biacore)测定BAY 1213790测试样品和BAY1213790参考标准品与人因子XIa(FXIa)抗原的结合。将测试样品的结合亲和力与BAY1213790参考标准品进行比较。该标准品已通过相当的生产方法生产,并在<-60℃下储存在pH 6的10mM组氨酸/130mM甘氨酸缓冲液中。
结果:
对于缓冲液筛选,在5.0至7.5的pH范围内选择适合于肠胃外剂型的缓冲系统的pH范围。在第一次测试(热稳定性测定)中制备的制剂的抗体浓度为约1mg/ml。没有添加另外的助剂。
表1:各种缓冲系统中BAY1213790(1mg/ml)的TM1(DSC方法)
TM1值(解折叠温度)在65.4℃和78.7℃之间。选择具有高于72.0℃的TM1的制剂用于进一步测试,因为具有高TM1值的蛋白制剂是稳定制剂的指标。
含有Na2HPO4(pH 6.0至7.5)、L-甘氨酸(pH 6.0至7.5)、L-组氨酸(pH 7.0至7.5)和10mM组氨酸和130mM甘氨酸的组合(pH 6.0至7.5)的抗因子XIa Ab BAY1213790制剂显示最高的热稳定性。
由于制剂的目标浓度被确立为25mg/mL,所以使用制备型SEC系统将蛋白再缓冲至下一步骤中的选择的缓冲系统中,并使用Vivapore 10/20浓缩(从约6至40mg/ml)。
表2:BAY1213790的再缓冲/浓缩
1由于不同的缓冲液组成和与之相关的作用,再缓冲后的样品具有不同的浓度。
组氨酸和组氨酸/甘氨酸制剂表现出pH依赖性的蛋白回收率,其中随着pH增加,回收率降低。在pH 6.0下发现良好的回收率(≥95%)。磷酸盐缓冲液没有显示该趋势。对于具有高回收率的样品,另外确定SEC。没有显示单体含量或视觉图像的差异。
通常,蛋白对搅拌应激敏感,剧烈振荡可能潜在地导致蛋白的聚集并且可能形成寡聚物(HMW)直至可见颗粒。已知添加表面活性剂诸如聚山梨醇酯80和聚山梨醇酯20对蛋白具有针对表面应激的保护作用。将聚山梨醇酯80添加至选择的制剂中,使得所述制剂含有总共0.01%聚山梨醇酯80。
用搅拌应激测试(在300rpm和室温下24小时)测试抗因子XIa Ab制剂的稳定性。随后,通过以下方法的方式研究制剂的变化:
1)视觉图像
2)蛋白回收率(C280):
3)SEC(HMW,单体,LMW)
4)DLS(中值)。
在搅拌应激之后,所有Na2HPO4制剂在SEC中显示增加的寡聚物(HMW>2%)。一些样品另外具有可见颗粒。
在搅拌期间,pH 6.5至7.5的组氨酸制剂絮凝。pH 6.0的溶液在开始时看起来良好,但寡聚物已增加(2.9%)并且回收率为仅91%。
这显示样品之间的严重差异,这取决于选择的缓冲系统。
pH 6.0的组氨酸/甘氨酸制剂显示98.0%的良好单体含量,且回收率为95%。
磷酸氢钠系统的DLS值(流体动力学直径)在d(H):23至30nm之间,而优选制剂中的抗体的直径保持在19nm。构象的这种差异表明形成相对大的聚集体(由有吸引力的分子间相互作用引起),这在通过SEC(HMW的增加)和通过一些溶液中的可见颗粒的分析研究中得到证实。
这些观察显示pH 6.0的组氨酸/甘氨酸系统对BAY 1213790抗体具有比其他系统更好的稳定作用,尽管通过考虑未应激样品,这并不明显。
表3:在搅拌应激测试后含有0.01%(w/v)聚山梨醇酯80的制剂中的BAY 1213790
1由于不同的缓冲液组成和与之相关的作用,再缓冲后的样品具有不同的浓度。
为了能够展现各种助剂浓度对所述抗体的影响,在该领域中实施另外的测试。同时修改用于测定DLS数据的技术,并且还在另一浓度(25mg/mL)下实施测试,使得结果略微不同,但其趋势相似。
表4:T0:各种缓冲系统中BAY 1213790(25mg/mL)的未应激样品,所述缓冲系统全部包含:0.01%(w/v)聚山梨醇酯80,且pH为6.0(使用来自Malvern的Zetasizer Nano-ZS测量DLS值)
表5:T24(24h,300rpm):各种缓冲系统中的应激的BAY 1213790样品(25mg/mL),所述缓冲系统全部包含:0.01%(w/v)聚山梨醇酯80,且pH为6(使用来自Malvern的ZetasizerNano-ZS测量DLS值)
可以看到,与优选的制剂(样品2)相比,磷酸氢钠样品(样品5)的DLS数据已增加。该现象是由于分子间相互作用增加,这通过测定第二维里系数(A2值)得到证实。在该情况下,正A2值描述系统内的“排斥”相互作用。由于它们的表面电荷,所述抗体相互排斥。负值描述系统内的有吸引力的条件-这在这里意味着数值越远离“0”,效果越明显。在图1中,可以找到来自表4的五种未应激制剂的测量的第二维里系数。可以看到,样品1(pH 6.0的5mM组氨酸/200mM甘氨酸)是具有正A2值且因此具有排斥相互作用的唯一样品。然而,由于低组氨酸比例的缓冲能力低,选择制剂2(pH 6.0的10mM组氨酸/130mM甘氨酸),其在该系列中具有最低的负A2值,并且仍然能够在处理和储存期间在制剂中保持pH稳定。
在下文中,使用稳定剂海藻糖二水合物或蔗糖,使所述制剂为等张的。
使四种制剂(His/Gly 10/130mM或50mM Na2HPO4,各自含有蔗糖或海藻糖二水合物和0.05%(w/v)聚山梨醇酯80)经受三次应激测试:
1.搅拌应激测试(在300rpm和RT下24小时)
2.FTC-80℃(冷冻-解冻循环,在-80℃下):
3x冷冻和解冻(>2h),在室温下(>2h)
3.FTC-20℃(冷冻-解冻循环,在-20℃下):3x冷冻和解冻(>2h),在室温下(>2h)。
随后,已研究所述制剂的BAY 1213790的稳定性的变化,其包括视觉图像,蛋白回收率(C蛋白),SEC(HMW,单体,LMW),CGE,未还原的(1H1L、2H、2H1L和IgG)和DLS(中值)。
表6a:制备之后和搅拌应激之后的制剂
His/Gly:10mM组氨酸,130mM甘氨酸,0.05%(w/v)聚山梨醇酯80,pH 6和5%(w/v)海藻糖二水合物或5%(w/v)蔗糖
PO4:50mM Na2HPO4,0.05%(w/v)聚山梨醇酯80,pH 6和5%(w/v)海藻糖二水合物或5%(w/v)蔗糖
所有制剂都包含25mg/ml BAY1213790
为了简化,下表中使用以下赋形剂缩写:Tre=海藻糖二水合物;Suc=蔗糖;Mono=单体;Vis=视觉测试;CGE分析:2H=由两条重链构成的片段;2H1L=由两条重链和一条轻链构成的片段。(使用来自Horiba的LB-550测量DLS值)
表6b.FTC之后的制剂
His/Gly:10mM组氨酸,130mM甘氨酸,0.05%(w/v)聚山梨醇酯80,pH 6和5%(w/v)海藻糖二水合物或5%(w/v)蔗糖
PO4:50mM Na2HPO4,0.05%(w/v)聚山梨醇酯80,pH 6和5%(w/v)海藻糖二水合物或5%(w/v)蔗糖
所有制剂都包含25mg/ml BAY1213790
为了简化,下表中使用以下赋形剂缩写:Tre=海藻糖二水合物;Suc=蔗糖;Mono=单体;Vis=视觉测试;CGE分析:2H=由两条重链构成的片段;2H1L=由两条重链和一条轻链构成的片段。(使用来自Horiba的LB-550测量DLS值)
下面用各种稳定剂(海藻糖二水合物和蔗糖)研究遇到的效果(DLS大小变化)。
为此目的,实施与上述类似的测试:然而,应当注意,由于时间的差异,存在起始材料的一些差异或已使用其他/新的分析设备。
表7:起始材料,FTC(-20℃),以蔗糖作为稳定剂(使用来自Malvern的ZetasizerNano-ZS测量DLS值)
所有样品都包含:25mg/mL BAY 1213790,0.05%(w/v)聚山梨醇酯80,5%(w/v)蔗糖,且pH为6
表8:起始材料,FTC(-20℃),以海藻糖二水合物作为稳定剂(使用来自Malvern的Zetasizer Nano-ZS测量DLS值)。所有样品都包含:25mg/mL BAY 1213790,0.05%(w/v)聚山梨醇酯80,5%(w/v)海藻糖二水合物,且pH为6
粘度
制剂的粘度是浓度依赖性的,并且取决于蛋白浓度,在1.14mPa*s(10mg/mL BAY1213790)和2.25mPa*s(40mg/mL BAY 1213790)之间。对于测试,仅改变蛋白浓度,而制剂的其他成分未被改变(pH 6的10/130mM组氨酸/甘氨酸,5%(w/v)海藻糖二水合物和0.05%(w/v)聚山梨醇酯80)。
冷冻-干燥
将25mg/mL BAY 1213790配制于含有5%(w/v)海藻糖二水合物和0.05%(w/v)聚山梨醇酯80的pH 6的10mM组氨酸/130mM甘氨酸缓冲液(10/130His/Gly)中。随后用表9中所述的冷冻-干燥循环冻干制剂。
表9:制剂(10/130His/Gly、5%(w/v)海藻糖二水合物、0.05%(w/v)聚山梨醇酯80(pH6)中的25mg/mL BAY 1213790)的冷冻-干燥循环
在冷冻-干燥之后,将小瓶储存在2-8℃。表10显示在储存36个月之前和之后冻干制剂的稳定性数据。
还测量0和36个月之间的另外的时间点,并且所有数据在这里也都在规格内。来自表10的以下数据证实,选择的制剂可以冻干,并且随后甚至稳定3年的时段。
表10:冻干的制剂(10/130His/Gly、5%(w/v)海藻糖二水合物、0.05%(w/v)聚山梨醇酯80(pH 6)中的25mg/mL BAY 1213790)的稳定性数据
结论:
由于目前的结果,选择pH 6.0的10mM组氨酸/130mM甘氨酸缓冲系统,其具有足够的缓冲能力,在应激测试期间已显示最佳的稳定效果。
尽管未应激样品在不同制剂中具有相似的稳定性特征,但在应激样品中展示关于以下在组氨酸-甘氨酸系统和其他制剂之间的明显差异:
-蛋白构象(DLS)
-分子间相互作用(A2值)
-单体级分(SEC)
-可见颗粒(视觉图像)。
这显示pH 6的组氨酸/甘氨酸系统对BAY1213790抗体具有比其他系统更好的稳定作用。通过分析未应激样品无法预测这一点。
序列表
<110> Bayer Pharma AG
<120> 用于FXIa抗体的新型稳定制剂
<130> BHC161051
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗FXIa抗体BAY1213790的重链
<400> 1
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gln Tyr
20 25 30
Gly Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Gly Pro Ser Gly Gly Ser Thr Val Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Gly Pro Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 2
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗FXIa抗体BAY1213790的轻链
<400> 2
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Ala Asp Ser Phe Pro Val
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
Claims (16)
1.液体药物制剂,其包含浓度为10-40mg/ml的抗FXIa抗体BAY1213790、10mM组氨酸和130mM甘氨酸,其中所述制剂具有6.0的pH,其中所述的抗FXIa抗体BAY1213790包含根据SEQID NO:1的重链和根据SEQ ID NO:2的轻链的序列。
2.根据权利要求1所述的液体药物制剂,其包含选自防腐剂、载体、润湿剂和稳定剂的另外的成分。
3.根据前述权利要求中任一项所述的液体药物制剂,其包含1-10%(w/v)的稳定剂。
4.根据权利要求1或2所述的液体药物制剂,其包含3-7%(w/v)海藻糖二水合物。
5.根据权利要求1或2所述的液体药物制剂,其包含浓度为0.001%至0.5%(w/v)的润湿剂。
6.根据权利要求5所述的液体药物制剂,其中所述润湿剂是聚山梨醇酯80。
7.根据权利要求1的液体药物制剂,其包含浓度为25mg/ml的抗FXIa抗体BAY1213790、5%(w/v)海藻糖二水合物和0.05%(w/v)聚山梨醇酯80。
8.通过冷冻-干燥根据前述权利要求中任一项所述的液体药物制剂可获得的冻干物。
9.根据权利要求8所述的冻干物,其包含至多2%残余水。
10.一种产品,其包含根据权利要求1至7中任一项所述的液体药物制剂或根据权利要求8或9所述的冻干物,以及使用说明。
11.根据权利要求10所述的产品,包括容器,所述容器包含根据权利要求1至7中任一项所述的液体药物制剂或根据权利要求8或9所述的冻干物。
12.根据权利要求11所述的产品,其中所述容器是瓶子、小瓶、管或注射器。
13.根据权利要求12所述的产品,其中所述注射器包括注射针头。
14.根据权利要求12所述的产品,其中所述注射器包含在注射装置中。
15.根据权利要求10或11所述的产品,其特征在于,所述产品为试剂盒。
16.根据权利要求1-7中任一项所述的液体药物制剂或根据权利要求8或9所述的冻干物或根据权利要求10-15中任一项所述的产品,其用于治疗或预防血栓形成或血栓栓塞性病症。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17152108.1 | 2017-01-19 | ||
EP17152108 | 2017-01-19 | ||
PCT/EP2018/050951 WO2018134184A1 (en) | 2017-01-19 | 2018-01-16 | Novel stable formulation for fxia antibodies |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110234353A CN110234353A (zh) | 2019-09-13 |
CN110234353B true CN110234353B (zh) | 2023-07-04 |
Family
ID=57914707
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880007721.1A Active CN110234353B (zh) | 2017-01-19 | 2018-01-16 | 用于FXIa抗体的新型稳定制剂 |
Country Status (25)
Country | Link |
---|---|
US (1) | US20190367636A1 (zh) |
EP (1) | EP3570882B1 (zh) |
JP (1) | JP7072577B2 (zh) |
KR (1) | KR20190105588A (zh) |
CN (1) | CN110234353B (zh) |
AR (1) | AR110762A1 (zh) |
AU (1) | AU2018209118A1 (zh) |
BR (1) | BR112019014785A2 (zh) |
CA (1) | CA3050172A1 (zh) |
CY (1) | CY1124922T1 (zh) |
DK (1) | DK3570882T3 (zh) |
ES (1) | ES2904474T3 (zh) |
HR (1) | HRP20220011T1 (zh) |
HU (1) | HUE056858T2 (zh) |
IL (1) | IL267917B2 (zh) |
LT (1) | LT3570882T (zh) |
MX (1) | MX2019008544A (zh) |
PE (1) | PE20191476A1 (zh) |
PL (1) | PL3570882T3 (zh) |
PT (1) | PT3570882T (zh) |
RS (1) | RS62780B1 (zh) |
SG (1) | SG11201906557UA (zh) |
SI (1) | SI3570882T1 (zh) |
TW (1) | TWI753087B (zh) |
WO (1) | WO2018134184A1 (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JOP20200312A1 (ar) | 2015-06-26 | 2017-06-16 | Novartis Ag | الأجسام المضادة للعامل xi وطرق الاستخدام |
TW201802121A (zh) | 2016-05-25 | 2018-01-16 | 諾華公司 | 抗因子XI/XIa抗體之逆轉結合劑及其用途 |
IL308980A (en) | 2016-12-23 | 2024-01-01 | Novartis Ag | Antibodies against factor XI and methods of their use |
AU2020225202B2 (en) | 2019-02-18 | 2023-10-26 | Eli Lilly And Company | Therapeutic antibody formulation |
WO2021127525A1 (en) * | 2019-12-20 | 2021-06-24 | Anthos Therapeutics, Inc. | Pharmaceutical formulations and dosage regimens for factor xi/xia antibodies |
KR20230035079A (ko) | 2020-07-03 | 2023-03-10 | 수조우 알파맵 씨오., 엘티디. | 응고인자 xi(fxi) 결합 단백질 |
WO2022122993A1 (en) * | 2020-12-11 | 2022-06-16 | Boehringer Ingelheim International Gmbh | Formulation for multi-purpose application |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030190316A1 (en) * | 2000-08-11 | 2003-10-09 | Masaya Kakuta | Stabilized antibody-containing preparations |
US20110293605A1 (en) * | 2008-11-12 | 2011-12-01 | Hasige Sathish | Antibody formulation |
WO2013167669A1 (en) * | 2012-05-10 | 2013-11-14 | Bayer Pharma Aktiengesellschaft | Antibodies capable of binding to the coagulation factor xi and/or its activated form factor xia and uses thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040191243A1 (en) | 2002-12-13 | 2004-09-30 | Bei Chen | System and method for stabilizing antibodies with histidine |
ES2658596T3 (es) * | 2008-09-19 | 2018-03-12 | Pfizer Inc. | Formulación líquida estable de anticuerpos |
PL3060256T3 (pl) * | 2013-10-25 | 2019-10-31 | Bayer Pharma AG | Nowa stabilna formulacja |
-
2018
- 2018-01-16 RS RS20220004A patent/RS62780B1/sr unknown
- 2018-01-16 IL IL267917A patent/IL267917B2/en unknown
- 2018-01-16 PE PE2019001433A patent/PE20191476A1/es unknown
- 2018-01-16 AU AU2018209118A patent/AU2018209118A1/en active Pending
- 2018-01-16 EP EP18702623.2A patent/EP3570882B1/en active Active
- 2018-01-16 CA CA3050172A patent/CA3050172A1/en active Pending
- 2018-01-16 HR HRP20220011TT patent/HRP20220011T1/hr unknown
- 2018-01-16 BR BR112019014785-3A patent/BR112019014785A2/pt unknown
- 2018-01-16 US US16/478,029 patent/US20190367636A1/en not_active Abandoned
- 2018-01-16 LT LTEPPCT/EP2018/050951T patent/LT3570882T/lt unknown
- 2018-01-16 JP JP2019538638A patent/JP7072577B2/ja active Active
- 2018-01-16 PT PT187026232T patent/PT3570882T/pt unknown
- 2018-01-16 CN CN201880007721.1A patent/CN110234353B/zh active Active
- 2018-01-16 SI SI201830483T patent/SI3570882T1/sl unknown
- 2018-01-16 SG SG11201906557UA patent/SG11201906557UA/en unknown
- 2018-01-16 MX MX2019008544A patent/MX2019008544A/es unknown
- 2018-01-16 WO PCT/EP2018/050951 patent/WO2018134184A1/en unknown
- 2018-01-16 HU HUE18702623A patent/HUE056858T2/hu unknown
- 2018-01-16 ES ES18702623T patent/ES2904474T3/es active Active
- 2018-01-16 DK DK18702623.2T patent/DK3570882T3/da active
- 2018-01-16 KR KR1020197020744A patent/KR20190105588A/ko active IP Right Grant
- 2018-01-16 PL PL18702623T patent/PL3570882T3/pl unknown
- 2018-01-17 TW TW107101631A patent/TWI753087B/zh active
- 2018-01-19 AR ARP180100130A patent/AR110762A1/es unknown
-
2022
- 2022-01-05 CY CY20221100009T patent/CY1124922T1/el unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030190316A1 (en) * | 2000-08-11 | 2003-10-09 | Masaya Kakuta | Stabilized antibody-containing preparations |
US20110293605A1 (en) * | 2008-11-12 | 2011-12-01 | Hasige Sathish | Antibody formulation |
WO2013167669A1 (en) * | 2012-05-10 | 2013-11-14 | Bayer Pharma Aktiengesellschaft | Antibodies capable of binding to the coagulation factor xi and/or its activated form factor xia and uses thereof |
Non-Patent Citations (2)
Title |
---|
陈志南等.冷冻干燥的过程.《抗体分子与肿瘤》.北京:人民军医出版社,2002,第581页. * |
陈玉祥等.第一节 蛋白质及多肽药物的传统处方.《分子药剂学》.湖南师范大学出版社,2010,第109页. * |
Also Published As
Publication number | Publication date |
---|---|
PE20191476A1 (es) | 2019-10-16 |
IL267917B2 (en) | 2023-10-01 |
PL3570882T3 (pl) | 2022-02-07 |
JP7072577B2 (ja) | 2022-05-20 |
JP2020506175A (ja) | 2020-02-27 |
PT3570882T (pt) | 2022-01-11 |
IL267917A (en) | 2019-09-26 |
MX2019008544A (es) | 2019-10-07 |
BR112019014785A2 (pt) | 2020-05-12 |
US20190367636A1 (en) | 2019-12-05 |
IL267917B1 (en) | 2023-06-01 |
ES2904474T3 (es) | 2022-04-05 |
RU2019125947A (ru) | 2021-02-19 |
HUE056858T2 (hu) | 2022-03-28 |
TW201831170A (zh) | 2018-09-01 |
AU2018209118A1 (en) | 2019-07-11 |
DK3570882T3 (da) | 2022-01-10 |
SG11201906557UA (en) | 2019-08-27 |
CN110234353A (zh) | 2019-09-13 |
CY1124922T1 (el) | 2023-01-05 |
EP3570882B1 (en) | 2021-11-17 |
SI3570882T1 (sl) | 2022-01-31 |
AR110762A1 (es) | 2019-05-02 |
EP3570882A1 (en) | 2019-11-27 |
TWI753087B (zh) | 2022-01-21 |
LT3570882T (lt) | 2021-12-10 |
KR20190105588A (ko) | 2019-09-17 |
HRP20220011T1 (hr) | 2022-04-01 |
WO2018134184A1 (en) | 2018-07-26 |
CA3050172A1 (en) | 2018-07-26 |
RU2019125947A3 (zh) | 2021-05-25 |
RS62780B1 (sr) | 2022-01-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110234353B (zh) | 用于FXIa抗体的新型稳定制剂 | |
US20230047111A1 (en) | Pharmaceutical formulations of tnf-alpha antibodies | |
JP7003183B2 (ja) | 凍結乾燥した組換え型vwf製剤 | |
TWI242443B (en) | Activated protein C formulations | |
JP7150804B2 (ja) | プラミノーゲンを含む医薬組成物及びその使用 | |
TW400234B (en) | Pharmaceutical compositions for subcutaneous, intramuscular or intradermal administration containing coagulation factor VIII or factor IX and additive | |
KR20130028894A (ko) | 항체의 제제 | |
JP6516829B2 (ja) | 第viii因子製剤 | |
TW202310873A (zh) | 含有抗人類tslp受體抗體之醫藥組成物 | |
JP2010163457A (ja) | 脈管形成に有効な単位用量のfgf−2および使用方法 | |
CN116322764A (zh) | 因子xii抗原结合蛋白的高浓度制剂 | |
KR20210028673A (ko) | 항-FXIa 항체에 대한 신규한 안정한 고농도 제형물 | |
RU2775692C2 (ru) | Новые стабильные композиции для fxia антител | |
CN108883160A (zh) | 因子xa解毒剂的冻干制剂 | |
HUE035692T2 (en) | Use of C1 inhibitor to prevent ischemia-reperfusion injury | |
US20230119254A1 (en) | Synergistic and targeting compositions for treatment of arterial and venous thrombosis | |
WO1999045953A1 (fr) | Compositions contenant un cofacteur ii de l'heparine et techniques de stabilisation | |
CN117835965A (zh) | 派姆单抗的药物组合物及其用途 | |
FR3053592A1 (fr) | Fibrinogene liquide stable |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40014147 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |