WO2015194233A1 - 血液凝固第viii因子および/または活性化血液凝固第viiiの活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療に用いられる医薬組成物 - Google Patents
血液凝固第viii因子および/または活性化血液凝固第viiiの活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療に用いられる医薬組成物 Download PDFInfo
- Publication number
- WO2015194233A1 WO2015194233A1 PCT/JP2015/060171 JP2015060171W WO2015194233A1 WO 2015194233 A1 WO2015194233 A1 WO 2015194233A1 JP 2015060171 W JP2015060171 W JP 2015060171W WO 2015194233 A1 WO2015194233 A1 WO 2015194233A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dose
- coagulation factor
- blood coagulation
- polypeptide
- initial dose
- Prior art date
Links
- 108010054218 Factor VIII Proteins 0.000 title claims abstract description 49
- 102000001690 Factor VIII Human genes 0.000 title claims abstract description 49
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 46
- 230000000694 effects Effects 0.000 title claims abstract description 27
- 108010061932 Factor VIIIa Proteins 0.000 title claims abstract description 19
- 201000010099 disease Diseases 0.000 title claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 18
- 230000002265 prevention Effects 0.000 title claims description 20
- 239000000427 antigen Substances 0.000 claims abstract description 49
- 102000036639 antigens Human genes 0.000 claims abstract description 49
- 108091007433 antigens Proteins 0.000 claims abstract description 49
- 108010074860 Factor Xa Proteins 0.000 claims abstract description 25
- 108010076282 Factor IX Proteins 0.000 claims abstract description 22
- 108010048049 Factor IXa Proteins 0.000 claims abstract description 19
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 100
- 229920001184 polypeptide Polymers 0.000 claims description 98
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 98
- 239000003112 inhibitor Substances 0.000 claims description 27
- 208000009292 Hemophilia A Diseases 0.000 claims description 26
- 102100026735 Coagulation factor VIII Human genes 0.000 claims description 20
- 201000003542 Factor VIII deficiency Diseases 0.000 claims description 20
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims description 20
- 230000003247 decreasing effect Effects 0.000 claims description 13
- 230000002950 deficient Effects 0.000 claims description 11
- 108010014173 Factor X Proteins 0.000 claims description 9
- 208000015957 Acquired Von Willebrand disease Diseases 0.000 claims description 6
- 208000033316 Acquired hemophilia A Diseases 0.000 claims description 6
- 125000003275 alpha amino acid group Chemical group 0.000 claims 6
- 150000001413 amino acids Chemical group 0.000 description 72
- 208000032843 Hemorrhage Diseases 0.000 description 43
- 208000034158 bleeding Diseases 0.000 description 43
- 231100000319 bleeding Toxicity 0.000 description 43
- 230000000740 bleeding effect Effects 0.000 description 43
- 238000002360 preparation method Methods 0.000 description 27
- 229950006925 emicizumab Drugs 0.000 description 25
- 229960000301 factor viii Drugs 0.000 description 25
- 238000000034 method Methods 0.000 description 15
- 239000003814 drug Substances 0.000 description 14
- 102100022641 Coagulation factor IX Human genes 0.000 description 13
- 229940079593 drug Drugs 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- 229940105774 coagulation factor ix Drugs 0.000 description 8
- 239000003114 blood coagulation factor Substances 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 208000031220 Hemophilia Diseases 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 229960004222 factor ix Drugs 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 102100029117 Coagulation factor X Human genes 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229940105756 coagulation factor x Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000009256 replacement therapy Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 3
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 210000001015 abdomen Anatomy 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940105778 coagulation factor viii Drugs 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000006798 recombination Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 2
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 210000001766 X chromosome Anatomy 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229940019700 blood coagulation factors Drugs 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 208000009429 hemophilia B Diseases 0.000 description 2
- 230000023597 hemostasis Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 description 1
- 102000008102 Ankyrins Human genes 0.000 description 1
- 108010049777 Ankyrins Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000011091 antibody purification Methods 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- -1 for example Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000001155 isoelectric focusing Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 235000006109 methionine Nutrition 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 230000020971 positive regulation of blood coagulation Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 108010013773 recombinant FVIIa Proteins 0.000 description 1
- 229940068953 recombinant fviia Drugs 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940126622 therapeutic monoclonal antibody Drugs 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
Definitions
- the present invention relates to a pharmaceutical composition or administration regimen used for the prevention and / or treatment of a disease that develops and / or develops due to decreased or deficient activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII. More specifically, the present invention relates to bispecific antigen binding that recognizes blood coagulation factor IX and / or activated blood coagulation factor IX and blood coagulation factor X and / or activated blood coagulation factor X.
- a pharmaceutical composition or administration regimen comprising molecules, with the emergence of hemophilia A, acquired hemophilia A, von Willebrand disease, and inhibitors of blood coagulation factor VIII and / or activated blood coagulation factor VIII
- the present invention relates to a pharmaceutical composition or administration regimen used for the prevention and / or treatment of hemophilia A.
- the present invention relates to a product comprising a document relating to the administration of a pharmaceutical composition comprising said bispecific antigen binding molecule.
- Hemophilia is a bleeding disorder caused by a congenital deficiency or dysfunction of coagulation factor VIII (FVIII) or coagulation factor IX (FIX).
- the former is called hemophilia A and the latter is called hemophilia B.
- hemophilia A Since both genes are present on the X chromosome and genetic abnormalities take the X chromosome-linked recessive form, more than 99% of affected patients are male. It is known that the prevalence is approximately 1 per 10,000 male births, and the ratio of hemophilia A to hemophilia B is approximately 5: 1.
- the severity of hemophilia A is defined by FVIII activity in the blood. Patients with an activity of less than 1% are classified as severe, patients with an activity of 1% or more but less than 5% are moderate, and those with an activity of 5% or more but less than 40% are classified as mild. Severe patients, which account for about half of hemophilia A patients, present bleeding symptoms several times a month, which is significantly more frequent than moderate and mild patients.
- FVIII preparations are usually administered for bleeding in hemophilia A patients (on-demand therapy).
- FVIII preparations have been administered prophylactically to prevent bleeding events (periodic replacement therapy, Non-Patent Documents 1 and 2).
- the blood half-life of the FVIII preparation is about 8-12 hours. Therefore, for continuous prevention, FVIII preparations are administered to patients three times a week (Non-patent Documents 3 and 4).
- additional FVIII preparations are given at regular intervals as needed to prevent rebleeding.
- administration of FVIII preparations is mainly carried out at home, but since it is administered intravenously, difficulty in securing blood vessels is a problem. Therefore, there has been a strong demand for a drug that has a lower administration burden than the FVIII preparation.
- Patent Documents 1, 2, 3, and 4 Non-Patent Documents 5, 6, and 7.
- the present invention relates to a more effective pharmaceutical composition or administration for the prevention and / or treatment of a disease that develops and / or develops due to decreased or deficient activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII.
- the challenge is to provide a regimen.
- a pharmaceutical composition comprising an antigen-binding molecule is more effective for the prevention and / or treatment of diseases that develop and / or develop due to decreased or deficient activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII Succeeded in finding a suitable dosing regimen.
- the present invention relates to a pharmaceutical composition or administration regimen used for the prevention and / or treatment of diseases that develop and / or progress due to decreased or deficient activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII. More specifically, it relates to the following. [1] A pharmaceutical composition for use in the prevention and / or treatment of a disease that develops and / or develops due to a decrease or deficiency in the activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII.
- the pharmaceutical composition wherein the pharmaceutical composition is administered as an initial dose of ⁇ 100 mg / kg, and is continuously administered multiple times at a continuous dose approximately the same as or less than the initial dose, and the interval between each administration is at least one day or more .
- the continuation dose is the same as the initial dose, about a half of the initial dose, about a third dose, about 0.3 times the dose, about a quarter dose, about [1]
- the pharmaceutical composition according to [2], wherein the initial dose is 3 mg / kg and at least one continuous dose is 3 mg / kg.
- the disease is hemophilia A, acquired hemophilia A, von Willebrand disease, and hemophilia in which inhibitors for blood coagulation factor VIII and / or activated blood coagulation factor VIII have appeared.
- the antigen-binding molecule is a bispecific antibody as described below, wherein the first polypeptide and the third polypeptide are associated, and the second polypeptide and the fourth polypeptide are The pharmaceutical composition according to any one of [1] to [7], which is an associated bispecific antibody: A first polypeptide that is an H chain consisting of the amino acid sequence set forth in SEQ ID NO: 20; a second polypeptide that is an H chain consisting of the amino acid sequence set forth in SEQ ID NO: 25; and a sequence described in SEQ ID NO: 32 A bispecific antibody consisting of third and fourth polypeptides that are common L chains consisting of amino acid sequences.
- a pharmaceutical composition in the container comprising a binding molecule; and (iii) administering the antigen binding molecule as an initial dose of about 0.001 to 100 mg / kg, continuing multiple times with a continuous dose approximately equal to or less than the initial dose
- the pharmaceutical composition can be used for the prevention and / or treatment of diseases that develop and / or progress due to decreased or deficient activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII.
- the label is hemophilia A, acquired hemophilia A, von Willebrand disease, and hemophilia in which an inhibitor of blood coagulation factor VIII and / or activated blood coagulation factor VIII appears.
- the antigen-binding molecule is a bispecific antibody as described below, wherein the first polypeptide and the third polypeptide are associated, and the second polypeptide and the fourth polypeptide are The product according to any one of [10] to [14], which is an associated bispecific antibody: A first polypeptide that is an H chain consisting of the amino acid sequence set forth in SEQ ID NO: 20; a second polypeptide that is an H chain consisting of the amino acid sequence set forth in SEQ ID NO: 25; and a sequence described in SEQ ID NO: 32 A bispecific antibody consisting of third and fourth polypeptides that are common L chains consisting of amino acid sequences.
- a bispecific antigen-binding molecule that recognizes blood coagulation factor IX and / or activated blood coagulation factor IX and blood coagulation factor X and / or activated blood coagulation factor X is about 0.001 to 100 mg / administering as an initial dose of kg, and continuously administering the antigen-binding molecule a plurality of times at a continuous dose approximately the same as or less than the initial dose, wherein the administration interval is at least one day or more.
- a bispecific antigen-binding molecule that recognizes blood coagulation factor IX and / or activated blood coagulation factor IX and blood coagulation factor X and / or activated blood coagulation factor X is about 0.001 to 100 mg blood coagulation factor VIII and / or characterized in that it is administered as an initial dose of / kg, administered multiple times with a continuous dose approximately equal to or less than the initial dose, and the dosing interval is at least 1 day or more
- a bispecific antigen-binding molecule that recognizes blood coagulation factor IX and / or activated blood coagulation factor IX and blood coagulation factor X and / or activated blood coagulation factor X is about 0.001 to 100 mg.
- Use of the antigen-binding molecule for the manufacture of a pharmaceutical composition for use in the prevention and / or treatment of a disease that develops and / or develops due to decreased or deficient activity of activated blood coagulation factor VIII.
- the numbers on the horizontal axis indicate the numbers of patients who participated in the study. It is a graph which shows the change of the bleeding frequency of the patient with the inhibitor who administered ACE910 in the 12th week of the study 2, and the patient without the inhibitor.
- the numbers on the horizontal axis indicate the numbers of patients who participated in the study. It is a graph which shows the change of the bleeding frequency of the patient with an inhibitor who administered ACE910 in the 12th week of the trial 3, and a patient without an inhibitor.
- the numbers on the horizontal axis indicate the numbers of patients who participated in the study.
- Bispecific antigen-binding molecules that recognize blood coagulation factor IX and / or activated blood coagulation factor IX and blood coagulation factor X and / or activated blood coagulation factor X It is preferred to have an alternative activity.
- “substituting the function of coagulation factor VIII” means coagulation factor IX (FIX) or coagulation factor IXa (FIXa) and coagulation factor X (FX). It means to promote activation (to promote FXa production by FIXa).
- FXa production promoting activity can be evaluated by a measurement system comprising, for example, FIXa, FX, synthetic substrate S-2222 (FXa synthetic substrate), and phospholipid.
- a measurement system correlates with disease severity and clinical symptoms in hemophilia A cases (Rosen S, Andersson M, Blomba ⁇ ck M et al. Clinical applications of a chromogenic substrate method for determination of FVIII activity. Thromb Haemost 1985; 54: 811-23).
- Such an antigen-binding molecule can be obtained according to a method described in, for example, WO2005 / 035756, WO2006 / 109592, WO2012 / 067176, and the like. Specifically, based on the sequence of an antibody against coagulation factor IX and / or activated coagulation factor IX and an antibody against coagulation factor X, an antibody is produced using a gene recombination technique known to those skilled in the art. Is possible. A polynucleotide encoding an antibody is constructed based on the sequences of an antibody against coagulation factor IX and / or activated coagulation factor IX and an antibody against coagulation factor X, and this is introduced into an expression vector, and then an appropriate host cell.
- Such a bispecific antigen-binding molecule can be isolated from the inside of the host cell or outside the cell (such as a medium) and purified as a substantially pure and homogeneous antibody. Separation and purification of antibodies may be carried out using separation and purification methods used in normal antibody purification, and are not limited in any way. For example, chromatography column, filter, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, etc. are appropriately selected, When combined, antibodies can be separated and purified.
- the bispecific antigen-binding molecule in the present invention includes antibodies described in WO2005 / 035756, WO2006 / 109592, WO2012 / 067176, and the like.
- the bispecific antigen-binding molecule includes a first antigen-binding site and a second antigen-binding site that can specifically bind to at least two different antigens.
- the first antigen-binding site and the second antigen-binding site in the bispecific antigen-binding molecule of the present invention bind to coagulation factor IX and / or activated coagulation factor IX and coagulation factor X, respectively.
- bonding with antigens such as an antibody, Scaffold molecule
- a Scaffold molecule is a molecule that performs its function by binding to a target molecule. Any three-dimensionally stable polypeptide that can bind to at least one target antigen can be used. Examples of such polypeptides include, for example, antibody variable regions, fibronectin (WO2002 / 032925), Protein A domain (WO1995 / 001937), LDL receptor A domain (WO2004 / 044011, WO2005 / 040229), ankyrin (WO2002). Nygren et al. (Current Opinion in Structural Biology, 7: 463-469 (1997), Journal of Immunol Methods, 290: 3-28 (2004)), Binz et al.
- Bispecific antigen-binding molecules can be produced, for example, using genetic recombination techniques (see, for example, Borrebaeck® CAK and Larrick JW, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990).
- Recombinant antibodies are produced by cloning DNA encoding them from hybridomas or antibody-producing cells such as sensitized lymphocytes that produce antibodies, incorporating them into appropriate vectors, and introducing them into a host (host cell). Can be obtained.
- Bispecific antigen binding molecules may include whole antibodies as well as antibody fragments, low molecular weight antibodies, and antibody modifications.
- antibody fragments and low molecular weight antibodies include diabody (Db), linear antibodies, single chain antibody (hereinafter also referred to as scFv) molecules, and the like.
- Db diabody
- scFv single chain antibody
- the “Fv” fragment is the smallest antibody fragment and contains a complete antigen recognition site and a binding site.
- Bispecific antibodies include human antibodies, mouse antibodies, rat antibodies, etc., and their origin is not limited. Further, it may be a genetically modified antibody such as a chimeric antibody or a humanized antibody.
- a target human antibody can be obtained by immunizing a transgenic animal having all repertoires of human antibody genes with a target antigen (International Patent Application Publication) No. WO 93/12227, WO 92/03918, WO 94/02602, WO 94/25585, WO 96/34096, WO 96/33735).
- a chimeric antibody is an antibody comprising the H chain and L chain variable regions of an immunized animal antibody, and the H chain and L chain constant regions of a human antibody.
- a chimeric antibody can be obtained by ligating a DNA encoding the variable region of an antibody derived from an immunized animal with a DNA encoding the constant region of a human antibody, incorporating it into an expression vector, introducing it into a host, and producing it. .
- a humanized antibody is a modified antibody also referred to as a reshaped human antibody.
- Humanized antibodies are constructed by grafting the CDRs of antibodies from immunized animals to the complementarity determining regions of human antibodies. Its general genetic recombination techniques are also known (European Patent Application Publication Number EP 239400, International Patent Application Publication Number WO 96/02576, Sato K et al, Cancer Research 1993, 53: 851-856, International Patent Application Publication number WO 99/51743).
- the first polypeptide and the third polypeptide are associated, and the second polypeptide and the fourth polypeptide are associated.
- It is a bispecific antibody, preferably an antibody described in any of the following.
- a bispecific antibody (Q1-G4k / J268-G4h / L45-k) consisting of a third and a fourth polypeptide that is a common L chain consisting of the amino acid sequence described in (B) a first polypeptide that is an H chain consisting of the amino acid sequence set forth in SEQ ID NO: 1; a second polypeptide that is an H chain consisting of the amino acid sequence set forth in SEQ ID NO: 5; and SEQ ID NO: 9 A bispecific antibody (Q1-G4k / J321-G4h / L45-k) consisting of a third and a fourth polypeptide that is a common L chain consisting of the amino acid sequence described in (C) a first polypeptide that is
- the pharmaceutical composition of the present invention to be used for therapeutic or prophylactic purposes may be prepared by mixing with an appropriate pharmaceutically acceptable carrier, vehicle, etc., if necessary, to obtain a lyophilized preparation or a solution preparation.
- suitable pharmaceutically acceptable carriers and media include, for example, sterilized water, physiological saline, stabilizers, excipients, antioxidants (ascorbic acid, etc.), buffers (phosphoric acid, citric acid, histidine, Other organic acids), preservatives, surfactants (PEG, Tween, etc.), chelating agents (EDTA, etc.), binders and the like can be mentioned.
- polypeptides such as serum albumin, gelatin and immunoglobulin, glycine, glutamine, asparagine, glutamic acid, aspartic acid, methionine, arginine and lysine and other amino acids, polysaccharides and monosaccharides such as saccharides and carbohydrates
- sugar alcohols such as mannitol and sorbitol may be contained.
- aqueous solution for injection for example, isotonic solutions containing physiological saline, glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol, sodium chloride
- adjuvants such as alcohol (ethanol etc.), polyalcohol (propylene glycol, PEG, etc.), nonionic surfactants (polysorbate 80, polysorbate 20, poloxamer 188, HCO-50) etc.
- It is also possible to administer a larger liquid volume subcutaneously by mixing hyaluronidase in the preparation (Expert Opin Drug Deliv. 2007 Jul; 4 (4): 427-40.).
- the pharmaceutical composition of the present invention may be previously placed in a syringe.
- the solution preparation can be prepared according to the method described in WO2011 / 090088.
- the antigen-binding molecule of the present invention can be enclosed in microcapsules (microcapsules such as hydroxymethylcellulose, gelatin, poly [methylmethacrylic acid]) or colloid drug delivery systems (liposomes, albumin microspheres, microemulsions, Nanoparticles, nanocapsules, etc.) (see “Remington's Pharmaceuticals Science 16th edition”, “Oslo Ed.” (1980), etc.).
- microcapsules such as hydroxymethylcellulose, gelatin, poly [methylmethacrylic acid]
- colloid drug delivery systems liposomes, albumin microspheres, microemulsions, Nanoparticles, nanocapsules, etc.
- a method of making a drug a sustained-release drug is also known and can be applied to the antigen-binding molecule of the present invention (Langer et al., J. Biomed. Mater. Res. 15: 267-277 (1981); Langer, Chemtech.
- the administration of the pharmaceutical composition of the present invention can be administered to a patient via any appropriate route.
- any appropriate route for example, by intravenous, intramuscular, intraperitoneal, intracerebral spinal, transdermal, subcutaneous, intraarticular, sublingual, intrasynovial, oral, inhalation, topical or topical route as a bolus or by continuous infusion over a period of time To be administered.
- Intravenous or subcutaneous administration is preferred.
- the initial dose means, for example, a dose when the bispecific antigen-binding molecule of the present invention is first administered to a patient.
- the initial dose is in the range of about 0.001 mg / kg to about 100 mg / kg, for example about 0.001 mg / kg, about 0.002 mg / kg, about 0.0025 mg / kg, about 0.003 mg / kg, about 0.004 mg / kg.
- a continuous dose refers to a dose that is administered continuously, for example, after the initial dose has been administered.
- the continuation dose is approximately the same dose or less than the initial dose.
- the continuation dose is, for example, about the same dose as the initial dose, about one half of the initial dose, about one third, about one quarter, about one fifth, about six minutes 1 dose, approximately 1/7 dose, approximately 1/8 dose, approximately 1/9 dose, approximately 1/10 dose, approximately 1/20 dose, approximately 1/25 About 1 / 30th dose, about 1 / 40th dose, about 1 / 50th dose, about 1 / 60th dose, about 1 / 70th dose, about 1 / 80th dose About 90 times dose, about 100 times dose, about 0.01 times dose, about 0.02 times dose, about 0.03 times dose, about 0.04 times dose, about 0.05 times dose, about 0.06 times dose, about 0.07 times dose, about 0.08 times dose, about 0.09 times dose, about 0.1 times dose, about 0.0 times. 2 times dose, about 0.25 times dose, about 0.3 times dose,
- the continuation dose may vary within the range as long as it is approximately the same dose or less than the initial dose, and it is not necessary that all the multiple administrations are the same dose.
- the dose may be gradually decreased, and multiple types of doses may be administered repeatedly repeatedly.
- the initial dose is 10 mg / kg and at least one continuation dose is 10 mg / kg
- the initial dose is 10 mg / kg and at least one continuation dose is 3 mg / kg and the initial dose is 10 mg / kg and at least one Continuation dose is 1 mg / kg
- initial dose is 10 mg / kg
- at least one continuous dose is 0.3 mg / kg
- initial dose is 10 mg / kg
- at least one continuous dose is 0.1 mg / kg
- initial dose is 3 mg / kg kg and at least one continuous dose of 3 mg / kg
- the initial dose is 3 mg / kg and at least one continuous dose is 0.1 mg / kg
- the initial dose is 1 mg / kg
- at least one continuous dose is 1 mg / kg
- the initial dose is 1 mg / kg and at least one continuous dose Is 0.3 mg
- the initial dose is 10 mg / kg and the continuation dose is 10 mg / kg
- the initial dose is 10 mg / kg and the continuation dose is 3 mg / kg
- the initial dose is 10 mg / kg and the continuation dose is 1 mg / kg
- the initial dose Dose is 10 mg / kg
- continuation dose is 0.3 mg / kg
- initial dose is 10 mg / kg
- continuation dose is 0.1 mg / kg
- initial dose is 3 mg / kg
- continuation dose is 3 mg / kg
- initial dose is 3 mg / kg
- initial dose is 3 mg / kg
- initial dose is 3 mg / kg
- initial dose is 3 mg / kg
- continuous dose 0.1 mg / kg
- the continuous dose is 0.1 mg / kg.
- the dose can also be expressed as a fixed dose (mg / body) and / or body surface area equivalent dose (mg / m 2 ) corresponding to the aforementioned body weight equivalent dose.
- the continuous dose is administered, for example, once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, fifteen times 20 times, 25 times, 35 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 500 times, 1000 times, and 10,000 times.
- the administration interval is the interval between the administration of the first dose and the administration of the first continuation dose, the administration of the nth administration (n is an integer of 1 or more) and the n + 1 continuation administration dose. Refers to the interval between administrations.
- the administration interval may be one day or more, for example, 2, 3, 4, 5, 6, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 Week, 9 week, 10 week, 11 week, 12 week, 13 week, 14 week, 15 week, 16 week, 17 week, 18 week, 19 week, 20 week, 21 week, 22 week, 23 week, 24 week, 25 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year.
- the administration interval can be expressed in another expression, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, Once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, every nine weeks Once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 17 weeks Once, every 18 weeks, once every 19 weeks, once every 20 weeks, once every 21 weeks, once every 22 weeks, once every 23 weeks, once every 24 weeks, once every 25 weeks, Once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, every nine months Once every 10 months, once every 10 months, once every 11 months, or once a year.
- the interval between administrations can be expressed in different expressions: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 Every week, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, every 14 weeks, every 15 weeks, every 16 weeks, every 17 weeks Every 18 weeks, every 19 weeks, every 20 weeks, every 21 weeks, every 22 weeks, every 23 weeks, every 24 weeks, every 25 weeks, every 1 month, every 2 months, every 3 months, every 4 months, 5 Every month, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, and every year.
- the interval between the administration of the first dose and the administration of the first continuation dose, and the interval between the administration of the continuation dose of the nth (n is an integer of 1 or more) and administration of the n + 1 continuation dose are all It may be the same, but not all need to be the same.
- the interval between administration of the first dose and administration of the first continuation dose may be longer than the interval between administration of the nth continuation dose and administration of the n + 1 continuation dose,
- the interval between administration and administration of the first continuation dose may be shorter than the interval between administration of the nth continuation dose and administration of the (n + 1) continuation dose.
- the intervals may be the same or different. For example, as the number of administrations of the continuous dose increases, the administration interval may become longer or shorter.
- the initial dose is 10 mg / kg and at least one continuous dose is 10 mg / kg with a dosing interval of 1 week, the initial dose is 10 mg / kg and at least one continuous dose is 3 mg / kg
- the interval is 1 week, the initial dose is 10 mg / kg, at least one continuous dose is 1 mg / kg, the dosing interval is 1 week, the initial dose is 10 mg / kg, and at least one continuous dose is 0.3 mg / kg
- the administration interval is 1 week, the initial dose is 10 mg / kg, at least one continuous dose is 0.1 mg / kg, the administration interval is 1 week, the initial dose is 3 mg / kg, and at least one continuous dose is 3 mg 1 kg / kg with a dosing interval of 1 week, initial dose of 3 mg / kg and at least one continuous dose of 1 mg / kg with a dosing interval of 1 week, initial dose of 3 mg / kg and at least one continuous dose of 1 mg / kg with a dosing interval of 1 week, initial dose of
- 1 mg / kg with a dosing interval of 1 week initial dose of 1 mg / kg and at least one continuous dose of 1 mg / kg with a dosing interval of 1 week, initial dose of 1 mg / kg and at least one continuous
- the dose is 0.3 mg / kg and the dosing interval is 1 week, the initial dose is 1 mg / kg, at least one continuous dose is 0.1 mg / kg, the dosing interval is 1 week, the initial dose is 10 mg / kg At least one continuous dose of 10 mg / kg with a dosing interval of 2 weeks, initial dose of 10 mg / kg, at least one continuous dose of 3 mg / kg with a dosing interval of 2 weeks, initial dose of 10 mg / kg At least one continuous dose of 1 mg / kg with a dosing interval of 2 weeks, initial dose of 10 mg / kg and at least one continuous dose of 0.3 mg / kg with a dosing interval of 2 weeks, the initial dose of 10 mg / kg, at least one continuous dose is 0.1
- initial dose 3 mg / kg and at least one continuous dose of 0.3 mg / kg between doses 4 weeks, initial dose is 3 mg / kg, at least one continuous dose is 0.1 mg / kg, dosing interval is 4 weeks, initial dose is 1 mg / kg, and at least one continuous dose is 1 mg / kg.
- the administration interval is 4 weeks, the initial dose is 1 mg / kg and at least one continuous dose is 0.3 mg / kg, the administration interval is 4 weeks, the initial dose is 1 mg / kg, and at least one continuous dose is 0.1 mg / kg with dosing interval of 4 weeks, initial dose of 10 mg / kg and at least one continuous dose of 10 mg / kg with dosing interval of 1 month, initial dose of 10 mg / kg and at least one continuous dose Is 3 mg / kg with a dosing interval of 1 month, initial dose of 10 mg / kg and at least one continuous dose of 1 mg / kg with a dosing interval of 1 month, initial dose of 10 mg / kg and at least one Continuation dose is 0.3 mg / kg, dosing interval is 1 month, initial dose is 10 mg / kg and at least one continuation dose is 0.1 mg / kg kg with a dosing interval of 1 month, initial dose of 3 mg / kg and at least one continuous dose of 3 mg / kg, dosing interval of 1
- the initial dose is 10 mg / kg and the continuation dose is 10 mg / kg and the administration interval is 1 week, the initial dose is 10 mg / kg and the continuation dose is 3 mg / kg and the administration interval is 1 week, The initial dose is 10 mg / kg and the continuation dose is 1 mg / kg, the dosing interval is 1 week, the initial dose is 10 mg / kg, the continuation dose is 0.3 mg / kg, the dosing interval is 1 week, the initial dose is 10 mg / kg with a continuous dose of 0.1 mg / kg with a dosing interval of 1 week, initial dose of 3 mg / kg with a continuous dose of 3 mg / kg with a dosing interval of 1 week, initial dose of 3 mg / kg And the continuous dose is 1 mg / kg, the administration interval is 1 week, the initial dose is 3 mg / kg, the continuous dose is 0.3 mg / kg, the administration interval is 1 week, and the initial dose is 3 mg / kg The dose is 0.1 mg / kg with a
- the administration interval is 4 weeks, the initial dose is 3 mg / kg, the continuous dose is 1 mg / kg, the administration interval is 4 weeks, the initial dose is 3 mg / kg, and the continuous dose is 0.3 mg / kg.
- Interval is 4 weeks, initial dose is 3mg / kg
- the follow-up dose is 0.1 mg / kg and the dosing interval is 4 weeks, the initial dose is 1 mg / kg and the continue dose is 1 mg / kg and the dosing interval is 4 weeks, the initial dose is 1 mg / kg and the continue dose is 0.3 mg / kg with a dosing interval of 4 weeks, initial dose of 1 mg / kg and continuing dose of 0.1 mg / kg with a dosing interval of 4 weeks, initial dose of 10 mg / kg and continuing dose of 10 mg / kg kg with a dosing interval of 1 month, initial dose of 10 mg / kg and continuous dose of 3 mg / kg, dosing interval of 1 month, initial dose of 10 mg / kg and continuous dose of 1
- the administration interval is 1 month, the initial dose is 10 mg / kg, the continuous dose is 10 mg / kg, the administration interval is 2 months, the initial dose is 10 mg / kg, the continuous dose is 3 mg / kg, and the administration interval is 2 months, initial dose of 10 mg / kg and continuous dose of 1 mg / kg with dosing interval of 2 months, initial dose of 10 mg / kg with continuous dose of 0.3 mg / kg and dosing interval of 2 months, The initial dose is 10 mg / kg and the continuation dose is 0.1 mg / kg, the dosing interval is 2 months, the initial dose is 3 mg / kg, the continuation dose is 3 mg / kg, the dosing interval is 2 months, the initial dose is 3 mg / kg and the continuous dose was 1 mg / kg Dosing interval is 2 months, initial dose is 3 mg / kg, continuous dose is 0.3 mg / kg, dosing interval is 2 months, initial dose is 3 mg / kg, continuous dose is 0.1 mg / kg, dosing interval 2 months,
- the dosage regimen is determined taking into account, for example, effects and safety. Furthermore, the dosage regimen is determined in consideration of patient convenience within a range that does not impair the efficacy and safety. For example, the dosage regimen for hemophilia A patients can be determined in view of the bleeding prevention effect in the patient and clinically acceptable safety.
- substantially the same means that the difference is within about 20%, preferably within 10%, more preferably within 5%, within 4%, within 3%, Difference within 2%, difference within 1%.
- Blood coagulation factor VIII and / or activated blood coagulation factor VIII include, for example, the appearance of inhibitors against hemophilia A and FVIII / FVIIIa Hemophilia A, acquired hemophilia A, von Willebrand disease, and the like, which are not particularly limited.
- the present invention provides at least (i) a container; (ii) blood clotting factor IX and / or activated blood clotting factor IX and blood clotting factor X and / or activated blood clotting factor X
- a pharmaceutical composition in a container comprising the antigen-binding molecule; and (iii) administering said antigen-binding molecule as an initial dose of about 0.001 to 100 mg / kg and continuing multiple times at a continuous dose approximately equal to or less than the initial dose
- a product is provided that includes a dosing and instructions to administer the dosing interval to be at least one day or longer.
- a label, a syringe barrel, a syringe needle, a pharmaceutically acceptable medium, an alcohol cotton cloth, a bandage, and the like can be packaged in the product.
- the container is, for example, a bottle, a glass bottle, a syringe barrel, etc., and can be made of various materials such as glass or plastic.
- the container contains a pharmaceutical composition, and the entrance is sealed with, for example, a rubber stopper.
- the container is labeled, for example, indicating that the pharmaceutical composition is used for the prevention or treatment of the selected medical condition.
- the treatment of hemophilia is the administration of hemostasis to hemophilia patients who are presenting with bleeding symptoms (treatment of bleeding) and / or administration to patients who have had bleeding.
- treatment of bleeding refers to the prevention of the occurrence of bleeding and the reduction of bleeding frequency (prevention of bleeding), but is not limited thereto.
- the treatment and prevention of bleeding may be understood synonymously depending on the case.
- the bleeding to be investigated as the number of bleeding of a patient refers to bleeding that requires hemostasis treatment with a blood coagulation factor preparation, for example.
- the blood coagulation factor preparation refers to, for example, an FVIII preparation or a bypass preparation (an activated prothrombin complex preparation, a recombinant FVIIa preparation, etc.).
- ABR Annualized Bleeding Rate
- Example 1 Preparation of a bispecific antibody that recognizes blood coagulation factor IX and / or activated blood coagulation factor IX and blood coagulation factor X and / or activated blood coagulation factor X One. 2013; 8 (2): e57479) and ACE910 (Q499-z121 / J327-z119 / L404-k) (SEQ ID NO: 20) which is a bispecific antibody described in the patent literature (WO 2012/067176)
- the H chain consisting of the described amino acid sequence and the L chain described in SEQ ID NO: 32 are associated, and the H chain consisting of the amino acid sequence described in SEQ ID NO: 25 and the L chain described in SEQ ID NO: 32 are associated.
- Bispecific antibodies were prepared according to the description of the non-patent literature or patent literature.
- ACE910 has an activity to substitute for the function of coagulation factor VIII as described in the above-mentioned patent document.
- Example 2 Test by single subcutaneous administration in Japanese and Caucasian healthy adult males
- the dose volume ( ⁇ L) of ACE910 shown in Table 1 / kg) was administered subcutaneously once in the abdomen.
- diluted solution diluted auxiliary solution diluted about 100 times with physiological saline
- 0.3 mg / kg in physiological saline The dose volume ( ⁇ L / kg) prepared to the ACE910 administration solution concentration (mg / mL) was administered.
- Example 3 An open-label, interindividual dose escalation study by repeated subcutaneous administration in Japanese hemophilia A patients (Studies 1 and 2) Patients who met the following criteria were selected as subjects. (1) Severe congenital hemophilia A patient (2) Japanese (3) Weight over 40 kg (4) Bleeding episode (bleeding time, bleeding site) and blood for 6 months before enrollment (5) Those who satisfy any of the following conditions at the time of registration: (a) In the case of an inhibitor-bearing patient, he / she has 6 or more bleedings within 6 months before registration (B) In the case of patients who do not have inhibitors, those who have been administered FVIII preparations 150 times or more before registration and who have been undergoing regular replacement therapy for FVIII preparations for 6 months before registration
- the dose volume of ACE910 shown in Table 2 was repeatedly subcutaneously administered to the abdomen at a frequency of once a week for 12 weeks (12 times in total).
- the test drug is one vial filled with 1.0 mL of a solution containing 80 mg of ACE910.
- an 80 mg / mL ACE910-containing solution was prepared with physiological saline to the ACE910 administration solution concentration (mg / mL) shown in Table 2, and then the administration volume ( ⁇ L / mL) shown in Table 2 was used. kg).
- the maximum volume per administration site was 1.5 mL, and when it exceeded that, it was administered subcutaneously in two or more locations.
- periodic replacement therapy with FVIII preparations was discontinued.
- the number of bleedings in the 6 months before ACE910 administration and the number of bleedings during the ACE910 administration period (12 weeks) were investigated. Bleeding that required hemostatic treatment with FVIII or bypass was investigated. In addition, the number of bleeding before and after ACE910 administration was converted into the bleeding frequency per year. Specifically, the number of bleedings per year (ABR: Annualized Bleeding Rate) was calculated as (Bleeding frequency x 365.25) / number of observation days.
- ABR Annualized Bleeding Rate
- ACE910 is an excellent drug because it has a long half-life in blood, so it is less frequently administered, can be administered subcutaneously, is effective for inhibitor patients, and may not induce inhibitors. It is thought that.
- Example 4 Open-label, inter-individual dose escalation study with repeated subcutaneous administration in Japanese hemophilia A patients (Study 3) Patients were selected according to the same criteria as in Example 3, and the test 3 described in Table 3 was conducted to examine the number of bleedings per year. Based on the body weight measured most recently, the dose of ACE910 shown in Table 3 was repeatedly subcutaneously administered to the abdomen at a frequency of once a week for 12 weeks (12 times in total). The test drug is one vial filled with 1.0 mL of a solution containing 80 mg of ACE910.
- a pharmaceutical composition comprising a bispecific antigen binding molecule that recognizes blood coagulation factor IX and / or activated blood coagulation factor IX and blood coagulation factor X and / or activated blood coagulation factor X, or administration thereof A regimen was provided.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
〔1〕血液凝固第VIII因子および/または活性化血液凝固第VIII因子の活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療に用いられる医薬組成物であって、血液凝固第IX因子および/または活性化血液凝固第IX因子ならびに血液凝固第X因子および/または活性化血液凝固第X因子を認識する二重特異性抗原結合分子を含み、該抗原結合分子が、約0.001~100mg/kgの初回用量として投与され、初回用量とほぼ同じ又はそれ未満の継続用量で複数回継続投与され、各投与の間隔が少なくとも1日以上であることを特徴とする、前記医薬組成物。
〔2〕継続用量が、初回用量と同じ用量、初回用量の約2分の1の用量、約3分の1の用量、約0.3倍の用量、約約4分の1の用量、約5分の1の用量、約10分の1の用量からなる群より選択される用量である、〔1〕に記載の医薬組成物。
〔3〕初回用量が1mg/kgであり、少なくとも一つの継続用量が0.3mg/kgである、〔2〕に記載の医薬組成物。
〔4〕初回用量が3mg/kgであり、少なくとも一つの継続用量が1mg/kgである、〔2〕に記載の医薬組成物。
〔5〕初回用量が3mg/kgであり、少なくとも一つの継続用量が3mg/kgである、〔2〕に記載の医薬組成物。
〔6〕各投与の間隔のうち少なくとも一つが1週間である、〔1〕から〔5〕のいずれかに記載の医薬組成物。
〔7〕前記疾患が、血友病A、後天性血友病A、フォンビルブランド病、ならびに血液凝固第VIII因子および/または活性化血液凝固第VIII因子に対するインヒビターが出現している血友病Aからなる群より選択される、〔1〕から〔6〕のいずれかに記載の医薬組成物。
〔8〕前記抗原結合分子が、以下に記載の二重特異性抗体であって、第一のポリペプチドと第三のポリペプチドが会合し、かつ第二のポリペプチドと第四のポリペプチドが会合する二重特異性抗体である、〔1〕から〔7〕のいずれかに記載の医薬組成物:
配列番号:20に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:25に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:32に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体。
〔9〕前記抗原結合分子を皮下投与する、〔1〕から〔8〕のいずれかに記載の医薬組成物。
〔10〕(i)容器;(ii)血液凝固第IX因子および/または活性化血液凝固第IX因子ならびに血液凝固第X因子および/または活性化血液凝固第X因子を認識する二重特異性抗原結合分子を含む、前記容器内の医薬組成物;ならびに(iii)前記抗原結合分子を約0.001~100mg/kgの初回用量として投与し、初回用量とほぼ同じ又はそれ未満の継続用量で複数回継続投与し、各投与の間隔が少なくとも1日以上であるように投与することを指示する文書を含む製品。
〔11〕初回用量が1mg/kgであり、少なくとも一つの継続用量が0.3mg/kgである、〔10〕に記載の製品。
〔12〕各投与の間隔のうち少なくとも一つが1週間である、〔10〕又は〔11〕に記載の製品。
〔13〕前記医薬組成物を、血液凝固第VIII因子および/または活性化血液凝固第VIII因子の活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療に使用することができることを示す、容器に付されたラベルをさらに含む、〔10〕から〔12〕のいずれかに記載の製品。
〔14〕前記ラベルが、血友病A、後天性血友病A、フォンビルブランド病、ならびに血液凝固第VIII因子および/または活性化血液凝固第VIII因子に対するインヒビターが出現している血友病Aの治療に前記医薬組成物を使用できることを示す、〔13〕に記載の製品。
〔15〕前記抗原結合分子が、以下に記載の二重特異性抗体であって、第一のポリペプチドと第三のポリペプチドが会合し、かつ第二のポリペプチドと第四のポリペプチドが会合する二重特異性抗体である、〔10〕から〔14〕のいずれかに記載の製品:
配列番号:20に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:25に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:32に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体。
〔16〕血液凝固第IX因子および/または活性化血液凝固第IX因子ならびに血液凝固第X因子および/または活性化血液凝固第X因子を認識する二重特異性抗原結合分子を約0.001~100mg/kgの初回用量として投与する工程、ならびに、初回用量とほぼ同じ又はそれ未満の継続用量で前記抗原結合分子を複数回継続投与する工程を含み、投与間隔が少なくとも1日以上であることを特徴とする、血液凝固第VIII因子および/または活性化血液凝固第VIII因子の活性の低下ないし欠損によって発症および/または進展する疾患を予防および/または治療する方法。
〔17〕血液凝固第IX因子および/または活性化血液凝固第IX因子ならびに血液凝固第X因子および/または活性化血液凝固第X因子を認識する二重特異性抗原結合分子が、約0.001~100mg/kgの初回用量として投与され、初回用量とほぼ同じ又はそれ未満の継続用量で複数回継続投与され、投与間隔が少なくとも1日以上であることを特徴とする、血液凝固第VIII因子および/または活性化血液凝固第VIII因子の活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療において使用するための前記抗原結合分子。
〔18〕血液凝固第IX因子および/または活性化血液凝固第IX因子ならびに血液凝固第X因子および/または活性化血液凝固第X因子を認識する二重特異性抗原結合分子が、約0.001~100mg/kgの初回用量として投与され、初回用量とほぼ同じ又はそれ未満の継続用量で複数回継続投与され、投与間隔が少なくとも1日以上であることを特徴とする、血液凝固第VIII因子および/または活性化血液凝固第VIII因子の活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療に用いられる医薬組成物を製造するための、前記抗原結合分子の使用。
例えば抗体断片や低分子化抗体としては、ダイアボディ(diabody;Db)、線状抗体、一本鎖抗体(以下、scFvとも記載する)分子などが含まれる。ここで、「Fv」断片は最小の抗体断片であり、完全な抗原認識部位と結合部位を含む。
(a) 配列番号:1に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:4に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:9に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q1-G4k/J268-G4h/L45-k)、
(b) 配列番号:1に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:5に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:9に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q1-G4k/J321-G4h/L45-k)、
(c) 配列番号:2に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:6に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:8に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q31-z7/J326-z107/L2-k)、
(d) 配列番号:3に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:7に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:9に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q64-z55/J344-z107/L45-k)、
(e) 配列番号:10に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:6に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:30に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q64-z7/J326-z107/L334-k)、
(f) 配列番号:10に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:7に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:33に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q64-z7/J344-z107/L406-k)、
(g) 配列番号:11に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:4に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:33に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q85-G4k/J268-G4h/L406-k)、
(h) 配列番号:11に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:5に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:30に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q85-G4k/J321-G4h/L334-k)、
(i) 配列番号:12に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:21に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:33に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q153-G4k/J232-G4h/L406-k)、
(j) 配列番号:13に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:22に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:29に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q354-z106/J259-z107/L324-k)、
(k) 配列番号:14に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:21に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:33に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q360-G4k/J232-G4h/L406-k)、
(l) 配列番号:15に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:23に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:30に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q360-z118/J300-z107/L334-k)、
(m) 配列番号:16に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:21に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:28に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q405-G4k/J232-G4h/L248-k)、
(n) 配列番号:17に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:27に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:34に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q458-z106/J346-z107/L408-k)、
(o) 配列番号:18に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:25に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:30に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q460-z121/J327-z119/L334-k)、
(p) 配列番号:19に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:24に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:30に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q499-z118/J327-z107/L334-k)、
(q) 配列番号:19に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:24に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:31に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q499-z118/J327-z107/L377-k)、
(r) 配列番号:19に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:27に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:28に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q499-z118/J346-z107/L248-k)、
(s) 配列番号:20に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:25に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:32に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q499-z121/J327-z119/L404-k)、
(t) 配列番号:20に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:26に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:31に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q499-z121/J339-z119/L377-k)、
(u) 配列番号:12に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:35に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:36に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体(Q153-G4k/J142-G4h/L180-k)。
特に好ましくは、前記(s)の二重特異性抗体である。
継続用量は、例えば初回用量を投与された以降に継続して投与される用量を意味する。継続用量は初回用量とほぼ同じ用量又はそれ未満の用量である。継続用量は、例えば初回用量とほぼ同じ用量、初回用量の約2分の1の用量、約3分の1の用量、約4分の1の用量、約5分の1の用量、約6分の1の用量、約7分の1の用量、約8分の1の用量、約9分の1の用量、約10分の1の用量、約20分の1の用量、約25分の1の用量、約30分の1の用量、約40分の1の用量、約50分の1の用量、約60分の1の用量、約70分の1の用量、約80分の1の用量、約90分の1の用量、約100分の1の用量、約0.01倍の用量、約0.02倍の用量、約0.03倍の用量、約0.04倍の用量、約0.05倍の用量、約0.06倍の用量、約0.07倍の用量、約0.08倍の用量、約0.09倍の用量、約0.1倍の用量、約0.2倍の用量、約0.25倍の用量、約0.3倍の用量、約0.4倍の用量、約0.5倍の用量、約0.6倍の用量、約0.7倍の用量、約0.8倍の用量、約0.9倍の用量、約1倍の用量である。
非特許文献(PLoS One. 2013;8(2):e57479)及び特許文献(WO 2012/067176)に記載の二重特異性抗体であるACE910 (Q499-z121/J327-z119/L404-k)(配列番号:20に記載のアミノ酸配列からなるH鎖と配列番号:32に記載のL鎖が会合し、配列番号:25に記載のアミノ酸配列からなるH鎖と配列番号:32に記載のL鎖が会合している二重特異性抗体)を、前記非特許文献又は特許文献の記載に従って作製した。尚、ACE910は前記特許文献に記載されているように凝固第VIII因子の機能を代替する活性を有している。
Part A(日本人)及びPartB(白人)の被験薬群においては、表1に示すACE910の投与容量(μL/kg)を腹部に単回皮下投与した。なお、0.1 mg/kg以下の投与については希釈液(希釈補助液を生理食塩液で約100倍希釈したもの)にて、0.3 mg/kgの投与については生理食塩液にて、下表に示すACE910投与液濃度(mg/mL)に調製した投与容量(μL/kg)を投与した。
以下の基準を満たす患者を被験者として選択した。
(1)重症の先天性血友病A患者
(2)日本人である者
(3)体重が40 kg以上の者
(4)登録前6カ月間の出血エピソード(出血時期、出血部位)と血液凝固因子製剤による治療状況の記録が残されている者
(5)登録時に以下のいずれかの条件を満たす者
(ア)インヒビター保有患者の場合、登録前6カ月間に6回以上の出血を呈している者
(イ)インヒビター非保有患者の場合、登録前にFVIII製剤が150回以上投与され、登録前6カ月間はFVIII製剤の定期補充療法を施行している者
ACE910の投与量を変えて行った試験2については、出血に対する予防療法が施行されていないインヒビター保有患者及びFVIII製剤の定期補充療法が施行されているインヒビター非保有患者ともに、ACE910の投与により、年間あたりの出血頻度が劇的に減少した(図2)。
実施例3と同じ基準で患者を選択し、表3に記載された試験3を行い、年間出血回数を調べた。
表3に示すACE910の投与容量を直近に測定した体重に基づいて、週1回の頻度で12週間(計12回)、腹部に反復皮下投与した。尚、被験薬は1バイアル中に80 mgのACE910を含有する液1.0 mLを充てんしたものである。
Claims (15)
- 血液凝固第VIII因子および/または活性化血液凝固第VIII因子の活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療に用いられる医薬組成物であって、血液凝固第IX因子および/または活性化血液凝固第IX因子ならびに血液凝固第X因子および/または活性化血液凝固第X因子を認識する二重特異性抗原結合分子を含み、該抗原結合分子が、約0.001~100mg/kgの初回用量として投与され、初回用量とほぼ同じ又はそれ未満の継続用量で複数回継続投与され、各投与の間隔が少なくとも1日以上であることを特徴とする、前記医薬組成物。
- 継続用量が、初回用量と同じ用量、初回用量の約2分の1の用量、約3分の1の用量、約0.3倍の用量、約約4分の1の用量、約5分の1の用量、約10分の1の用量からなる群より選択される用量である、請求項1に記載の医薬組成物。
- 初回用量が1mg/kgであり、少なくとも一つの継続用量が0.3mg/kgである、請求項2に記載の医薬組成物。
- 初回用量が3mg/kgであり、少なくとも一つの継続用量が1mg/kgである、請求項2に記載の医薬組成物。
- 初回用量が3mg/kgであり、少なくとも一つの継続用量が3mg/kgである、請求項2に記載の医薬組成物。
- 各投与の間隔のうち少なくとも一つが1週間である、請求項1から5のいずれかに記載の医薬組成物。
- 前記疾患が、血友病A、後天性血友病A、フォンビルブランド病、ならびに血液凝固第VIII因子および/または活性化血液凝固第VIII因子に対するインヒビターが出現している血友病Aからなる群より選択される、請求項1から6のいずれかに記載の医薬組成物。
- 前記抗原結合分子が、以下に記載の二重特異性抗体であって、第一のポリペプチドと第三のポリペプチドが会合し、かつ第二のポリペプチドと第四のポリペプチドが会合する二重特異性抗体である、請求項1から7のいずれかに記載の医薬組成物:
配列番号:20に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:25に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:32に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体。 - 前記抗原結合分子を皮下投与する、請求項1から8のいずれかに記載の医薬組成物。
- (i)容器;(ii)血液凝固第IX因子および/または活性化血液凝固第IX因子ならびに血液凝固第X因子および/または活性化血液凝固第X因子を認識する二重特異性抗原結合分子を含む、前記容器内の医薬組成物;ならびに(iii)前記抗原結合分子を約0.001~100mg/kgの初回用量として投与し、初回用量とほぼ同じ又はそれ未満の継続用量で複数回継続投与し、各投与の間隔が少なくとも1日以上であるように投与することを指示する文書を含む、製品。
- 初回用量が1mg/kgであり、少なくとも一つの継続用量が0.3mg/kgである、請求項10に記載の製品。
- 各投与の間隔のうち少なくとも一つが1週間である、請求項10又は11に記載の製品。
- 前記医薬組成物を、血液凝固第VIII因子および/または活性化血液凝固第VIII因子の活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療に使用することができることを示す、容器に付されたラベルをさらに含む、請求項10から12のいずれかに記載の製品。
- 前記ラベルが、血友病A、後天性血友病A、フォンビルブランド病、ならびに血液凝固第VIII因子および/または活性化血液凝固第VIII因子に対するインヒビターが出現している血友病Aの治療に前記医薬組成物を使用できることを示す、請求項13に記載の製品。
- 前記抗原結合分子が、以下に記載の二重特異性抗体であって、第一のポリペプチドと第三のポリペプチドが会合し、かつ第二のポリペプチドと第四のポリペプチドが会合する二重特異性抗体である、請求項10から14のいずれかに記載の製品:
配列番号:20に記載のアミノ酸配列からなるH鎖である第一のポリペプチド;配列番号:25に記載のアミノ酸配列からなるH鎖である第二のポリペプチド;ならびに配列番号:32に記載のアミノ酸配列からなる共通L鎖である第三および第四のポリペプチドからなる二重特異性抗体。
Priority Applications (26)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MYPI2016704659A MY189333A (en) | 2014-06-20 | 2015-03-31 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US15/319,016 US20170253663A1 (en) | 2014-06-20 | 2015-03-31 | Methods for treating a disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
SG11201610581RA SG11201610581RA (en) | 2014-06-20 | 2015-03-31 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
MX2016016380A MX2016016380A (es) | 2014-06-20 | 2015-03-31 | Composicion farmaceutica para usarse en la prevencion y/o tratamiento de enfermedades que se desarrollan o progresan como resultado de una disminucion o perdida de actividad del factor viii de coagulacion sanguinea activado. |
KR1020177001413A KR20170015517A (ko) | 2014-06-20 | 2015-03-31 | 혈액 응고 제 viii 인자 및/또는 활성화 혈액 응고 제 viii 인자의 활성의 저하 내지 결손에 의해 발증 및/또는 진전되는 질환의 예방 및/또는 치료에 이용되는 의약 조성물 |
AU2015275440A AU2015275440B2 (en) | 2014-06-20 | 2015-03-31 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor Vlll and/or activated blood coagulation factor Vlll. |
EP15809216.3A EP3159006A4 (en) | 2014-06-20 | 2015-03-31 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
CN201580039806.4A CN106559987A (zh) | 2014-06-20 | 2015-03-31 | 预防和/或治疗由于凝血因子viii和/或活化的凝血因子viii活性下降或丧失而发生或进展的疾病的药物组合物 |
RU2017101705A RU2721910C2 (ru) | 2014-06-20 | 2015-03-31 | Фармацевтическая композиция, предназначенная для применения для предупреждения и/или лечения заболевания, которое развивается или прогрессирует вследствие снижения или утраты активности фактора свертывания крови viii и/или активированного фактора свертывания крови viii |
CA2951622A CA2951622C (en) | 2014-06-20 | 2015-03-31 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
BR112016029316-9A BR112016029316A2 (ja) | 2014-06-20 | 2015-03-31 | the [blood-coagulation-factor-XIII and/or activation blood coagulation] -- a medicine constituent used for prevention and/or medical treatment of a disease which develops [the symptoms of] and/or progresses by an active fall thru/or a deficit of VIII |
NZ727218A NZ727218B2 (en) | 2015-03-31 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii | |
JP2016529118A JP6663846B2 (ja) | 2014-06-20 | 2015-03-31 | 血液凝固第viii因子および/または活性化血液凝固第viiiの活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療に用いられる医薬組成物 |
EP23157462.5A EP4218816A3 (en) | 2014-06-20 | 2015-03-31 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
KR1020247013296A KR20240063162A (ko) | 2014-06-20 | 2015-03-31 | 혈액 응고 제 viii 인자 및/또는 활성화 혈액 응고 제 viii 인자의 활성의 저하 내지 결손에 의해 발증 및/또는 진전되는 질환의 예방 및/또는 치료에 이용되는 의약 조성물 |
IL249330A IL249330B (en) | 2014-06-20 | 2016-12-01 | Pharmaceutical preparations for use in the prevention and/or treatment of a disease that develops or progresses as a result of a decrease or loss of factor viii blood clotting activity and/or activated blood clotting factor viii |
ZA2017/00459A ZA201700459B (en) | 2014-06-20 | 2017-01-19 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US16/432,790 US20190309090A1 (en) | 2014-06-20 | 2019-06-05 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US16/780,977 US20200157243A1 (en) | 2014-06-20 | 2020-02-04 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US17/017,971 US20200407463A1 (en) | 2014-06-20 | 2020-09-11 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US17/235,445 US20210238307A1 (en) | 2014-06-20 | 2021-04-20 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US17/534,566 US20220073645A1 (en) | 2014-06-20 | 2021-11-24 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US17/849,879 US20220324999A1 (en) | 2014-06-20 | 2022-06-27 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US18/164,709 US20230174673A1 (en) | 2014-06-20 | 2023-02-06 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US18/479,149 US20240052060A1 (en) | 2014-06-20 | 2023-10-02 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US18/734,434 US20240317891A1 (en) | 2014-06-20 | 2024-06-05 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2014-127240 | 2014-06-20 | ||
JP2014127240 | 2014-06-20 | ||
JP2014226988 | 2014-11-07 | ||
JP2014-226988 | 2014-11-07 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/319,016 A-371-Of-International US20170253663A1 (en) | 2014-06-20 | 2015-03-31 | Methods for treating a disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
US16/432,790 Continuation US20190309090A1 (en) | 2014-06-20 | 2019-06-05 | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015194233A1 true WO2015194233A1 (ja) | 2015-12-23 |
Family
ID=54935230
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2015/060171 WO2015194233A1 (ja) | 2014-06-20 | 2015-03-31 | 血液凝固第viii因子および/または活性化血液凝固第viiiの活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療に用いられる医薬組成物 |
Country Status (16)
Country | Link |
---|---|
US (10) | US20170253663A1 (ja) |
EP (2) | EP3159006A4 (ja) |
JP (2) | JP6663846B2 (ja) |
KR (2) | KR20170015517A (ja) |
CN (1) | CN106559987A (ja) |
AU (1) | AU2015275440B2 (ja) |
BR (1) | BR112016029316A2 (ja) |
CA (1) | CA2951622C (ja) |
IL (1) | IL249330B (ja) |
MX (1) | MX2016016380A (ja) |
MY (1) | MY189333A (ja) |
RU (1) | RU2721910C2 (ja) |
SG (2) | SG10201811185YA (ja) |
TW (2) | TWI831106B (ja) |
WO (1) | WO2015194233A1 (ja) |
ZA (1) | ZA201700459B (ja) |
Cited By (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018021450A1 (ja) * | 2016-07-29 | 2018-02-01 | 中外製薬株式会社 | 増強されたfviii補因子機能代替活性を有する二重特異性抗体 |
WO2018047813A1 (en) * | 2016-09-06 | 2018-03-15 | Chugai Seiyaku Kabushiki Kaisha | Methods of using a bispecific antibody that recognizes coagulation factor ix and/or activated coagulation factor ix and coagulation factor x and/or activated coagulation factor x |
WO2018181870A1 (ja) * | 2017-03-31 | 2018-10-04 | 公立大学法人奈良県立医科大学 | 血液凝固第viii因子の機能を代替する多重特異性抗原結合分子を含有する、血液凝固第ix因子異常症の予防および/または治療に用いられる医薬組成物 |
KR20190003596A (ko) * | 2016-04-28 | 2019-01-09 | 추가이 세이야쿠 가부시키가이샤 | 항체 함유 제제 |
US10450381B2 (en) | 2010-11-17 | 2019-10-22 | Chugai Seiyaku Kabushiki Kaisha | Methods of treatment that include the administration of bispecific antibodies |
JP2019532057A (ja) * | 2016-09-23 | 2019-11-07 | シーエスエル、リミテッド | 凝固因子結合タンパク質及びその使用 |
US10759870B2 (en) | 2017-09-29 | 2020-09-01 | Chugai Seiyaku Kabushiki Kaisha | Multispecific antigen-binding molecules having blood coagulation factor VIII (FVIII) cofactor function-substituting activity and pharmaceutical formulations containing such a molecule as an active ingredient |
US10815308B2 (en) | 2018-12-21 | 2020-10-27 | Kymab Limited | FIXaxFX bispecific antibody with common light chain |
US10934344B2 (en) | 2006-03-31 | 2021-03-02 | Chugai Seiyaku Kabushiki Kaisha | Methods of modifying antibodies for purification of bispecific antibodies |
JP6836696B1 (ja) * | 2019-10-11 | 2021-03-03 | 中外製薬株式会社 | 後天性血友病aの予防および/または治療に用いられる医薬組成物、および当該医薬組成物を含む製品 |
WO2021070885A1 (ja) * | 2019-10-11 | 2021-04-15 | 中外製薬株式会社 | 後天性血友病aの予防および/または治療に用いられる医薬組成物、および当該医薬組成物を含む製品 |
US11046784B2 (en) | 2006-03-31 | 2021-06-29 | Chugai Seiyaku Kabushiki Kaisha | Methods for controlling blood pharmacokinetics of antibodies |
US11124576B2 (en) | 2013-09-27 | 2021-09-21 | Chungai Seiyaku Kabushiki Kaisha | Method for producing polypeptide heteromultimer |
US11142587B2 (en) | 2015-04-01 | 2021-10-12 | Chugai Seiyaku Kabushiki Kaisha | Method for producing polypeptide hetero-oligomer |
US11150254B2 (en) | 2014-09-26 | 2021-10-19 | Chugai Seiyaku Kabushiki Kaisha | Method for measuring reactivity of FVIII |
US11168344B2 (en) | 2005-03-31 | 2021-11-09 | Chugai Seiyaku Kabushiki Kaisha | Methods for producing polypeptides by regulating polypeptide association |
US11214623B2 (en) | 2014-09-26 | 2022-01-04 | Chugai Seiyaku Kabushiki Kaisha | Antibody capable of neutralizing substance having activity alternative to function of coagulation factor VIII (FVIII) |
US11248053B2 (en) | 2007-09-26 | 2022-02-15 | Chugai Seiyaku Kabushiki Kaisha | Method of modifying isoelectric point of antibody via amino acid substitution in CDR |
US11649262B2 (en) | 2015-12-28 | 2023-05-16 | Chugai Seiyaku Kabushiki Kaisha | Method for promoting efficiency of purification of Fc region-containing polypeptide |
WO2023166094A1 (en) | 2022-03-02 | 2023-09-07 | Novo Nordisk Health Care Ag | Methods of administering fviii mimetic bispecific antibodies once weekly |
WO2023166096A1 (en) | 2022-03-02 | 2023-09-07 | Novo Nordisk Health Care Ag | Methods of administering fviii mimetic bispecific antibodies once monthly |
WO2023166097A1 (en) | 2022-03-02 | 2023-09-07 | Novo Nordisk Health Care Ag | Methods of administering fviii mimetic bispecific antibodies every second week |
US11787874B2 (en) | 2017-11-15 | 2023-10-17 | Novo Nordisk A/S | Factor X binders enhancing FX activation |
US11919969B2 (en) | 2017-06-22 | 2024-03-05 | Kymab Limited | Bispecific antibodies for factor IX and factor X |
RU2821642C2 (ru) * | 2016-07-29 | 2024-06-25 | Чугаи Сейяку Кабусики Кайся | Биспецифическое антитело, обладающее повышенной активностью, альтернативной функции кофактора fviii |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI609698B (zh) | 2010-01-20 | 2018-01-01 | Chugai Pharmaceutical Co Ltd | 穩定化的含抗體溶液製劑 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012067176A1 (ja) * | 2010-11-17 | 2012-05-24 | 中外製薬株式会社 | 血液凝固第viii因子の機能を代替する機能を有する多重特異性抗原結合分子 |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
IE52535B1 (en) | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
HUT35524A (en) | 1983-08-02 | 1985-07-29 | Hoechst Ag | Process for preparing pharmaceutical compositions containing regulatory /regulative/ peptides providing for the retarded release of the active substance |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
DK0814159T3 (da) | 1990-08-29 | 2005-10-24 | Genpharm Int | Transgene, ikke-humane dyr, der er i stand til at danne heterologe antistoffer |
CA2124967C (en) | 1991-12-17 | 2008-04-08 | Nils Lonberg | Transgenic non-human animals capable of producing heterologous antibodies |
CA2140638C (en) | 1992-07-24 | 2010-05-04 | Raju Kucherlapati | Generation of xenogeneic antibodies |
CA2161351C (en) | 1993-04-26 | 2010-12-21 | Nils Lonberg | Transgenic non-human animals capable of producing heterologous antibodies |
FR2707189B1 (fr) | 1993-07-09 | 1995-10-13 | Gradient Ass | Procédé de traitement de résidus de combustion et installation de mise en Óoeuvre dudit procédé. |
AU701342B2 (en) | 1994-07-13 | 1999-01-28 | Chugai Seiyaku Kabushiki Kaisha | Reconstituted human antibody against human interleukin-8 |
EP1709970A1 (en) | 1995-04-27 | 2006-10-11 | Abgenix, Inc. | Human antibodies against EGFR, derived from immunized xenomice |
AU2466895A (en) | 1995-04-28 | 1996-11-18 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
ATE512225T1 (de) | 1998-04-03 | 2011-06-15 | Chugai Pharmaceutical Co Ltd | Humanisierter antikörper gegen den menschlichen gewebefaktor (tf) und verfahren für die konstruktion eines solchen humanisierten antikörpers. |
WO2002020565A2 (en) | 2000-09-08 | 2002-03-14 | Universität Zürich | Collections of repeat proteins comprising repeat modules |
AU2002213251B2 (en) | 2000-10-16 | 2007-06-14 | Bristol-Myers Squibb Company | Protein scaffolds for antibody mimics and other binding proteins |
US20030157561A1 (en) | 2001-11-19 | 2003-08-21 | Kolkman Joost A. | Combinatorial libraries of monomer domains |
WO2005035753A1 (ja) * | 2003-10-10 | 2005-04-21 | Chugai Seiyaku Kabushiki Kaisha | 機能蛋白質を代替する二重特異性抗体 |
EP2311945A1 (en) | 2003-10-14 | 2011-04-20 | Chugai Seiyaku Kabushiki Kaisha | Bispecific antibodies substituting for functional proteins |
AU2004284090A1 (en) | 2003-10-24 | 2005-05-06 | Avidia, Inc. | LDL receptor class A and EGF domain monomers and multimers |
CA2603264C (en) * | 2005-04-08 | 2017-03-21 | Chugai Seiyaku Kabushiki Kaisha | Antibody substituting for function of blood coagulation factor viii |
TWI609698B (zh) | 2010-01-20 | 2018-01-01 | Chugai Pharmaceutical Co Ltd | 穩定化的含抗體溶液製劑 |
CA2802072A1 (en) * | 2010-06-14 | 2011-12-22 | Paion Deutschland Gmbh | Treatment of coagulopathy with hyperfibrinolysis |
-
2015
- 2015-03-27 TW TW110149549A patent/TWI831106B/zh active
- 2015-03-27 TW TW104109925A patent/TW201625299A/zh unknown
- 2015-03-31 EP EP15809216.3A patent/EP3159006A4/en not_active Withdrawn
- 2015-03-31 WO PCT/JP2015/060171 patent/WO2015194233A1/ja active Application Filing
- 2015-03-31 EP EP23157462.5A patent/EP4218816A3/en active Pending
- 2015-03-31 SG SG10201811185YA patent/SG10201811185YA/en unknown
- 2015-03-31 SG SG11201610581RA patent/SG11201610581RA/en unknown
- 2015-03-31 AU AU2015275440A patent/AU2015275440B2/en active Active
- 2015-03-31 US US15/319,016 patent/US20170253663A1/en not_active Abandoned
- 2015-03-31 JP JP2016529118A patent/JP6663846B2/ja active Active
- 2015-03-31 CA CA2951622A patent/CA2951622C/en active Active
- 2015-03-31 BR BR112016029316-9A patent/BR112016029316A2/ja active Search and Examination
- 2015-03-31 MX MX2016016380A patent/MX2016016380A/es unknown
- 2015-03-31 KR KR1020177001413A patent/KR20170015517A/ko not_active IP Right Cessation
- 2015-03-31 CN CN201580039806.4A patent/CN106559987A/zh active Pending
- 2015-03-31 RU RU2017101705A patent/RU2721910C2/ru active
- 2015-03-31 KR KR1020247013296A patent/KR20240063162A/ko active Search and Examination
- 2015-03-31 MY MYPI2016704659A patent/MY189333A/en unknown
-
2016
- 2016-12-01 IL IL249330A patent/IL249330B/en unknown
-
2017
- 2017-01-19 ZA ZA2017/00459A patent/ZA201700459B/en unknown
-
2019
- 2019-06-05 US US16/432,790 patent/US20190309090A1/en not_active Abandoned
- 2019-12-16 JP JP2019226196A patent/JP2020055864A/ja active Pending
-
2020
- 2020-02-04 US US16/780,977 patent/US20200157243A1/en not_active Abandoned
- 2020-09-11 US US17/017,971 patent/US20200407463A1/en not_active Abandoned
-
2021
- 2021-04-20 US US17/235,445 patent/US20210238307A1/en not_active Abandoned
- 2021-11-24 US US17/534,566 patent/US20220073645A1/en not_active Abandoned
-
2022
- 2022-06-27 US US17/849,879 patent/US20220324999A1/en not_active Abandoned
-
2023
- 2023-02-06 US US18/164,709 patent/US20230174673A1/en not_active Abandoned
- 2023-10-02 US US18/479,149 patent/US20240052060A1/en not_active Abandoned
-
2024
- 2024-06-05 US US18/734,434 patent/US20240317891A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012067176A1 (ja) * | 2010-11-17 | 2012-05-24 | 中外製薬株式会社 | 血液凝固第viii因子の機能を代替する機能を有する多重特異性抗原結合分子 |
Non-Patent Citations (6)
Cited By (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11168344B2 (en) | 2005-03-31 | 2021-11-09 | Chugai Seiyaku Kabushiki Kaisha | Methods for producing polypeptides by regulating polypeptide association |
US11046784B2 (en) | 2006-03-31 | 2021-06-29 | Chugai Seiyaku Kabushiki Kaisha | Methods for controlling blood pharmacokinetics of antibodies |
US10934344B2 (en) | 2006-03-31 | 2021-03-02 | Chugai Seiyaku Kabushiki Kaisha | Methods of modifying antibodies for purification of bispecific antibodies |
US11248053B2 (en) | 2007-09-26 | 2022-02-15 | Chugai Seiyaku Kabushiki Kaisha | Method of modifying isoelectric point of antibody via amino acid substitution in CDR |
US12116414B2 (en) | 2007-09-26 | 2024-10-15 | Chugai Seiyaku Kabushiki Kaisha | Method of modifying isoelectric point of antibody via amino acid substitution in CDR |
US12122840B2 (en) | 2007-09-26 | 2024-10-22 | Chugai Seiyaku Kabushiki Kaisha | Method of modifying isoelectric point of antibody via amino acid substitution in CDR |
US10450381B2 (en) | 2010-11-17 | 2019-10-22 | Chugai Seiyaku Kabushiki Kaisha | Methods of treatment that include the administration of bispecific antibodies |
US11124576B2 (en) | 2013-09-27 | 2021-09-21 | Chungai Seiyaku Kabushiki Kaisha | Method for producing polypeptide heteromultimer |
US11214623B2 (en) | 2014-09-26 | 2022-01-04 | Chugai Seiyaku Kabushiki Kaisha | Antibody capable of neutralizing substance having activity alternative to function of coagulation factor VIII (FVIII) |
US11150254B2 (en) | 2014-09-26 | 2021-10-19 | Chugai Seiyaku Kabushiki Kaisha | Method for measuring reactivity of FVIII |
US11142587B2 (en) | 2015-04-01 | 2021-10-12 | Chugai Seiyaku Kabushiki Kaisha | Method for producing polypeptide hetero-oligomer |
US11649262B2 (en) | 2015-12-28 | 2023-05-16 | Chugai Seiyaku Kabushiki Kaisha | Method for promoting efficiency of purification of Fc region-containing polypeptide |
KR20190003596A (ko) * | 2016-04-28 | 2019-01-09 | 추가이 세이야쿠 가부시키가이샤 | 항체 함유 제제 |
KR102456742B1 (ko) * | 2016-04-28 | 2022-10-19 | 추가이 세이야쿠 가부시키가이샤 | 항체 함유 제제 |
CN109415444A (zh) * | 2016-07-29 | 2019-03-01 | 中外制药株式会社 | 显示增加的备选fviii辅因子功能活性的双特异性抗体 |
JP7050677B2 (ja) | 2016-07-29 | 2022-04-08 | 中外製薬株式会社 | 増強されたfviii補因子機能代替活性を有する二重特異性抗体 |
CN109415444B (zh) * | 2016-07-29 | 2024-03-01 | 中外制药株式会社 | 显示增加的备选fviii辅因子功能活性的双特异性抗体 |
KR20190037271A (ko) * | 2016-07-29 | 2019-04-05 | 추가이 세이야쿠 가부시키가이샤 | 증강된 fviii 보인자 기능 대체 활성을 갖는 이중특이성 항체 |
KR102591955B1 (ko) * | 2016-07-29 | 2023-10-19 | 추가이 세이야쿠 가부시키가이샤 | 증강된 fviii 보인자 기능 대체 활성을 갖는 이중특이성 항체 |
RU2821642C2 (ru) * | 2016-07-29 | 2024-06-25 | Чугаи Сейяку Кабусики Кайся | Биспецифическое антитело, обладающее повышенной активностью, альтернативной функции кофактора fviii |
WO2018021450A1 (ja) * | 2016-07-29 | 2018-02-01 | 中外製薬株式会社 | 増強されたfviii補因子機能代替活性を有する二重特異性抗体 |
JPWO2018021450A1 (ja) * | 2016-07-29 | 2019-05-23 | 中外製薬株式会社 | 増強されたfviii補因子機能代替活性を有する二重特異性抗体 |
KR20230117462A (ko) | 2016-09-06 | 2023-08-08 | 추가이 세이야쿠 가부시키가이샤 | 응고 제 ix 인자 및/또는 활성화 응고 제 ix 인자 및응고 제 x 인자 및/또는 활성화 응고 제 x 인자를 인식하는 이중특이성 항체의 사용법 |
CN109661241A (zh) * | 2016-09-06 | 2019-04-19 | 中外制药株式会社 | 使用识别凝血因子ix和/或活化凝血因子ix以及凝血因子x和/或活化凝血因子x的双特异性抗体的方法 |
WO2018047813A1 (en) * | 2016-09-06 | 2018-03-15 | Chugai Seiyaku Kabushiki Kaisha | Methods of using a bispecific antibody that recognizes coagulation factor ix and/or activated coagulation factor ix and coagulation factor x and/or activated coagulation factor x |
IL265144B2 (en) * | 2016-09-06 | 2024-10-01 | Chugai Pharmaceutical Co Ltd | Methods for using a bispecific antibody that recognizes coagulation factor IX and/or activated coagulation factor IX and coagulation factor X and/or activated coagulation factor X |
JP2019530654A (ja) * | 2016-09-06 | 2019-10-24 | 中外製薬株式会社 | 凝固第ix因子および/または活性化凝固第ix因子ならびに凝固第x因子および/または活性化凝固第x因子を認識する二重特異性抗体の使用法 |
US11352438B2 (en) | 2016-09-06 | 2022-06-07 | Chugai Seiyaku Kabushiki Kaisha | Methods of using a bispecific antibody that recognizes coagulation factor IX and/or activated coagulation factor IX and coagulation factor X and/or activated coagulation factor X |
RU2766233C2 (ru) * | 2016-09-06 | 2022-02-10 | Чугаи Сейяку Кабусики Кайся | Способы применения биспецифического антитела, которое распознает фактор свертывания ix и/или активированный фактор свертывания ix и фактор свертывания x и/или активированный фактор свертывания x |
JP7125932B2 (ja) | 2016-09-06 | 2022-08-25 | 中外製薬株式会社 | 凝固第ix因子および/または活性化凝固第ix因子ならびに凝固第x因子および/または活性化凝固第x因子を認識する二重特異性抗体の使用法 |
IL265144B1 (en) * | 2016-09-06 | 2024-06-01 | Chugai Pharmaceutical Co Ltd | Methods for using a bispecific antibody that recognizes coagulation factor IX and/or activated coagulation factor IX and coagulation factor X and/or activated coagulation factor X |
TWI786061B (zh) * | 2016-09-06 | 2022-12-11 | 日商中外製藥股份有限公司 | 使用辨識凝血因子ix及/或活化的凝血因子ix以及凝血因子x及/或活化的凝血因子x之雙特異性抗體之方法 |
KR20190044673A (ko) | 2016-09-06 | 2019-04-30 | 추가이 세이야쿠 가부시키가이샤 | 응고 제 ix 인자 및/또는 활성화 응고 제 ix 인자 및 응고 제 x 인자 및/또는 활성화 응고 제 x 인자를 인식하는 이중특이성 항체의 사용법 |
KR102560808B1 (ko) | 2016-09-06 | 2023-07-27 | 추가이 세이야쿠 가부시키가이샤 | 응고 제 ix 인자 및/또는 활성화 응고 제 ix 인자 및 응고 제 x 인자 및/또는 활성화 응고 제 x 인자를 인식하는 이중특이성 항체의 사용법 |
JP2019532057A (ja) * | 2016-09-23 | 2019-11-07 | シーエスエル、リミテッド | 凝固因子結合タンパク質及びその使用 |
JP7051826B2 (ja) | 2016-09-23 | 2022-04-11 | シーエスエル、リミテッド | 凝固因子結合タンパク質及びその使用 |
WO2018181870A1 (ja) * | 2017-03-31 | 2018-10-04 | 公立大学法人奈良県立医科大学 | 血液凝固第viii因子の機能を代替する多重特異性抗原結合分子を含有する、血液凝固第ix因子異常症の予防および/または治療に用いられる医薬組成物 |
US11919969B2 (en) | 2017-06-22 | 2024-03-05 | Kymab Limited | Bispecific antibodies for factor IX and factor X |
US10759870B2 (en) | 2017-09-29 | 2020-09-01 | Chugai Seiyaku Kabushiki Kaisha | Multispecific antigen-binding molecules having blood coagulation factor VIII (FVIII) cofactor function-substituting activity and pharmaceutical formulations containing such a molecule as an active ingredient |
US11787874B2 (en) | 2017-11-15 | 2023-10-17 | Novo Nordisk A/S | Factor X binders enhancing FX activation |
US11976135B2 (en) | 2018-12-21 | 2024-05-07 | Kymab Limited | FIXaxFX bispecific antibody with common light chain |
US10815308B2 (en) | 2018-12-21 | 2020-10-27 | Kymab Limited | FIXaxFX bispecific antibody with common light chain |
KR20220082000A (ko) | 2019-10-11 | 2022-06-16 | 추가이 세이야쿠 가부시키가이샤 | 후천성 혈우병 a의 예방 및/또는 치료에 이용되는 의약 조성물, 및 당해 의약 조성물을 포함하는 제품 |
WO2021070885A1 (ja) * | 2019-10-11 | 2021-04-15 | 中外製薬株式会社 | 後天性血友病aの予防および/または治療に用いられる医薬組成物、および当該医薬組成物を含む製品 |
JP6836696B1 (ja) * | 2019-10-11 | 2021-03-03 | 中外製薬株式会社 | 後天性血友病aの予防および/または治療に用いられる医薬組成物、および当該医薬組成物を含む製品 |
WO2023166097A1 (en) | 2022-03-02 | 2023-09-07 | Novo Nordisk Health Care Ag | Methods of administering fviii mimetic bispecific antibodies every second week |
WO2023166096A1 (en) | 2022-03-02 | 2023-09-07 | Novo Nordisk Health Care Ag | Methods of administering fviii mimetic bispecific antibodies once monthly |
WO2023166094A1 (en) | 2022-03-02 | 2023-09-07 | Novo Nordisk Health Care Ag | Methods of administering fviii mimetic bispecific antibodies once weekly |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2015194233A1 (ja) | 血液凝固第viii因子および/または活性化血液凝固第viiiの活性の低下ないし欠損によって発症および/または進展する疾患の予防および/または治療に用いられる医薬組成物 | |
RU2766233C2 (ru) | Способы применения биспецифического антитела, которое распознает фактор свертывания ix и/или активированный фактор свертывания ix и фактор свертывания x и/или активированный фактор свертывания x | |
NZ727218B2 (en) | Pharmaceutical composition for use in prevention and/or treatment of disease that develops or progresses as a result of decrease or loss of activity of blood coagulation factor viii and/or activated blood coagulation factor viii | |
KR20220082000A (ko) | 후천성 혈우병 a의 예방 및/또는 치료에 이용되는 의약 조성물, 및 당해 의약 조성물을 포함하는 제품 | |
TW202426487A (zh) | 抗人masp-3抗體之治療方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15809216 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 249330 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 2016529118 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2951622 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2016/016380 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15319016 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112016029316 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2015275440 Country of ref document: AU Date of ref document: 20150331 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20177001413 Country of ref document: KR Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2015809216 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015809216 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2017101705 Country of ref document: RU Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112016029316 Country of ref document: BR Kind code of ref document: A2 Effective date: 20161214 |