RU2013142004A - Конъюгаты "антитело-лекарственное средство" - Google Patents
Конъюгаты "антитело-лекарственное средство" Download PDFInfo
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- RU2013142004A RU2013142004A RU2013142004/10A RU2013142004A RU2013142004A RU 2013142004 A RU2013142004 A RU 2013142004A RU 2013142004/10 A RU2013142004/10 A RU 2013142004/10A RU 2013142004 A RU2013142004 A RU 2013142004A RU 2013142004 A RU2013142004 A RU 2013142004A
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- 239000000611 antibody drug conjugate Substances 0.000 claims abstract 12
- 229940049595 antibody-drug conjugate Drugs 0.000 claims abstract 12
- 239000000427 antigen Substances 0.000 claims abstract 11
- 102000036639 antigens Human genes 0.000 claims abstract 11
- 108091007433 antigens Proteins 0.000 claims abstract 11
- 239000012634 fragment Substances 0.000 claims abstract 9
- 239000003814 drug Substances 0.000 claims abstract 7
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims abstract 6
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 claims abstract 4
- BLUGYPPOFIHFJS-UUFHNPECSA-N (2s)-n-[(2s)-1-[[(3r,4s,5s)-3-methoxy-1-[(2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-[[(1s)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]-3-methyl-2-(methylamino)butanamid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 BLUGYPPOFIHFJS-UUFHNPECSA-N 0.000 claims abstract 4
- 208000007934 ACTH-independent macronodular adrenal hyperplasia Diseases 0.000 claims abstract 3
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract 2
- 239000000562 conjugate Substances 0.000 claims 8
- 229940125644 antibody drug Drugs 0.000 claims 7
- 229940079593 drug Drugs 0.000 claims 6
- 206010028980 Neoplasm Diseases 0.000 claims 3
- 201000011510 cancer Diseases 0.000 claims 3
- 238000000034 method Methods 0.000 claims 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 150000007523 nucleic acids Chemical class 0.000 claims 2
- 102000039446 nucleic acids Human genes 0.000 claims 2
- 108020004707 nucleic acids Proteins 0.000 claims 2
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 125000000539 amino acid group Chemical group 0.000 claims 1
- 238000004113 cell culture Methods 0.000 claims 1
- 230000021615 conjugation Effects 0.000 claims 1
- 238000012258 culturing Methods 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- DASWEROEPLKSEI-UIJRFTGLSA-N monomethyl auristatin e Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)C1=CC=CC=C1 DASWEROEPLKSEI-UIJRFTGLSA-N 0.000 claims 1
- MFRNYXJJRJQHNW-NARUGQRUSA-N monomethyl auristatin f Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)C([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-NARUGQRUSA-N 0.000 claims 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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- 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
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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Abstract
1. Конъюгат «антитело-лекарственное средство» формулы:Ab-(LU-D)pили его фармацевтически приемлемая соль, где:a) Ab представляет собой антитело против 5T4 или его антигенсвязывающий фрагмент, содержащие вариабельную область тяжелой цепи (VH), имеющую:1) область VH CDR1 (определяющая комплементарность область 1), как показано в SEQ ID NO: 5,2) область VH CDR2, как показано в SEQ ID NO: 6, и3) область VH CDR3, как показано в SEQ ID NO: 7;б) LU представляет собой линкерную единицу, выбранную из группы, состоящей из малеимидокапроила и малеимидокапроил-Val-Cit;в) p представляет собой целое число от приблизительно 1 до приблизительно 8, иг) D представляет собой структурную единицу лекарственного средства, выбранную из группы, состоящей из ММАЕ (монометилауристатин E), MMAD (монометилауристатин D) и MMAF (монометилауристатин F).2. Конъюгат «антитело-лекарственное средство» по п.1, где указанные антитело против 5Т4 или его антигенсвязывающий фрагмент содержат вариабельную область легкой цепи (VL), имеющую:а) область VL CDR1, как показано в SEQ ID NO: 8,б) область VL CDR2, как показано в SEQ ID NO: 9, ив) область VL CDR3, как показано в SEQ ID NO: 10.3. Конъюгат «антитело-лекарственное средство» по п.1, где указанные антитело против 5T4 или его антигенсвязывающий фрагмент дополнительно содержат:1) вариабельную область тяжелой цепи, имеющую:а) область VH CDR1, как показано в SEQ ID NO: 5,б) область VH CDR2, как показано в SEQ ID NO: 6, ив) область VH CDR3, как показано в SEQ ID NO: 7;2) вариабельную область легкой цепи, имеющую:а) область VL CDR1, как показано в SEQ ID NO: 8,б) область VL CDR2, как показано в SEQ ID NO: 9, ив) область VL CDR3, как показано в SEQ ID NO: 10.4. Конъюгат «антитело-лекарственное средство» по п.1, где указанные антитело против 5T4 или его антигенсвязы
Claims (21)
1. Конъюгат «антитело-лекарственное средство» формулы:
Ab-(LU-D)p
или его фармацевтически приемлемая соль, где:
a) Ab представляет собой антитело против 5T4 или его антигенсвязывающий фрагмент, содержащие вариабельную область тяжелой цепи (VH), имеющую:
1) область VH CDR1 (определяющая комплементарность область 1), как показано в SEQ ID NO: 5,
2) область VH CDR2, как показано в SEQ ID NO: 6, и
3) область VH CDR3, как показано в SEQ ID NO: 7;
б) LU представляет собой линкерную единицу, выбранную из группы, состоящей из малеимидокапроила и малеимидокапроил-Val-Cit;
в) p представляет собой целое число от приблизительно 1 до приблизительно 8, и
г) D представляет собой структурную единицу лекарственного средства, выбранную из группы, состоящей из ММАЕ (монометилауристатин E), MMAD (монометилауристатин D) и MMAF (монометилауристатин F).
2. Конъюгат «антитело-лекарственное средство» по п.1, где указанные антитело против 5Т4 или его антигенсвязывающий фрагмент содержат вариабельную область легкой цепи (VL), имеющую:
а) область VL CDR1, как показано в SEQ ID NO: 8,
б) область VL CDR2, как показано в SEQ ID NO: 9, и
в) область VL CDR3, как показано в SEQ ID NO: 10.
3. Конъюгат «антитело-лекарственное средство» по п.1, где указанные антитело против 5T4 или его антигенсвязывающий фрагмент дополнительно содержат:
1) вариабельную область тяжелой цепи, имеющую:
а) область VH CDR1, как показано в SEQ ID NO: 5,
б) область VH CDR2, как показано в SEQ ID NO: 6, и
в) область VH CDR3, как показано в SEQ ID NO: 7;
2) вариабельную область легкой цепи, имеющую:
а) область VL CDR1, как показано в SEQ ID NO: 8,
б) область VL CDR2, как показано в SEQ ID NO: 9, и
в) область VL CDR3, как показано в SEQ ID NO: 10.
4. Конъюгат «антитело-лекарственное средство» по п.1, где указанные антитело против 5T4 или его антигенсвязывающий фрагмент содержат область VH с SEQ ID NO: 3 и область VL с SEQ ID NO: 4.
5. Конъюгат «антитело-лекарственное средство» по п.1, где указанные антитело против 5T4 или его антигенсвязывающий фрагмент состоят из тяжелой цепи, имеющей SEQ ID NO: 1, и легкой цепи, имеющей SEQ ID NO: 2.
6. Конъюгат «антитело-лекарственное средство» по п.1, где указанные антитело или его антигенсвязывающий фрагмент распознают эпитоп человеческого антигена 5Т4, содержащий аминокислотные остатки 173-258 и 282-361 аминокислотной последовательности SEQ ID NO: 11.
7. Конъюгат «антитело-лекарственное средство» по п.1, где указанная LU представляет собой малеимидокапроил.
8. Конъюгат «антитело-лекарственное средство» по п.1, где указанное лекарственное средство представляет собой MMAF.
9. Конъюгат «антитело-лекарственное средство» по п.1, где p представляет собой целое число от приблизительно 1 до приблизительно 4.
10. Конъюгат «антитело-лекарственное средство» по п.1, где:
а) указанное антитело против 5T4 состоит из тяжелой цепи, имеющей SEQ ID NO: 1, и легкой цепи, имеющей SEQ ID NO: 2,
б) указанная LU представляет собой малеимидокапроил,
в) указанное лекарственное средство представляет собой MMAF и
г) p представляет собой 4.
11. Фармацевтическая композиция, содержащая конъюгат «антитело-лекарственное средство» по любому из пп.1-10 и фармацевтически приемлемый носитель.
12. Способ лечения 5T4-положительного рака у пациента, нуждающегося в этом, включающий введение указанному пациенту конъюгата «антитело-лекарственное средство» по любому из пп.1-10.
13. Способ по п.12, где указанный рак выбран из группы, состоящей из колоректального рака, рака молочной железы, рака поджелудочной железы и немелкоклеточных карцином легкого.
14. Конъюгат «антитело-лекарственное средство» по любому из пп.1-10 для применения в терапии.
15. Применение конъюгата «антитело-лекарственное средство» по любому из пп.1-10 для изготовления лекарственного средства.
16. Применение по пп.14 или 15 для лечения 5Т4-положительного рака.
17. Нуклеиновая кислота, кодирующая антитело против 5Т4 по любому из пп.1-6.
18. Вектор, содержащий нуклеиновую кислоту по п.17.
19. Клетка-хозяин, содержащая вектор по п.18.
20. Способ получения антитела, включающий культивирование клетки-хозяина по п.19 и выделение антитела из культуры.
21. Способ получения конъюгата «антитело против 5Т4-лекарственное средство», включающий:
а) химическое связывание линкерной единицы, выбранной из группы, состоящей из малеимидокапроила и малеимидокапроил-Val-Cit, со структурной единицей лекарственного средства, выбранной из группы, состоящей из MMAE, MMAD или MMAF;
б) конъюгирование указанного «линкер-лекарственное средство» с антителом, выделенным из клеточной культуры по п.20 и
в) очистку конъюгата «антитело-лекарственное средство».
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Families Citing this family (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8435529B2 (en) | 2002-06-14 | 2013-05-07 | Immunomedics, Inc. | Combining radioimmunotherapy and antibody-drug conjugates for improved cancer therapy |
US9745380B2 (en) | 2002-03-01 | 2017-08-29 | Immunomedics, Inc. | RS7 antibodies |
ATE417067T1 (de) | 2002-03-01 | 2008-12-15 | Immunomedics Inc | Rs7 antikörper |
US9770517B2 (en) | 2002-03-01 | 2017-09-26 | Immunomedics, Inc. | Anti-Trop-2 antibody-drug conjugates and uses thereof |
CA2508831C (en) | 2002-12-13 | 2012-05-01 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US10058621B2 (en) | 2015-06-25 | 2018-08-28 | Immunomedics, Inc. | Combination therapy with anti-HLA-DR antibodies and kinase inhibitors in hematopoietic cancers |
US9707302B2 (en) | 2013-07-23 | 2017-07-18 | Immunomedics, Inc. | Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
AU2007226696C1 (en) | 2006-03-10 | 2016-02-04 | Wyeth Llc | Anti-5T4 antibodies and uses thereof |
MX2012013664A (es) * | 2010-06-04 | 2013-01-24 | Wyeth Llc | Formulaciones de vacuna. |
CN103517719B (zh) * | 2011-04-01 | 2016-10-12 | 惠氏有限责任公司 | 抗体-药物缀合物 |
WO2013068874A1 (en) * | 2011-11-11 | 2013-05-16 | Pfizer Inc. | Antibody-drug conjugates |
CN104094116B (zh) | 2012-01-24 | 2017-05-31 | 辉瑞公司 | 在哺乳动物个体中检测5t4阳性循环肿瘤细胞的方法和诊断5t4阳性癌症的方法 |
US9764041B2 (en) * | 2012-04-04 | 2017-09-19 | Perseus Proteomics Inc. | Drug conjugate comprising anti-CDH3 (P-cadherin) antibody |
HUE038285T2 (hu) * | 2012-10-23 | 2018-10-29 | Synaffix Bv | Módosított antitest, antitest-konjugátum és eljárás ezek elõállítására |
TW201431880A (zh) | 2012-11-07 | 2014-08-16 | Pfizer | 抗切口3(anti-notch3)抗體及抗體-藥物共軛體 |
EP2928503B1 (en) | 2012-12-10 | 2019-02-20 | Mersana Therapeutics, Inc. | Conjugates of auristatin compounds |
US10206918B2 (en) | 2012-12-13 | 2019-02-19 | Immunomedics, Inc. | Efficacy of anti-HLA-DR antiboddy drug conjugate IMMU-140 (hL243-CL2A-SN-38) in HLA-DR positive cancers |
US9492566B2 (en) | 2012-12-13 | 2016-11-15 | Immunomedics, Inc. | Antibody-drug conjugates and uses thereof |
KR20230078823A (ko) | 2012-12-13 | 2023-06-02 | 이뮤노메딕스, 인코오포레이티드 | 개선된 효능 및 감소된 독성을 위한 항체 및 sn-38의 면역컨쥬게이트의 투약 |
US10137196B2 (en) | 2012-12-13 | 2018-11-27 | Immunomedics, Inc. | Dosages of immunoconjugates of antibodies and SN-38 for improved efficacy and decreased toxicity |
WO2014137931A1 (en) * | 2013-03-06 | 2014-09-12 | Imaginab, Inc. | Antigen binding constructs to 5t4 |
JP2016514157A (ja) | 2013-03-14 | 2016-05-19 | アルバニー モレキュラー リサーチ, インコーポレイテッド | リガンド−治療薬コンジュゲートおよびケイ素ベースのリンカー |
SI2991683T1 (sl) | 2013-05-02 | 2020-01-31 | Glykos Finland Oy | Konjugati glikoproteina ali glikana s toksično obremenitvijo |
US9517276B2 (en) | 2013-06-04 | 2016-12-13 | Cytomx Therapeutics, Inc. | Compositions and methods for conjugating activatable antibodies |
US11253606B2 (en) | 2013-07-23 | 2022-02-22 | Immunomedics, Inc. | Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, Bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
CN105722534B (zh) * | 2013-08-01 | 2019-05-31 | 艾更斯司股份有限公司 | 结合cd37蛋白的抗体药物偶联物(adc) |
WO2015051159A1 (en) * | 2013-10-02 | 2015-04-09 | The Rockefeller University | Amyloid protofibril antibodies and methods of use thereof |
EA032231B1 (ru) | 2013-10-11 | 2019-04-30 | Мерсана Терапьютикс, Инк. | Конъюгаты белок-полимер-лекарственное средство |
HUE046816T2 (hu) * | 2013-10-11 | 2020-03-30 | Asana Biosciences Llc | Fehérje-polimer-gyógyszer konjugátumok |
CN105828841A (zh) | 2013-11-04 | 2016-08-03 | 辉瑞大药厂 | 抗-efna4抗体-药物缀合物 |
MX2016010683A (es) | 2014-02-21 | 2017-05-11 | Ibc Pharmaceuticals Inc | Terapia para tratar enfermedades mediante la induccion de respuesta inmune de las células que expresan trop-2. |
WO2015155345A1 (en) * | 2014-04-11 | 2015-10-15 | Medimmune Limited | Antibodies and antibody-drug conjugates |
WO2015173133A1 (en) | 2014-05-12 | 2015-11-19 | Chiesi Farmaceutici S.P.A. | Formulations and methods of treating alzheimer's disease and other proteinopathies by combination therapy |
JP6517240B2 (ja) * | 2014-05-22 | 2019-05-22 | シントン・バイオファーマシューティカルズ・ビー.ブイ.Synthon Biopharmaceuticals B.V. | 抗体へのリンカー薬物の部位特異的コンジュゲーションおよび得られるadc |
PL3148580T3 (pl) | 2014-05-29 | 2021-07-12 | Macrogenics, Inc. | Trójswoiste cząsteczki wiążące, które wiążą się swoiście z wieloma antygenami nowotworowymi, i sposoby ich zastosowania |
WO2016022939A1 (en) * | 2014-08-08 | 2016-02-11 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Human monoclonal antibodies specific for 5t4 and methods of their use |
EP3549583A1 (en) | 2014-10-10 | 2019-10-09 | Pfizer Inc | Synergistic auristatin combinations |
US20180028658A1 (en) * | 2015-02-16 | 2018-02-01 | New York Blood Center, Inc. | Antibody-drug conjugates for reducing the latent hiv reservoir |
JP6746845B2 (ja) | 2015-04-22 | 2020-08-26 | イミューノメディクス、インコーポレイテッドImmunomedics, Inc. | 循環trop−2陽性癌細胞の単離、検出、診断及び/または特徴付け |
CN106279352B (zh) | 2015-05-29 | 2020-05-22 | 上海新理念生物医药科技有限公司 | 海兔毒素10的衍生物及其应用 |
US10195175B2 (en) | 2015-06-25 | 2019-02-05 | Immunomedics, Inc. | Synergistic effect of anti-Trop-2 antibody-drug conjugate in combination therapy for triple-negative breast cancer when used with microtubule inhibitors or PARP inhibitors |
LT3380122T (lt) | 2015-11-24 | 2021-10-11 | Byondis B.V. | Antikūnai prieš 5t4 ir antikūno-vaistų konjugatai |
CN110698558B (zh) * | 2015-12-24 | 2021-09-10 | 凯惠科技发展(上海)有限公司 | 一种tpbg抗体及其制备方法、其偶联物和应用 |
CA3011372A1 (en) | 2016-02-10 | 2017-08-17 | Immunomedics, Inc. | Combination of abcg2 inhibitors with sacituzumab govitecan (immu-132) overcomes resistance to sn-38 in trop-2 expressing cancers |
US11135307B2 (en) | 2016-11-23 | 2021-10-05 | Mersana Therapeutics, Inc. | Peptide-containing linkers for antibody-drug conjugates |
WO2018119314A1 (en) * | 2016-12-22 | 2018-06-28 | Ardeagen Corporation | Anti-ror1 antibody and conjugates thereof |
CN108285487B (zh) | 2017-01-08 | 2021-02-19 | 浙江昭华生物医药有限公司 | 抗5t4抗体-药物偶联物及其应用 |
EP3595705A1 (en) * | 2017-03-15 | 2020-01-22 | Oxford BioMedica (UK) Limited | Method |
WO2018183041A1 (en) | 2017-03-27 | 2018-10-04 | Immunomedics, Inc. | Treatment of trop-2 expressing triple negative breast cancer with sacituzumab govitecan and a rad51 inhibitor |
WO2018184558A1 (zh) | 2017-04-05 | 2018-10-11 | 凯惠科技发展(上海)有限公司 | 一种人源化抗tpbg抗体及其制备方法、其偶联物和应用 |
EP3624854A1 (en) * | 2017-05-16 | 2020-03-25 | Université de Strasbourg | Protein-drug conjugates and their use in the treatment of cancers |
US11638760B2 (en) | 2017-11-27 | 2023-05-02 | Mersana Therapeutics, Inc. | Pyrrolobenzodiazepine antibody conjugates |
WO2019126691A1 (en) | 2017-12-21 | 2019-06-27 | Mersana Therapeutics, Inc. | Pyrrolobenzodiazepine antibody conjugates |
CN110507824A (zh) * | 2018-05-21 | 2019-11-29 | 荣昌生物制药(烟台)有限公司 | 一种抗间皮素抗体及其抗体药物缀合物 |
JP2022513400A (ja) | 2018-10-29 | 2022-02-07 | メルサナ セラピューティクス インコーポレイテッド | ペプチド含有リンカーを有するシステイン操作抗体-薬物コンジュゲート |
WO2021048423A1 (en) * | 2019-09-12 | 2021-03-18 | Genmab A/S | Bispecific antibodies binding to 5t4 and cd3 for use in treatment of cancer |
KR20230015888A (ko) | 2020-03-20 | 2023-01-31 | 이뮤노메딕스, 인코오포레이티드 | 사시투주맙 고비테칸 요법에 대한 바이오마커 |
WO2023045141A1 (zh) * | 2021-09-26 | 2023-03-30 | 上海迈泰君奥生物技术有限公司 | 一种双功能融合蛋白 |
WO2023107954A1 (en) * | 2021-12-08 | 2023-06-15 | Dragonfly Therapeutics, Inc. | Antibodies targeting 5t4 and uses thereof |
WO2023155925A1 (en) * | 2022-02-21 | 2023-08-24 | Concept To Medicine Biotech Co., Ltd. | Anti-5t4 antibodies and uses thereof |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5869053A (en) | 1988-03-04 | 1999-02-09 | Cancer Research Campaign Technology, Ltd. | 5T4 antigen from human trophoblasts |
US6884869B2 (en) | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
US7256257B2 (en) | 2001-04-30 | 2007-08-14 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
US20090068178A1 (en) * | 2002-05-08 | 2009-03-12 | Genentech, Inc. | Compositions and Methods for the Treatment of Tumor of Hematopoietic Origin |
CA3062320C (en) | 2003-11-06 | 2022-11-15 | Seattle Genetics, Inc. | Monomethylvaline compounds capable of conjugation to ligands |
BRPI0515113A (pt) * | 2004-09-10 | 2008-07-01 | Wyeth Corp | anticorpos anti-5t4 humanizados e conjugados de anticorpo anti-5t4/caliqueamicina |
EP2511299A1 (en) | 2005-04-19 | 2012-10-17 | Seattle Genetics, Inc. | Humanized anti-CD70 binding agents and uses thereof |
EP1942944A2 (en) | 2005-10-31 | 2008-07-16 | Genentech, Inc. | Macrocyclic depsipeptide antibody-drug conjugates and methods |
AU2006321975A1 (en) * | 2005-12-06 | 2007-06-14 | Wyeth | Interleukin-11 compositions and methods of use |
US7750116B1 (en) * | 2006-02-18 | 2010-07-06 | Seattle Genetics, Inc. | Antibody drug conjugate metabolites |
AU2007226696C1 (en) * | 2006-03-10 | 2016-02-04 | Wyeth Llc | Anti-5T4 antibodies and uses thereof |
AR059900A1 (es) * | 2006-03-17 | 2008-05-07 | Genentech Inc | Anticuerpos anti-tat226 e inmunoconjugados |
US8044778B2 (en) * | 2007-07-12 | 2011-10-25 | Henry Schein, Inc. | Injection device and case with reporting ability |
JP5394246B2 (ja) * | 2007-03-30 | 2014-01-22 | ジェネンテック, インコーポレイテッド | 抗体及びイムノコンジュゲートとこれらの使用方法 |
EP2211904B1 (en) * | 2007-10-19 | 2016-08-17 | Seattle Genetics, Inc. | Cd19 binding agents and uses thereof |
US8521761B2 (en) * | 2008-07-18 | 2013-08-27 | Google Inc. | Transliteration for query expansion |
WO2010111659A1 (en) | 2009-03-27 | 2010-09-30 | Wyeth Llc | Tumor-initiating cells and methods for using same |
CN103517719B (zh) * | 2011-04-01 | 2016-10-12 | 惠氏有限责任公司 | 抗体-药物缀合物 |
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