RU2013141976A - Новые модуляторы и способы их применения - Google Patents
Новые модуляторы и способы их применения Download PDFInfo
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- RU2013141976A RU2013141976A RU2013141976/10A RU2013141976A RU2013141976A RU 2013141976 A RU2013141976 A RU 2013141976A RU 2013141976/10 A RU2013141976/10 A RU 2013141976/10A RU 2013141976 A RU2013141976 A RU 2013141976A RU 2013141976 A RU2013141976 A RU 2013141976A
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- 102000001708 Protein Isoforms Human genes 0.000 claims abstract 10
- 108010029485 Protein Isoforms Proteins 0.000 claims abstract 10
- 101710099452 Inactive tyrosine-protein kinase 7 Proteins 0.000 claims abstract 5
- 102100039813 Inactive tyrosine-protein kinase 7 Human genes 0.000 claims abstract 5
- 101000606465 Homo sapiens Inactive tyrosine-protein kinase 7 Proteins 0.000 claims abstract 4
- 239000012634 fragment Substances 0.000 claims abstract 4
- 102000049511 human PTK7 Human genes 0.000 claims abstract 4
- 230000000779 depleting effect Effects 0.000 claims abstract 2
- 230000002401 inhibitory effect Effects 0.000 claims abstract 2
- 230000003472 neutralizing effect Effects 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims 7
- 210000005102 tumor initiating cell Anatomy 0.000 claims 5
- 125000003275 alpha amino acid group Chemical group 0.000 claims 4
- 210000004027 cell Anatomy 0.000 claims 4
- 150000007523 nucleic acids Chemical class 0.000 claims 4
- 206010028980 Neoplasm Diseases 0.000 claims 3
- 201000011510 cancer Diseases 0.000 claims 3
- 229940127089 cytotoxic agent Drugs 0.000 claims 3
- 239000002254 cytotoxic agent Substances 0.000 claims 3
- 231100000599 cytotoxic agent Toxicity 0.000 claims 3
- 229940127121 immunoconjugate Drugs 0.000 claims 3
- 102000039446 nucleic acids Human genes 0.000 claims 3
- 108020004707 nucleic acids Proteins 0.000 claims 3
- 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 208000000453 Skin Neoplasms Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 238000012544 monitoring process Methods 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
- 201000000849 skin cancer Diseases 0.000 claims 1
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- 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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Abstract
1. Выделенное антитело, которое специфически связывается с PTK7 (протеинтирозинкиназа 7) человека и конкурирует за связывание с PTK7 человека с антителом, содержащим:а) вариабельную область легкой цепи, представленную в SEQ ID NO: 48, и вариабельную область тяжелой цепи, представленную в SEQ ID NO: 49; илиб) вариабельную область легкой цепи, представленную в SEQ ID NO: 50, и вариабельную область тяжелой цепи, представленную в SEQ ID NO: 51.2. Антитело по п. 1, ингибирующее связывание контрольного антитела по меньшей мере на примерно 40%.3. Антитело по п. 1, представляющее собой нейтрализирующее, истощающее и/или интернализованное антитело.4. Антитело по п. 1, которое специфически связывается с изоформой PTK7, выбранной из группы, состоящей из изоформы a, изоформы b, изоформы с и изоформы d.5. Антитело по п. 1, представляющее собой моноклональное, химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело, или его фрагмент.6. Антитело по п. 1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область тяжелой цепи содержит три CDR, представленные как остатки 26-35 из SEQ ID NO: 49, остатки 53-59 из SEQ ID NO: 49 и остатки 98-120 из SEQ ID NO: 49.7. Антитело по п. 1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область легкой цепи содержит три CDR, представленные как остатки 24-32 из SEQ ID NO: 48, остатки 50-56 из SEQ ID NO: 48 и остатки 89-107 из SEQ ID NO: 48.8. Антитело по п. 1, содержащееа) вариабельную область тяжелой цепи, содержащую три CDR, представленные как остатки 26-35
Claims (28)
1. Выделенное антитело, которое специфически связывается с PTK7 (протеинтирозинкиназа 7) человека и конкурирует за связывание с PTK7 человека с антителом, содержащим:
а) вариабельную область легкой цепи, представленную в SEQ ID NO: 48, и вариабельную область тяжелой цепи, представленную в SEQ ID NO: 49; или
б) вариабельную область легкой цепи, представленную в SEQ ID NO: 50, и вариабельную область тяжелой цепи, представленную в SEQ ID NO: 51.
2. Антитело по п. 1, ингибирующее связывание контрольного антитела по меньшей мере на примерно 40%.
3. Антитело по п. 1, представляющее собой нейтрализирующее, истощающее и/или интернализованное антитело.
4. Антитело по п. 1, которое специфически связывается с изоформой PTK7, выбранной из группы, состоящей из изоформы a, изоформы b, изоформы с и изоформы d.
5. Антитело по п. 1, представляющее собой моноклональное, химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело, или его фрагмент.
6. Антитело по п. 1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область тяжелой цепи содержит три CDR, представленные как остатки 26-35 из SEQ ID NO: 49, остатки 53-59 из SEQ ID NO: 49 и остатки 98-120 из SEQ ID NO: 49.
7. Антитело по п. 1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область легкой цепи содержит три CDR, представленные как остатки 24-32 из SEQ ID NO: 48, остатки 50-56 из SEQ ID NO: 48 и остатки 89-107 из SEQ ID NO: 48.
8. Антитело по п. 1, содержащее
а) вариабельную область тяжелой цепи, содержащую три CDR, представленные как остатки 26-35 из SEQ ID NO: 49, остатки 53-59 из SEQ ID NO: 49 и остатки 98-120 из SEQ ID NO: 49; и
б) вариабельную область легкой цепи, содержащую три CDR, представленные как остатки 24-32 из SEQ ID NO: 48, остатки 50-56 из SEQ ID NO: 48 и остатки 89-107 из SEQ ID NO: 48.
9. Антитело по п. 1, содержащее вариабельную область тяжелой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO: 63, и вариабельную область легкой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO: 62.
10. Антитело по п. 9, содержащее вариабельную область тяжелой цепи, представленную в SEQ ID NO: 63, и вариабельную область легкой цепи, представленную в SEQ ID NO: 62.
11. Антитело по п. 1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область тяжелой цепи содержит три CDR, представленные как остатки 26-33 из SEQ ID NO: 51, остатки 51-58 из SEQ ID NO: 51 и остатки 97-119 из SEQ ID NO: 51.
12. Антитело по п. 1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область легкой цепи содержит три CDR, представленные как остатки 24-36 из SEQ ID NO: 50, остатки 54-60 из SEQ ID NO: 50 и остатки 93-111 из SEQ ID NO: 50.
13. Антитело по п.1, содержащее
а) вариабельную область тяжелой цепи, содержащую три CDR, представленные как остатки 26-33 из SEQ ID NO: 51, остатки 51-58 из SEQ ID NO: 51 и остатки 97-119 из SEQ ID NO: 51; и
б) вариабельную область легкой цепи, содержащую три CDR, представленные как остатки 24-36 из SEQ ID NO: 50, остатки 54-60 из SEQ ID NO: 50 и остатки 93-111 из SEQ ID NO: 50.
14. Антитело по п. 1, содержащее вариабельную область тяжелой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO: 65, и вариабельную область легкой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO: 64.
15. Антитело по п. 14, содержащее вариабельную область тяжелой цепи, представленную в SEQ ID NO: 65, и вариабельную область легкой цепи, представленную в SEQ ID NO: 64.
16. Антитело по п. 1, содержащее вариабельную область тяжелой цепи, представленную в SEQ ID NO: 49, 51, 63 или 65, и/или вариабельную область легкой цепи, представленную в SEQ ID NO: 48, 50, 62 или 64.
17. Антитело по п. 1, содержащее
а) вариабельную область тяжелой цепи, представленную как SEQ ID NO: 49 или 63, и вариабельную область легкой цепи, представленную как SEQ ID NO: 48 или 62; или
б) вариабельную область тяжелой цепи, представленную как SEQ ID NO: 51 или 65, и вариабельную область легкой цепи, представленную как SEQ ID NO: 50 или 64.
18. Конъюгат антитела, содержащий химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело или его фрагмент, которое(ый) специфически связывается с PTK7, причем это антитело конъюгировано, связано или иным образом ассоциировано с цитотоксическим агентом, и где это химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело или его фрагмент возможно представляет собой антитело по любому из пп. 1-17.
19. Фармацевтическая композиция, содержащая антитело по любому из пп. 1-17 или конъюгат антитела по п. 18.
20. Нуклеиновая кислота, кодирующая вариабельную область тяжелой цепи, представленную в SEQ ID NO: 49, 51, 63 или 65, и/или вариабельную область легкой цепи, представленную в SEQ ID NO: 48, 50, 62 или 64.
21. Вектор или клетка-хозяин, содержащий(ая) нуклеиновую кислоту по п. 20.
22. Клетка-хозяин, содержащая нуклеиновую кислоту по п. 20.
23. Способ лечения рака у субъекта, включающий введение этому субъекту терапевтически эффективной дозы конъюгата антитела, содержащего анти-PTK7 антитело, конъюгированное, связанное или иным образом ассоциированное с цитотоксическим агентом.
24 Способ обнаружения, диагностики или мониторинга рака у субъекта, включающий стадии:
(а) приведения клеток субъекта в контакт с анти-PTK7 антителом; и
(б) обнаружения анти-PTK7 антитела на опухоль-инициирующих клетках.
25. Способ по п. 23 или 24, где рак представляет собой рак молочной железы, рак яичников, колоректальный рак, рак поджелудочной железы, рак легкого или рак кожи.
26. Способ снижения частоты появления опухоль-инициирующих клеток у субъекта, включающий введение этому субъекту конъюгата анти-PTK7 антитела, содержащего анти-РТК7 антитело, конъюгированное, связанное или иным образом ассоциированное с цитотоксическим агентом, в количестве, эффективном для снижения частоты появления опухоль-инициирующих клеток у субъекта.
27. Способ идентификации, выделения или обогащения популяции опухоль-инициирующих клеток, включающий стадии (а) приведения клеток в контакт с анти-PTK7 антителом; и (б) селекции опухоль-инициирующих клеток, с которыми связано анти-PTK7 антитело.
28. Способ по любому из пп. 23, 24, 26 и 27, где анти-PTK7 антитело содержит антитело по любому из пп. 1-17.
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