RU2021114500A - НАПРАВЛЕННОЕ ИНГИБИРОВАНИЕ TGFβ - Google Patents
НАПРАВЛЕННОЕ ИНГИБИРОВАНИЕ TGFβ Download PDFInfo
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- 102000004887 Transforming Growth Factor beta Human genes 0.000 title claims 3
- 108090001012 Transforming Growth Factor beta Proteins 0.000 title claims 3
- 230000005764 inhibitory process Effects 0.000 title 1
- 102000004169 proteins and genes Human genes 0.000 claims 21
- 108090000623 proteins and genes Proteins 0.000 claims 21
- 125000003275 alpha amino acid group Chemical group 0.000 claims 10
- 206010028980 Neoplasm Diseases 0.000 claims 7
- 238000000034 method Methods 0.000 claims 7
- 239000012634 fragment Substances 0.000 claims 6
- 229920001184 polypeptide Polymers 0.000 claims 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims 6
- 102000008096 B7-H1 Antigen Human genes 0.000 claims 5
- 108010074708 B7-H1 Antigen Proteins 0.000 claims 5
- 201000011510 cancer Diseases 0.000 claims 5
- 239000000427 antigen Substances 0.000 claims 4
- 102000036639 antigens Human genes 0.000 claims 4
- 108091007433 antigens Proteins 0.000 claims 4
- 210000004027 cell Anatomy 0.000 claims 4
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 claims 2
- 102000003839 Human Proteins Human genes 0.000 claims 2
- 108090000144 Human Proteins Proteins 0.000 claims 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims 2
- 102000048776 human CD274 Human genes 0.000 claims 2
- 102000039446 nucleic acids Human genes 0.000 claims 2
- 108020004707 nucleic acids Proteins 0.000 claims 2
- 150000007523 nucleic acids Chemical class 0.000 claims 2
- 239000002773 nucleotide Substances 0.000 claims 2
- 125000003729 nucleotide group Chemical group 0.000 claims 2
- 201000000849 skin cancer Diseases 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
- 208000008334 Dermatofibrosarcoma Diseases 0.000 claims 1
- 206010057070 Dermatofibrosarcoma protuberans Diseases 0.000 claims 1
- 206010018338 Glioma Diseases 0.000 claims 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 claims 1
- 206010025323 Lymphomas Diseases 0.000 claims 1
- 206010027406 Mesothelioma Diseases 0.000 claims 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims 1
- 206010052399 Neuroendocrine tumour Diseases 0.000 claims 1
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 1
- 206010039491 Sarcoma Diseases 0.000 claims 1
- 206010041067 Small cell lung cancer Diseases 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 210000000270 basal cell Anatomy 0.000 claims 1
- 229940127089 cytotoxic agent Drugs 0.000 claims 1
- 210000004696 endometrium Anatomy 0.000 claims 1
- 208000005017 glioblastoma Diseases 0.000 claims 1
- 238000003306 harvesting Methods 0.000 claims 1
- 201000010536 head and neck cancer Diseases 0.000 claims 1
- 208000014829 head and neck neoplasm Diseases 0.000 claims 1
- 102000048362 human PDCD1 Human genes 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 230000003993 interaction Effects 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- 208000032839 leukemia Diseases 0.000 claims 1
- 210000004185 liver Anatomy 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 201000000050 myeloid neoplasm Diseases 0.000 claims 1
- 210000001989 nasopharynx Anatomy 0.000 claims 1
- 208000016065 neuroendocrine neoplasm Diseases 0.000 claims 1
- 201000011519 neuroendocrine tumor Diseases 0.000 claims 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 1
- 230000002611 ovarian Effects 0.000 claims 1
- 210000000496 pancreas Anatomy 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 230000005855 radiation Effects 0.000 claims 1
- 208000000587 small cell lung carcinoma Diseases 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- 210000001550 testis Anatomy 0.000 claims 1
- 210000001685 thyroid gland Anatomy 0.000 claims 1
- 230000004614 tumor growth Effects 0.000 claims 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 1
- 210000003932 urinary bladder Anatomy 0.000 claims 1
- 210000004291 uterus Anatomy 0.000 claims 1
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Claims (36)
1. Белок, содержащий:
Первый полипептид, содержащий:
a) по меньшей мере вариабельную область тяжелой цепи антитела или его антигенсвязывающего фрагмента, которое связывает человеческий белок лиганд программируемой смерти 1 (PD-L1); и b) человеческий TGFβRII или его фрагмент, способный связывать TGFβ; и
второй полипептид, содержащий по меньшей мере вариабельную область легкой цепи антитела или его антигенсвязывающего фрагмента, которое связывает человеческий белок PD-L1,
где тяжелая цепь первого полипептида и легкая цепь второго полипептида формирует сайт связывания антигена, который PD-L1.
2. Белок по п. 1, дополнительно содержащий аминокислотный линкер, соединяющий C-конец тяжелой цепи с N-концом человеческого TGFβRII или его фрагмента.
3. Белок по любому из пп. 1 или 2, где человеческий TGFβRII содержит аминокислотную последовательность, имеющую по меньшей мере идентичность последовательности SEQ ID NO: 8 или SEQ ID NO: 9, которая имеет по меньшей мере 20 аминокислот в длину.
4. Белок по любому из пп. 1-3, где человеческий TGFβRII содержит аминокислотную последовательность SEQ ID NO: 10.
5. Белок по любому из пп. 1-4, где
(a) тяжелая цепь включает HVR-H1, HVR-H2 и HVR-H3, имеющие по меньшей мере 80идентичность всей последовательности с SYIMM, SIYPSGGITFYADTVKG и IKLGTVTTVDY, соответственно, и
(b) легкая цепь включает HVR-L1, HVR-L2 и HVR-L3, имеющие по меньшей мере 80% идентичность всей последовательности с TGTSSDVGGYNYVS, DVSNRPS и SSYTSSSTRV, соответственно.
6. Белок по любому из пп. 1-5, где
вариабельная область тяжелой цепи включает HVR-H1, HVR-H2 и HVR-H3, имеющие аминокислотные последовательности SYIMM, SIYPSGGITFYADTVKG и IKLGTVTTVDY, соответственно, и;
вариабельная область легкой цепи включает HVR-L1, HVR-L2 и HVR-L3, имеющие аминокислотные последовательности TGTSSDVGGYNYVS, DVSNRPS и SSYTSSSTRV, соответственно.
7. Белок по любому из пп. 1-6, где
(a) тяжелая цепь содержит аминокислотную последовательность, имеющую по меньшей мере 85% идентичность с последовательностью:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMVWRQAPGKGLEWVSSIYPSGGITFYADWKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSS, и
(b) легкая цепь содержит аминокислотную последовательность, имеющую по меньшей мере 85% идентичность с последовательностью:
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL.
8. Белок по любому из пп. 1-7, где
(a) тяжелая цепь содержит аминокислотную последовательность:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMVWRQAPGKGLEWVSSIYPSGGITFYADWKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSS, и
(b) легкая цепь содержит аминокислотную последовательность:
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL.
9. Белок по любому из пп. 1-8, где тяжелая цепь содержит аминокислотную последовательность, которая имеет по меньшей мере 80% идентичность с последовательностью SEQ ID NO: 3.
10. Белок по любому из пп. 1-9, где легкая цепь содержит аминокислотную последовательность, которая имеет по меньшей мере 80% идентичность с последовательностью SEQ ID NO: 1.
11. Нуклеиновая кислота, содержащая первую нуклеотидную последовательность, кодирующую первый полипептид, указанный в п. 1, и вторую нуклеотидную последовательность, кодирующую второй полипептид, указанный в п. 1.
12. Клетка, содержащая нуклеиновую кислоту по п. 11.
13. Способ получения белка, содержащего a) TGFβRII или его фрагмент, способный связывать TGFβ, и b) антитело или его антигенсвязывающий фрагмент, которое связывает человеческий белок лиганд программируемой смерти 1 (PD-L1), где способ включает поддержание клетки по п. 12 в условиях, обеспечивающих экспрессию белка, и необязательно включает сбор белка.
14. Фармацевтическая композиция, содержащая терапевтически эффективное количество белка по п. 1.
15. Белок по п. 1 для применения в:
(i) способе ингибирования роста опухоли у пациента, где способ включает воздействие на опухоль белком; или
(ii) способе лечения рака у пациента, где способ включает введение белка пациенту, страдающему раком.
16. Белок для применения по п. 15, где способ дополнительно включает воздействие на пациента, страдающего раком, излучением и/или введение химиотерапевтического средства.
17. Белок для применения по п. 15 или 16, где опухоль или рак выбран из группы, состоящей из колоректального рака, рака молочной железы, яичников, поджелудочной железы, желудка, простаты, почек, шейки матки, миеломы, лимфомы, лейкемии, рака щитовидной железы, эндометрия, матки, мочевого пузыря, нейроэндокринной опухоли, рака головы и шеи, печени, носоглотки, семенников, мелкоклеточного рака легких, немелкоклеточного рака легких, меланомы, базальноклеточного рака кожи, плоскоклеточного рака кожи, выбухающей дерматофибросаркомы, карциномы из клеток Меркеля, глиобластомы, глиомы, саркомы, мезотелиомы и миелодиспластических синдромов.
18. Белок по п.1, где белок блокирует взаимодействие между человеческим PD-L1 и человеческим PD-1 рецептором.
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