RU2020124105A - Антитела против трансферринового рецептора, обладающие индивидуализированной аффинностью - Google Patents
Антитела против трансферринового рецептора, обладающие индивидуализированной аффинностью Download PDFInfo
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- RU2020124105A RU2020124105A RU2020124105A RU2020124105A RU2020124105A RU 2020124105 A RU2020124105 A RU 2020124105A RU 2020124105 A RU2020124105 A RU 2020124105A RU 2020124105 A RU2020124105 A RU 2020124105A RU 2020124105 A RU2020124105 A RU 2020124105A
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- mutations
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- 230000035772 mutation Effects 0.000 claims 30
- 229920001184 polypeptide Polymers 0.000 claims 20
- 102000004196 processed proteins & peptides Human genes 0.000 claims 20
- 108090000765 processed proteins & peptides Proteins 0.000 claims 20
- 101000766306 Homo sapiens Serotransferrin Proteins 0.000 claims 8
- 102000007238 Transferrin Receptors Human genes 0.000 claims 8
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 claims 8
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 claims 3
- 239000000427 antigen Substances 0.000 claims 3
- 102000036639 antigens Human genes 0.000 claims 3
- 108091007433 antigens Proteins 0.000 claims 3
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 claims 2
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 claims 2
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 claims 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims 2
- 102000001301 EGF receptor Human genes 0.000 claims 2
- 108060006698 EGF receptor Proteins 0.000 claims 2
- 108010017544 Glucosylceramidase Proteins 0.000 claims 2
- 102000004547 Glucosylceramidase Human genes 0.000 claims 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims 2
- 108090000185 alpha-Synuclein Proteins 0.000 claims 2
- 102000003802 alpha-Synuclein Human genes 0.000 claims 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 claims 2
- 210000004556 brain Anatomy 0.000 claims 2
- 230000001225 therapeutic effect Effects 0.000 claims 2
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- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
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Claims (44)
1. Мультиспецифичное гуманизированное антитело, имеющее
по меньшей мере одну специфичность связывания в отношении человеческого трансферринового рецептора, представляющее собой гуманизированное антитело, которое специфично связывается с человеческим трансферриновым рецептором, где указанное антитело содержит HVR (гипервариабельную область) SEQ ID NO 66, 68 и 72 в вариабельном домене тяжелой цепи и HVR SEQ ID NO 75, 76 и 78 в вариабельном домене легкой цепи, и
по меньшей мере одну специфичность связывания в отношении терапевтической мишени.
2. Антитело по п. 1, где указанная по меньшей мере одна специфичность связывания в отношении терапевтической мишени содержит антигенсвязывающий сайт, который связывается с мозговым антигеном.
3. Антитело по п. 2, где мозговой антиген выбран из группы, состоящей из Абета, рецептора эпидермального фактора роста (EGFR), рецептора 2 человеческого эпидермального фактора роста (HER2), альфа-синуклеина, CD20, белка-предшественника амилоида (АРР), фосфо-тау и глюкоцереброзидазы.
4. Антитело по любому из пп. 1-3, где оно связывается с обоими
i) человеческим трансферриновым рецептором и Абета, или
ii) человеческим трансферриновым рецептором и СD20, или
iii) человеческим трансферриновым рецептором и альфа-синуклеином, или
iv) человеческим трансферриновым рецептором и фосфо-тау, или
v) человеческим трансферриновым рецептором и глюкоцереброзидазой.
5. Антитело по любому из пп. 1-4, которое представляет собой биспецифичное антитело, содержащее
i) гуманизированное антитело, которое специфично связывается с человеческим трансферриновым рецептором, содержащим вариабельный домен тяжелой цепи SEQ ID NO 24 и вариабельный домен легкой цепи SEQ ID NO 37, и
ii) второй сайт связывания, выбранный из
а) вариабельного домена тяжелой цепи SEQ ID NO 81 и вариабельного домена легкой цепи SEQ ID NO 82, или
б) вариабельного домена тяжелой цепи SEQ ID NO 83 и вариабельного домена легкой цепи SEQ ID NO 84, или
в) вариабельного домена тяжелой цепи SEQ ID NO 85 и вариабельного домена легкой цепи SEQ ID NO 86, или
г) вариабельного домена тяжелой цепи SEQ ID NO 87 и вариабельного домена легкой цепи SEQ ID NO 88, или
д) вариабельного домена тяжелой цепи SEQ ID NO 91 и вариабельного домена легкой цепи SEQ ID NO 92, или
е) вариабельного домена тяжелой цепи SEQ ID NO 89 и вариабельного домена легкой цепи SEQ ID NO 90, или
ж) вариабельного домена тяжелой цепи SEQ ID NO 93 и вариабельного домена легкой цепи SEQ ID NO 94, или
з) вариабельного домена тяжелой цепи SEQ ID NO 79 и вариабельного домена легкой цепи SEQ ID NO 80.
6. Антитело по любому из пп. 1-5, которое представляет собой
а) полноразмерное антитело человеческого подкласса IgG1, или
б) полноразмерное антитело человеческого подкласса IgG4, или
в) полноразмерное антитело человеческого подкласса IgG1 с мутациями L234A, L235A и P329G,
г) полноразмерное антитело человеческого подкласса IgG4 с мутациями S228P, L235E и, возможно, P329G,
д) полноразмерное антитело человеческого подкласса IgG1 с мутациями L234A, L235A и P329G в обеих тяжелых цепях, и с мутациями T366W и S354C в одной тяжелой цепи и мутациями T366S, L368A, Y407V и Y349C в соответствующей другой тяжелой цепи, или
е) полноразмерное антитело человеческого подкласса IgG4 с мутациями S228P, L235E и, возможно, P329G в обеих тяжелых цепях, и с мутациями T366W и S354C в одной тяжелой цепи и мутациями T366S, L368A, Y407V и Y349C в соответствующей другой тяжелой цепи.
7. Антитело по любому из пп. 1-5, содержащее
i) гомодимерную область Fc человеческого подкласса IgG1, возможно с мутациями P329G, L234A и L235A; или
ii) гомодимерную область Fc человеческого подкласса IgG4, возможно с мутациями P329G, S228P и L235E; или
iii) гетеродимерную область Fc, в которой
а) один полипептид области Fc содержит мутацию T366W, и другой полипептид области Fc содержит мутации T366S, L368A и Y407V, или
б) один полипептид области Fc содержит мутации T366W и Y349C, и другой полипептид области Fc содержит мутации T366S, L368A, Y407V и S354C, или
в) один полипептид области Fc содержит мутации T366W и S354C, и другой полипептид области Fc содержит мутации T366S, L368A, Y407V и Y349C;
или iv) гетеродимерную область Fc человеческого подкласса IgG4, в которой оба полипептида области Fc содержат мутации P329G, L234A и L235A, и
а) один полипептид области Fc содержит мутацию T366W, и другой полипептид области Fc содержит мутации T366S, L368A и Y407V, или
б) один полипептид области Fc содержит мутации T366W и Y349C, и другой полипептид области Fc содержит мутации T366S, L368A, Y407V и S354C, или
в) один полипептид области Fc содержит мутации T366W и S354C, и другой полипептид области Fc содержит мутации T366S, L368A, Y407V и Y349C;
или v) гетеродимерную область Fc человеческого подкласса IgG4, в которой оба полипептида области Fc содержат мутации P329G, S228P и L235E, и
а) один полипептид области Fc содержит мутацию T366W, и другой полипептид области Fc содержит мутации T366S, L368A и Y407V, или
б) один полипептид области Fc содержит мутации T366W и Y349C, и другой полипептид области Fc содержит мутации T366S, L368A, Y407V и S354C, или
в) один полипептид области Fc содержит мутации T366W и S354C, и другой полипептид области Fc содержит мутации T366S, L368A, Y407V и Y349C.
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