RU2014110927A - Иммуноглобулин с двойными вариабельными доменами и его применения - Google Patents
Иммуноглобулин с двойными вариабельными доменами и его применения Download PDFInfo
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Abstract
1. Связывающий белок, содержащий первую и вторую полипептидные цепи, где указанная первая полипептидная цепь содержит VD1-(X1)n-VD2-C-(X2)n, где VD1 представляет собой первый вариабельный домен тяжелой цепи, VD2 представляет собой второй вариабельный домен тяжелой цепи, C представляет собой константный домен тяжелой цепи, X1 представляет собой линкер, при условии, что он не является CH1, и X2 представляет собой Fc-область; и указанная вторая полипептидная цепь содержит VD1-(X1)n-VD2-C-(X2)n, где VD1 представляет собой первый вариабельный домен легкой цепи, VD2 представляет собой второй вариабельный домен легкой цепи, C представляет собой константный домен легкой цепи, X1 представляет собой линкер, при условии, что он не является CH1, и X2 не содержит Fc-область.2. Связывающий белок по п. 1, где связывающий белок способен связывать одну или несколько мишеней.3. Связывающий белок по п. 2, где указанная одна или несколько мишеней выбрана из группы, состоящей из ABCF1; ACVR1; ACVR1B; ACVR2; ACVR2B; ACVRL1; ADORA2A; Aггрекана; AGR2; AICDA; AIF1; AIG1; AKAP1; AKAP2; AMH; AMHR2; ANGPT1; ANGPT2; ANGPTL3; ANGPTL4; ANPEP; APC; APOC1; AR; AZGP1 (цинк-a-гликопротеина); B7.1; B7.2; BAD; BAFF; BAG1; BAI1; BCL2; BCL6; BDNF; BLNK; BLR1 (MDR15); BlyS; BMP1; BMP2; BMP3B (GDF10); BMP4; BMP6; BMP8; BMPR1A; BMPR1B; BMPR2; BPAG1 (плектина); BRCA1; C19orf10 (IL27w); C3; C4A; C5; C5R1; CANT1; CASP1; CASP4; CAV1; CCBP2 (D6/JAB61); CCL1 (I-309); CCL11 (эотаксина); CCL13 (MCP-4); CCL15 (MIP-1d); CCL16 (HCC-4); CCL17 (TARC); CCL18 (PARC); CCL19(MIP-3b); CCL2 (MCP-1); MCAF; CCL20 (MIP-3a); CCL21 (MIP-2); SLC; эксодуса-2; CCL22 (MDC/STC-1); CCL23 (MPIF-1); CCL24 (MPIF-2/эотаксина-2); CCL25 (TECK); CCL26 (эотаксина-3); CCL27 (CTACK/ILC); CCL28; CCL3 (MIP-1a); CCL4 (MIP-1b); CCL5 (RANTES); CCL7 (MCP-3); CCL8 (mcp-2); CCNA1; CCNA2; CCND1; CCNE1; CCNE2; CCR1 (CKR1/HM145); CCR2 (mcp-1RB/RA);CCR3 (CKR3/CMKBR3); CCR4; CCR5 (CMKBR5/ChemR13); CCR6 (CMKBR6/CKR-L3/STRL22/DRY6); CCR7 (CKR7/EBI1); CCR8 (CMKBR8/TER1/CKR-L1); CCR9 (GPR-9-6); CCRL1 (VSHK1); CCRL2 (L-CCR); CD164; CD19; CD1C; CD20; CD200; CD-22; CD24; CD28; CD3; CD37; CD38; CD3E; CD3G; CD3Z; CD4; CD40; CD40L; CD44; CD45RB; CD52; CD69; CD72; C
Claims (54)
1. Связывающий белок, содержащий первую и вторую полипептидные цепи, где указанная первая полипептидная цепь содержит VD1-(X1)n-VD2-C-(X2)n, где VD1 представляет собой первый вариабельный домен тяжелой цепи, VD2 представляет собой второй вариабельный домен тяжелой цепи, C представляет собой константный домен тяжелой цепи, X1 представляет собой линкер, при условии, что он не является CH1, и X2 представляет собой Fc-область; и указанная вторая полипептидная цепь содержит VD1-(X1)n-VD2-C-(X2)n, где VD1 представляет собой первый вариабельный домен легкой цепи, VD2 представляет собой второй вариабельный домен легкой цепи, C представляет собой константный домен легкой цепи, X1 представляет собой линкер, при условии, что он не является CH1, и X2 не содержит Fc-область.
2. Связывающий белок по п. 1, где связывающий белок способен связывать одну или несколько мишеней.
3. Связывающий белок по п. 2, где указанная одна или несколько мишеней выбрана из группы, состоящей из ABCF1; ACVR1; ACVR1B; ACVR2; ACVR2B; ACVRL1; ADORA2A; Aггрекана; AGR2; AICDA; AIF1; AIG1; AKAP1; AKAP2; AMH; AMHR2; ANGPT1; ANGPT2; ANGPTL3; ANGPTL4; ANPEP; APC; APOC1; AR; AZGP1 (цинк-a-гликопротеина); B7.1; B7.2; BAD; BAFF; BAG1; BAI1; BCL2; BCL6; BDNF; BLNK; BLR1 (MDR15); BlyS; BMP1; BMP2; BMP3B (GDF10); BMP4; BMP6; BMP8; BMPR1A; BMPR1B; BMPR2; BPAG1 (плектина); BRCA1; C19orf10 (IL27w); C3; C4A; C5; C5R1; CANT1; CASP1; CASP4; CAV1; CCBP2 (D6/JAB61); CCL1 (I-309); CCL11 (эотаксина); CCL13 (MCP-4); CCL15 (MIP-1d); CCL16 (HCC-4); CCL17 (TARC); CCL18 (PARC); CCL19
(MIP-3b); CCL2 (MCP-1); MCAF; CCL20 (MIP-3a); CCL21 (MIP-2); SLC; эксодуса-2; CCL22 (MDC/STC-1); CCL23 (MPIF-1); CCL24 (MPIF-2/эотаксина-2); CCL25 (TECK); CCL26 (эотаксина-3); CCL27 (CTACK/ILC); CCL28; CCL3 (MIP-1a); CCL4 (MIP-1b); CCL5 (RANTES); CCL7 (MCP-3); CCL8 (mcp-2); CCNA1; CCNA2; CCND1; CCNE1; CCNE2; CCR1 (CKR1/HM145); CCR2 (mcp-1RB/RA);CCR3 (CKR3/CMKBR3); CCR4; CCR5 (CMKBR5/ChemR13); CCR6 (CMKBR6/CKR-L3/STRL22/DRY6); CCR7 (CKR7/EBI1); CCR8 (CMKBR8/TER1/CKR-L1); CCR9 (GPR-9-6); CCRL1 (VSHK1); CCRL2 (L-CCR); CD164; CD19; CD1C; CD20; CD200; CD-22; CD24; CD28; CD3; CD37; CD38; CD3E; CD3G; CD3Z; CD4; CD40; CD40L; CD44; CD45RB; CD52; CD69; CD72; CD74; CD79A; CD79B; CD8; CD80; CD81; CD83; CD86; CDH1 (E-кадгерина); CDH10; CDH12; CDH13; CDH18; CDH19; CDH20; CDH5; CDH7; CDH8; CDH9; CDK2; CDK3; CDK4; CDK5; CDK6; CDK7; CDK9; CDKN1A (p21Wap1/Cip1); CDKN1B (p27Kip1); CDKN1C; CDKN2A (p16INK4a); CDKN2B; CDKN2C; CDKN3; CEBPB; CER1; CHGA; CHGB; хитиназы; CHST10; CKLFSF2; CKLFSF3; CKLFSF4; CKLFSF5; CKLFSF6; CKLFSF7; CKLFSF8; CLDN3; CLDN7 (клаудина-7); CLN3; CLU (кластерина); CMKLR1; CMKOR1 (RDC1); CNR1; COL18A1; COL1A1; COL4A3; COL6A1; CR2; CRP; CSF1 (M-CSF); CSF2 (GM-CSF); CSF3 (GCSF); CTLA4; CTNNB1 (b-катенина); CTSB (катепсина B); CX3CL1 (SCYD1); CX3CR1 (V28); CXCL1 (GRO1); CXCL10 (IP-10); CXCL11 (I-TAC/IP-9); CXCL12 (SDF1); CXCL13; CXCL14; CXCL16; CXCL2 (GRO2); CXCL3 (GRO3); CXCL5 (ENA-78/LIX); CXCL6 (GCP-2); CXCL9 (MIG); CXCR3 (GPR9/CKR-L2); CXCR4; CXCR6 (TYMSTR /STRL33/Bonzo); CYB5; CYC1; CYSLTR1; DAB2IP; DES; DKFZp451J0118; DNCL1; DPP4; E2F1; ECGF1; EDG1; EFNA1; EFNA3; EFNB2; EGF; EGFR; ELAC2; ENG; ENO1; ENO2; ENO3; EPHB4; EPO; ERBB2 (Her-2); EREG;
ERK8; ESR1; ESR2; F3 (TF); FADD; FasL; FASN; FCER1A; FCER2; FCGR3A; FGF; FGF1 (aFGF); FGF10; FGF11; FGF12; FGF12B; FGF13; FGF14; FGF16; FGF17; FGF18; FGF19; FGF2 (bFGF); FGF20; FGF21; FGF22; FGF23; FGF3 (int-2); FGF4 (HST); FGF5; FGF6 (HST-2); FGF7 (KGF); FGF8; FGF9; FGFR3; FIGF (VEGFD); FIL1 (EPSILON); FIL1 (ZETA); FLJ12584; FLJ25530; FLRT1 (фибронектина); FLT1; FOS; FOSL1 (FRA-1); FY (DARC); GABRP (GABAa); GAGEB1; GAGEC1; GALNAC4S-6ST; GATA3; GDF5; GFI1; GGT1; GM-CSF; GNAS1; GNRH1; GPR2 (CCR10); GPR31; GPR44; GPR81 (FKSG80); GRCC10 (C10); GRP; GSN (гелсолина); GSTP1; HAVCR2; HDAC4; HDAC5; HDAC7A; HDAC9; HGF; HIF1A; HIP1; гистамина и рецепторов гистамина; HLA-A; HLA-DRA; HM74; HMOX1; HUMCYT2A; ICEBERG; ICOSL; ID2; IFN-a; IFNA1; IFNA2; IFNA4; IFNA5; IFNA6; IFNA7; IFNB1; IFNгамма; IFNW1; IGBP1; IGF1; IGF1R; IGF2; IGFBP2; IGFBP3; IGFBP6; IL-1; IL10; IL10RA; IL10RB; IL11; IL11RA; IL-12; IL12A; IL12B; IL12RB1; IL12RB2; IL13; IL13RA1; IL13RA2; IL14; IL15; IL15RA; IL16; IL17; IL17B; IL17C; IL17R; IL18; IL18BP; IL18R1; IL18RAP; IL19; IL1A; IL1B; IL1F10; IL1F5; IL1F6; IL1F7; IL1F8; IL1F9; IL1HY1; IL1R1; IL1R2; IL1RAP; IL1RAPL1; IL1RAPL2;IL1RL1;IL1RL2 IL1RN; IL2; IL20; IL20RA; IL21R; IL22; IL22R; IL22RA2; IL23; IL24; IL25; IL26; IL27; IL28A; IL28B; IL29; IL2RA; IL2RB; IL2RG; IL3; IL30; IL3RA; IL4; IL4R; IL5; IL5RA; IL6; IL6R; IL6ST (гликопротеина 130); IL7; IL7R; IL8; IL8RA; IL8RB; IL8RB; IL9; IL9R; ILK; INHA; INHBA; INSL3; INSL4; IRAK1; IRAK2; ITGA1; ITGA2; ITGA3; ITGA6 (a6 интегрина); ITGAV; ITGB3; ITGB4 (b4 интегрина); JAG1; JAK1; JAK3; JUN; K6HF; KAI1; KDR; KITLG; KLF5 (GC блока BP); KLF6; KLK10; KLK12; KLK13; KLK14; KLK15; KLK3; KLK4; KLK5; KLK6; KLK9;
KRT1; KRT19 (кератина 19); KRT2A; KRTHB6 (специфического для волос кератина типа II); LAMA5; LEP (лептина); Lingo-p75; Lingo-Troy; LPS; LTA (TNF-b); LTB; LTB4R (GPR16); LTB4R2; LTBR; MACMARCKS; MAG или Omgp; MAP2K7 (c-Jun); MDK; MIB1; мидкина; MIF; MIP-2; MKI67 (Ki-67); MMP2; MMP9; MS4A1; MSMB; MT3 (металлотионектина-III); MTSS1; MUC1 (муцина); MYC; MYD88; NCK2; нейрокана; NFKB1; NFKB2; NGFB (NGF); NGFR; NgR-Lingo; NgR-Nogo66 (Nogo); NgR-p75; NgR-Troy; NME1 (NM23A); NOX5; NPPB; NR0B1; NR0B2; NR1D1; NR1D2; NR1H2; NR1H3; NR1H4; NR1I2; NR1I3; NR2C1; NR2C2; NR2E1; NR2E3; NR2F1; NR2F2; NR2F6; NR3C1; NR3C2; NR4A1; NR4A2; NR4A3; NR5A1; NR5A2; NR6A1; NRP1; NRP2; NT5E; NTN4; ODZ1; OPRD1; P2RX7; PAP; PART1; PATE; PAWR; PCA3; PCNA; PDGFA; PDGFB; PECAM1; PF4 (CXCL4); PGF; PGR; фосфакана; PIAS2; PIK3CG; PLAU (uPA); PLG; PLXDC1; PPBP (CXCL7); PPID; PR1; PRKCQ; PRKD1; PRL; PROC; PROK2; PSAP; PSCA; PTAFR; PTEN; PTGS2 (COX-2); PTN; RAC2 (p21Rac2); RARB; RGS1; RGS13; RGS3; RNF110 (ZNF144); ROBO2; S100A2; SCGB1D2 (липофилина B); SCGB2A1 (маммаглобина 2); SCGB2A2 (маммаглобина 1); SCYE1 (эндотелиального активирующего моноциты цитокина); SDF2; SERPINA1; SERPINA3; SERPINB5 (маспина); SERPINE1 (PAI-1); SERPINF1; SHBG; SLA2; SLC2A2; SLC33A1; SLC43A1; SLIT2; SPP1; SPRR1B (Spr1); ST6GAL1; STAB1; STAT6; STEAP; STEAP2; TB4R2; TBX21; TCP10; TDGF1; TEK; TGFA; TGFB1; TGFB1I1; TGFB2; TGFB3; TGFBI; TGFBR1; TGFBR2; TGFBR3; TH1L; THBS1 (тромбоспондина-1); THBS2; THBS4; THPO; TIE (Tie-1); TIMP3; тканевого фактора; TLR10; TLR2; TLR3; TLR4; TLR5; TLR6; TLR7; TLR8; TLR9; TNF; TNF-a; TNFAIP2 (B94); TNFAIP3; TNFRSF11A; TNFRSF1A; TNFRSF1B; TNFRSF21; TNFRSF5; TNFRSF6 (Fas); TNFRSF7;
TNFRSF8; TNFRSF9; TNFSF10 (TRAIL); TNFSF11 (TRANCE); TNFSF12 (APO3L); TNFSF13 (April); TNFSF13B; TNFSF14 (HVEM-L); TNFSF15 (VEGI); TNFSF18; TNFSF4 (OX40-лиганда); TNFSF5 (CD40-лиганда); TNFSF6 (FasL); TNFSF7 (CD27-лиганда); TNFSF8 (CD30-лиганда); TNFSF9 (4-1BB-лиганда); TOLLIP; Toll-подобных рецепторов; TOP2A (топоизомеразы Iia); TP53; TPM1; TPM2; TRADD; TRAF1; TRAF2; TRAF3; TRAF4; TRAF5; TRAF6; TREM1; TREM2; TRPC6; TSLP; TWEAK; VEGF; VEGFB; VEGFC; версикана; VHL C5; VLA-4; XCL1 (лимфотактина); XCL2 (SCM-1b); XCR1 (GPR5/CCXCR1); YY1 и ZFPM2.
4. Связывающий белок по п. 1, где связывающий белок способен связываться с двумя мишенями, где указанные две мишени выбраны из группы, состоящей из CD138 и CD20; CD138 и CD40; CD20 и CD3; CD38 и CD138; CD38 и CD20; CD38 и CD40; CD40 и CD20; CD19 и CD20; CD-8 и IL-6; PDL-1 и CTLA-4; CTLA-4 и BTNO2; CSPGs и RGM A; IGF1 и IGF2; IGF1/2 и Erb2B; IL-12 и IL-18; IL-12 и TWEAK; IL-13 и ADAM8; IL-13 и CL25; IL-13 и IL-1бета; IL-13 и IL-25; IL-13 и IL-4; IL-13 и IL-5; IL-13 и IL-9; IL-13 и агониста LHR; IL-13 и MDC; IL-13 и MIF; IL-13 и PED2; IL-13 и SPRR2a; IL-13 и SPRR2b; IL-13 и TARC; IL-13 и TGF-β; IL-1α и IL-1β; MAG и RGM A; NgR и RGM A; NogoA и RGM A; OMGp и RGM A; RGM A и RGM B; Te38 и TNFα; TNFα и IL-12; TNFα и IL-12p40; TNFα и IL-13; TNFα и IL-15; TNFα и IL-17; TNFα и IL-18; TNFα и IL-1бета; TNFα и IL-23; TNFα и MIF; TNFα и PEG2; TNFα и PGE4; TNFα и VEGF; и VEGFR и EGFR; TNFα и RANK-лиганд; TNFα и Blys; TNFα и GP130; TNFα и CD-22; и TNFα и CTLA-4.
5. Связывающий белок по любому из пп. 1-4, где связывающий
белок способен модулировать биологическую функцию одной или нескольких мишеней.
6. Связывающий белок по любому из пп. 1-4, где связывающий белок способен нейтрализовать одну или несколько мишеней.
7. Связывающий белок по любому из пп. 1-4, где связывающий белок связывается с одной или несколькими мишенями, где одна или несколько мишеней выбрана из группы, состоящей из цитокинов, хемокинов, белков клеточной поверхности, ферментов и рецепторов.
8. Связывающий белок по п. 7, где цитокины выбраны из группы, состоящей из лимфокинов, монокинов и полипептидных гормонов.
9. Связывающий белок по п. 7, где связывающий белок связывается с цитокинами IL-1α and IL-1β.
10. Связывающий белок по п. 9, где связывающий белок содержит аминокислотную последовательность тяжелой цепи DVD, выбранную из группы, состоящей из SEQ ID NO:33, SEQ ID NO:37, SEQ ID NO:41, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57 и SEQ ID NO:59; и аминокислотную последовательность легкой цепи DVD, выбранную из группы, состоящей из SEQ ID NO:35, SEQ ID NO:39, SEQ ID NO:43, SEQ ID NO:46, SEQ ID NO:49, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58 и SEQ ID NO:60.
11. Связывающий белок по п. 7, где связывающий белок связывается с цитокинами TNF-α и IL-13.
12. Связывающий белок по п. 7, где связывающий белок связывается с цитокинами IL-12 и IL-18.
13. Связывающий белок по п. 12, где связывающий белок
содержит аминокислотную последовательность тяжелой цепи DVD, выбранную из группы, состоящей из SEQ ID NO:83, SEQ ID NO:90, SEQ ID NO:93, SEQ ID NO:95 и SEQ ID NO:114; и аминокислотную последовательность легкой цепи DVD, выбранную из группы, состоящей из SEQ ID NO:86, SEQ ID NO:91, SEQ ID NO:94, SEQ ID NO:46, SEQ ID NO:96 и SEQ ID NO:116.
14. Связывающий белок по п. 7, где хемокин выбран из группы, состоящей из CCR2, CCR5 и CXCL-13.
15. Связывающий белок по п. 7, где белок клеточной поверхности является интегрином.
16. Связывающий белок по п. 7, где белками клеточной поверхности являются CD-20 и CD3.
17. Связывающий белок по п. 16, где связывающий белок содержит аминокислотную последовательность тяжелой цепи DVD SEQ ID NO:97 и легкой цепи DVD SEQ ID NO:101.
18. Связывающий белок по п. 7, где фермент выбран из группы, состоящей из киназы и протеазы.
19. Связывающий белок по п. 7, где рецепторы выбран из группы, состоящей из рецепторов лимфокина, рецептора монокина и рецепторов полипептидного гормона.
20. Связывающий белок по п. 7, где связывающий белок имеет константу скорости ассоциации (Kon) в отношении указанных одной или нескольких мишеней, выбранную из группы, состоящей из: по меньшей мере приблизительно 102M-1с-1; по меньшей мере приблизительно 103M-1с-1; по меньшей мере приблизительно 104M-1с-1; по меньшей мере приблизительно 105M-1с-1 и по меньшей мере приблизительно 106M-1с-1, как измерено методом резонанса
поверхностного плазмона.
21. Связывающий белок по п. 7, где связывающий белок имеет константу скорости диссоциации (Koff) в отношении указанных одной или нескольких мишеней, выбранную из группы, состоящей из: самое большее приблизительно 10-3s-1; самое большее приблизительно 10-4s-1; самое большее приблизительно 10-5s-1 и самое большее приблизительно 10-6s-1, как измерено методом резонанса поверхностного плазмона.
22. Связывающий белок по п. 7, где связывающий белок имеет константу диссоциации (KD) в отношении указанных одной или нескольких мишеней, выбранную из группы, состоящей из: самое большее приблизительно 10-7 M; самое большее приблизительно 10-8 M; самое большее приблизительно 10-9 M; самое большее приблизительно 10-10 M; самое большее приблизительно 10-11 M; самое большее приблизительно 10-12 M и самое большее приблизительно 10-13 M.
23. Связывающий белок по п. 1, где связывающий белок является кристаллизованным связывающим белком.
24. Конъюгат связывающего белка для связывания одной или нескольких мишеней, содержащий связывающий белок по п. 1 и средство, выбранное из группы, состоящей из: молекулы иммуноадгезии, агента визуализации, терапевтического средства и цитотоксического средства.
25. Конъюгат связывающего белка по п. 24, где средством является агент визуализации, выбранный из группы, состоящей из радиоактивной метки, фермента, флуоресцентной метки, люминесцентной метки, биолюминесцентной метки, магнитной метки и
биотина.
26. Конъюгат связывающего белка по п. 25, где агент визуализации является радиоактивной меткой, выбранной из группы, состоящей из 3H, 14C, 35S, 90Y, 99Tc, 111In, 125I, 131I, 177Lu, 166Ho и 153Sm.
27. Конъюгат связывающего белка по п. 25, где средство является терапевтическим или цитотоксическим средством, выбранным из группы, состоящей из: антиметаболита, алкилирующего агента, антибиотика, фактора роста, цитокина, агента против ангиогенеза, антимитотического агента, антрациклина, токсина и апоптотического агента.
28. Выделенная нуклеиновая кислота, кодирующая полипептидную цепь, которая используется для получения связывающего белка по п. 1.
29. Вектор, содержащий выделенную нуклеиновую кислоту по п. 28, где указанный вектор подходит для экспрессии нуклеиновой кислоты.
30. Вектор по п. 29, где указанный вектор выбран из группы, состоящей из pcDNA, pTT, pTT3, pEFBOS, pBV, pJV, pcDNA3.1 TOPO, pEF6 TOPO и pBJ.
31. Вектор, содержащий выделенную нуклеиновую кислоту по п. 28, где указанный вектор подходит для репликации нуклеиновой кислоты.
32. Клетка-хозяин, содержащая вектор по п. 31, для репликации указанного вектора.
33. Клетка-хозяин, содержащая вектор по п. 29 или 30, для экспрессии связывающего белка, кодирующегося вектором.
34. Клетка-хозяин по п. 33, где указанная клетка-хозяин является прокариотической клеткой.
35. Клетка-хозяин по п. 34, где указанная клетка-хозяин является E.сoli.
36. Клетка-хозяин по п. 33, где указанная клетка-хозяин является эукариотической клеткой.
37. Клетка-хозяин по п. 36, где указанная эукариотическая клетка выбрана из группы, состоящей из: клетки протиста, клетки животного, клетки растения и грибковой клетки.
38. Клетка-хозяин по п. 36, где указанная эукариотическая клетка является клеткой животного, выбранной из группы, состоящей из: клетки млекопитающего, клетки птицы и клетки насекомого.
39. Клетка-хозяин по п. 36, где указанная эукариотическая клетка представляет собой клетку CHO.
40. Клетка-хозяин по п. 36, где указанная эукариотическая клетка представляет собой клетку COS.
41. Клетка-хозяин по п. 36, где указанная грибковая клетка является дрожжевой клеткой.
42. Клетка-хозяин по п. 41, где указанная дрожжевая клетка является Saccharomyces cerevisiae.
43. Клетка-хозяин по п. 36, где указанная клетка-хозяин представляет собой клетку Sf9 насекомого.
44. Способ получения связывающего белка, включающий культивирование клетки-хозяина, описанной в любом из пп. 33-43, в культуральной среде при условиях, достаточных для получения связывающего белка.
45. Способ по п. 44, где 50%-75% продуцируемого связывающего белка является четырехвалентным связывающим белком с двойной специфичностью.
46. Способ по п. 44, где 75%-90% продуцируемого связывающего белка являются четырехвалентным связывающим белком с двойной специфичностью.
47. Способ по п. 44, где 90-95% продуцируемого связывающего белка являются четырехвалентным связывающим белком с двойной специфичностью.
48. Белок по п. 1, полученный способом по п. 44.
49. Фармацевтическая композиция для лечения или профилактики заболевания или нарушения у индивида, содержащая связывающий белок по любому из пп. 1-27 и 48 и фармацевтически приемлемый носитель.
50. Фармацевтическая композиция по п. 49, дополнительно содержащая по меньшей мере один дополнительный терапевтический агент.
51. Фармацевтическая композиция по п. 50, где указанный дополнительный агент выбран из группы, состоящей из терапевтического агента, агента визуализации, цитотоксического агента, ингибиторов ангиогенеза; ингибиторов киназ; блокаторов молекул костимуляции; блокаторов молекул адгезии; анти-цитокинового антитела или его функционального фрагмента; метотрексата; циклоспорина; рапамицина; FK506; детектируемой метки или репортера; антагониста TNF; противоревматического агента; миорелаксанта, наркотического агента, нестероидного противовоспалительного лекарственного средства (NSAID),
аналгезирующего агента, анестезирующего агента, седативного средства, местного анестезирующего средства, нервно-мышечного блокатора, противомикробного агента, антипсориатического агента, кортикостероида, анаболического стероида, эритропоэтина, иммунизации, иммуноглобулина, иммунодепрессанта, гормона роста, замещающего гормон лекарственного средства, радиофармацевтического средства, антидепрессанта, антипсихотического средства, стимулятора, противоастматического средства, бета-агониста, ингалируемого стероида, эпинефрина или его аналога, цитокина и антагониста цитокина.
52. Способ лечения заболевания или нарушения у индивида путем введения индивиду связывающего белка по любому из пп. 1-27 и 48 для связывания с одной или несколькими мишенями, связанными с указанным заболеванием или нарушением.
53. Способ по п. 52, где указанное заболевание или нарушение выбрано из группы, включающей ревматоидный артрит, остеоартрит, хронический ювенильный артрит, септический артрит, артрит Лайма, псориатический артрит, реактивный артрит, спондилоартропатию, системную красную волчанку, болезнь Крона, язвенный колит, воспалительное заболевание кишечника, инсулинзависимый сахарный диабет, тиреоидит, астму, аллергические заболевания, псориаз, дерматит, склеродермию, болезнь трансплантат против хозяина, отторжение трансплантатов органов, острое или хроническое иммунное заболевание, ассоциированное с трансплантацией органов, саркоидоз, атеросклероз, диссеминированное внутрисосудистое свертывание, болезнь Кавасаки, болезнь Грейвса, нефротический синдром, синдром хронической усталости, гранулематоз Вегенера,
пурпуру Геноха-Шенлейна, микроскопический васкулит почек, хронический активный гепатит, увеит, септический шок, синдром токсического шока, синдром сепсиса, кахексию, инфекционные заболевания, паразитарные заболевания, синдром приобретенного иммунодефицита, острый поперечный миелит, хорею Гентингтона, болезнь Паркинсона, болезнь Альцгеймера, инсульт, первичный билиарный цирроз, гемолитическую анемию, злокачественные заболевания, сердечную недостаточность, инфаркт миокарда, болезнь Аддисона, спорадическую плюригландулярную недостаточность типа I и плюригландулярную недостаточность типа II, синдром Шмидта, (острый) респираторный дистресс-синдром взрослых, алопецию, гнездную (очаговую) алопецию, сероотрицательную артропатию, артропатию, болезнь Рейтера, псориатическую артропатию, артропатию язвенного колита, энтеропатический синовит, ассоциированную с Chlamydia, Yersinia и Salmonella артропатию, спондилоартропатию, атероматозное заболевание/артериосклероз, атопическую аллергию, аутоиммунное буллезное заболевание, пузырчатку обыкновенную, листовидную пузырчатку, пемфигоид, линейное IgA-заболевание, аутоиммунную гемолитическую анемию, положительную гемолитическую анемию Кумбса, приобретенную пернициозную анемию, ювенильную пернициозную анемию, миалгический энцефалит/британский миалгический энцефалит, хронический кожно-слизистый кандидоз, гигантоклеточный артериит, первичный склерозирующий гепатит, криптогенный аутоиммунный гепатит, синдром приобретенного иммунодефицита, заболевания, родственные приобретенному иммунодефициту, гепатит В, гепатит С, общий транзиторный
иммунодефицит (общую транзиторную гипогаммаглобулинемию), дилатационную кардиомиопатию, женское бесплодие, угасание функции яичников, преждевременное угасание функции яичников, фибротическое заболевание легких, криптогенный фиброзирующий альвеолит, послевоспалительное интерстициальное заболевание легких, интерстициальный пневмонит, ассоциированную с заболеванием соединительной ткани интерстициальную болезнь легких, ассоциированную с заболеванием смешанной соединительной ткани болезнь легких, ассоциированную с системным склерозом интерстициальную болезнь легких, ассоциированную с ревматоидным артритом интерстициальную болезнь легких, ассоциированную с системной красной волчанкой болезнь легких, ассоциированную с дерматомиозитом/полимиозитом болезнь легких, ассоциированную с болезнью Шегрена болезнь легких, ассоциированную с анкилозирующим спондилитом болезнь легких, васкулитное диффузное заболевание легких, ассоциированную с гемосидерозом болезнь легких, индуцированную лекарственным средством интерстициальную болезнь легких, фиброз, лучевой фиброз, облитерирующий бронхиолит, хроническую эозинофильную пневмонию, лимфоцитарное инфильтративное заболевание легких, постинфекционное интерстициальное заболевание легких, подагрический артрит, аутоиммунный гепатит, аутоиммунный гепатит типа-1 (классический аутоиммунный или люпоидный гепатит), аутоиммунный гепатит типа-2 (гепатит с анти-LKM-антителами), аутоиммунно опосредованную гипогликемию, инсулинорезистентность типа В с папиллярно-пигментной дистрофией кожи (acanthosis nigricans), гипопаратиреоз, острое иммунное заболевание, ассоциированное с
трансплантацией органа, хроническое иммунное заболевание, ассоциированное с трансплантацией органа, остеоартроз, первичный склерозирующий холангит, псориаз типа 1, псориаз типа 2, идиопатическую лейкопению, аутоиммунную нейтропению, почечное заболевание NOS (БДУ), гломерулонефрит, микроскопический васкулит почек, болезнь Лайма, дискоидную красную волчанку, мужское бесплодие, идиопатическое или NOS (БДУ), аутоиммунность спермы, рассеянный склероз (всех подтипов), симпатическую офтальмию, легочную гипертензию, вторичную относительно заболевания соединительной ткани, синдром Гудпасчера, легочную манифестацию нодозного полиартериита, острую ревматическую лихорадку, ревматоидный спондилит, болезнь Стилла, системный склероз, синдром Шегрена, болезнь Такаясу/артериит, аутоиммунную тромбоцитопению, идиопатическую тромбоцитопению, аутоиммунное заболевание щитовидной железы, гипертиреоз, зобный аутоиммунный гипотиреоз (болезнь Хашимото), атрофический аутоиммунный гипотиреоз, первичную микседему, факогенный увеит, первичный васкулит, витилиго, острое заболевание печени, хроническое заболевание печени, алкогольный цирроз, индуцированное алкоголем повреждение печени, холестаз, идиосинкратическую болезнь печени, индуцированный лекарственным средством гепатит, неалкогольный стеатогепатит, аллергию и астму, стрептококковую инфекцию группы В (GBS), психические нарушения (например, депрессию и шизофрению), Th типа 2- и Th типа 1-опосредованные заболевания, острую и хроническую боль (различные формы боли) и раковые заболевания, такие как рак легкого, молочной железы, желудка, мочевого пузыря, ободочной кишки, поджелудочной железы,
яичников, предстательной железы и прямой кишки, и гемопоэтические злокачественные заболевания (лейкоз и лимфому), абеталипопротеинемию, акроцианоз, острые и хронические паразитарные или инфекционные процессы, острый лейкоз, острый лимфобластный лейкоз (ALL), острый миелоидный лейкоз (AML), острую или хроническую бактериальную инфекцию, острый панкреатит, острую почечную недостаточность, аденокарциномы, предсердные эктопические систолы, комплекс СПИД-деменция, индуцированный алкоголем гепатит, аллергический конъюнктивит, аллергический контактный дерматит, аллергический ринит, отторжение аллотрансплантата, недостаточность альфа-l-антитрипсина, амиотрофический боковой склероз, анемию, стенокардию, дегенерацию клеток переднего рога спинного мозга, анти-cd3-терапию, антифосфолипидный синдром, аллергические реакции на противорецепторные антитела, аневризмы аорты и периферических сосудов, рассечение аорты, артериальную гипертензию, артериосклероз, атриовентрикулярную фистулу, атаксию, предсердную фибрилляцию (стойкую или пароксизмальную), трепетание предсердий, атриовентрикулярную блокаду, В-клеточную лимфому, отторжение костного трансплантата, отторжение трансплантата костного мозга (BMT), межжелудочковую блокаду, лимфому Беркитта, ожоги, сердечные аритмии, синдром временной остановки сердца, опухоли сердца, кардиомиопатию, воспалительную реакцию при искусственном кровообращении, отторжение трансплантата хряща, церебеллярные кортикальные дегенерации, церебеллярные нарушения, хаотическую или мультиочаговую предсердную тахикардию, ассоциированные с химиотерапией
нарушения, хронический миелоцитарный лейкоз (CML), хронический алкоголизм, хронические воспалительные патологии, хронический лимфоцитарный лейкоз (CLL), хроническую обструктивную болезнь легких (COPD), хроническую интоксикацию салицилатом, рак ободочной кишки, застойную сердечную недостаточность, конъюнктивит, контактный дерматит, легочное сердце, болезнь коронарных артерий, болезнь Крейтцфельдта-Якоба, отрицательный в культуре сепсис, муковисцидоз, ассоциированные с терапией цитокинами нарушения, боксерскую деменцию, демиелинизирующие заболевания, геморрагическую лихорадку Денге, дерматит, дерматологические состояния, диабет, сахарный диабет, диабетическое артериосклеротическое заболевание, заболевание с диффузными тельцами Леви, дилатационную застойную кардиомиопатию, нарушения базальных (подкорковых) ядер головного мозга, синдром Дауна в среднем возрасте, индуцированные лекарственными средствами нарушения движения, нарушения, индуцированные лекарственными средствами, которые блокируют рецепторы допамина ЦНС, чувствительность к лекарственным средствам, экзему, энцефаломиелит, эндокардит, эндокринопатию, эпиглоттит, инфекцию вирусом Эпштейна-Барр, эритромелалгию, экстрапирамидные и церебеллярные нарушения, семейный гематофагоцитарный лимфоцитарный гистиоцитоз, отторжение имплантата фетальной вилочковой железы, атаксию Фридрейха, функциональные периферические артериальные нарушения, грибковый сепсис, газовую (анаэробную) гангрену, язву желудка, гломерулонефрит, отторжение трансплантата любого органа или любой ткани, грамотрицательный сепсис, грамположительный сепсис,
гранулемы, вызываемые внутриклеточными организмами, лейкемический ретикулоэндотелиоз, болезнь Халлеррордена-Шпатца, тиреоидит Хашимото, сенную лихорадку, отторжение трансплантата сердца, гемохроматоз, гемодиализ, гемолитический уремический синдром/тромболитическую тромбоцитопеническую пурпуру, кровотечение, гепатит (A), аритмию пучка Гиса, ВИЧ-инфекцию/ВИЧ-невропатию, болезнь Ходжкина, гиперкинетические нарушения движения, аллергические реакции, аллергический пневмонит, гипертензию, гипокинетические нарушения движения, диагностику системы гипоталамус-гипофиз-надпочечники, идиопатическую болезнь Аддисона, идиопатический легочный фиброз, опосредованную антителами цитотоксичность, астению, детскую спинально-мышечную атрофию, воспаление аорты, грипп А, воздействие ионизирующей радиацией, иридоциклит/увеит/неврит зрительного нерва, ишемическое/реперфузионное повреждение, ишемический инсульт, ювенильный ревматоидный артрит, ювенильную спинально-мышечную атрофию, саркому Капоши, отторжение трансплантата почки, инфекции микобактерией Legionella, лейшманиоз, проказу, повреждения кортико-спинальной системы, жировой отек, отторжение трансплантата печени, лимфатический отек, малярию, злокачественную лимфому, злокачественный гистиоцитоз, злокачественную меланому, менингит, менингококкемию, метаболическую/идиопатическую, кластерную головную боль, митохондриальное мультисистемное нарушение, заболевание смешанной соединительной ткани, моноклональную гаммопатию, множественную миелому, дегенерации множественных систем (Mencel Dejerine- Thomas Shi-Drager и Machado-Joseph), тяжелую
псевдопаралитическую миастению, Мycobacterium avium intracellulare, туберкулезную бациллу, синдром миелодисплазии, инфаркт миокарда, ишемические нарушения миокарда, рак носоглотки, хроническое заболевание легких новорожденных, нефрит, нефроз, нейродегенеративные заболевания, нейрогенные I мышечные атрофии, нейрогенную лихорадку, не-Ходжкинскую лимфому, закупорку брюшной аорты и ее ответвлений, окклюзивные артериальные нарушения, okt3-терапию, орхит/эпидидимит, процедуру после лечения орхита/вазэктомии, органомегалию, остеопороз, отторжение трансплантата поджелудочной железы, рак поджелудочной железы, паранеопластический синдром/гиперкальциемию при злокачественных заболеваниях, отторжение трансплантата паращитовидной железы, воспалительное заболевание почечных лоханок, круглогодичный ринит, заболевание перикарда, периферическое атеросклеротическое заболевание, периферические васкулярные нарушения, перитонит, пернициозную анемию, пневмонию, вызываемую Рneumocystis carinii, пневмонию, синдром POEMS (полиневропатию, органомегалию, эндокринопатию, моноклональную гаммопатию и синдром изменений кожи), постперфузионный синдром, постгемодиализный синдром, синдром пост-MI-кардиотомию, преэклампсию, прогрессирующий супрануклеарный паралич, первичную легочную гипертензию, лучевую терапию, феномен и болезнь Рейно, болезнь Рейно, болезнь Рефсума, тахикардию с регулярными узкими QRS, реноваскулярную (почечно-сосудистую) гипертензию, реперфузионное повреждение, рестриктивную кардиомиопатию, саркомы, склеродермию, сенильную хорею, сенильную деменцию, ассоциированную с тельцами Леви,
сероотрицательные артропатии, шок, серповидно-клеточную анемию, отторжение аллотрансплантата кожи, синдром изменений кожи, отторжение трансплантата тонкой кишки, солидные опухоли, специфические аритмии, спинальную атаксию, спинально-церебеллярные дегенерации, стрептококковый миозит, структурные повреждения мозжечка, подострый склерозирующий панэнцефалит, обморок (синкопе), сердечно-сосудистый сифилис, системную анафилаксию, синдром системной воспалительной реакции, системный ювенильный ревматоидный артрит, T-клеточный или FAB ALL (острый лимфобластный лейкоз), телангиэктазию, облитерирующий тромбоангиит, тромбоцитопению, токсичность, трансплантаты, травму/кровотечение, аллергические реакции типа III, аллергию типа IV, нестабильную стенокардию, уремию, уросепсис, крапивницу, вальвулярные сердечные заболевания, варикозные вены, васкулит, венозные заболевания, венозный тромбоз, фибрилляцию (мерцание) желудочков, вирусные и грибковые инфекции, острый энцефалит с высоким риском смертельного исхода/асептический менингит, гемафагоцитарный синдром, ассоциированный с высоким риском смертельного исхода, синдром Вернике-Корсакова, заболевание Вильсона, отторжение ксенотрансплантата любого органа или любой ткани.
54. Способ по п. 52, где указанное введение индивиду осуществляют по меньшей мере одним из способов, выбранных из парентерального, подкожного, внутримышечного, внутривенного, внутрисуставного, внутрибронхиального, внутрибрюшного, интракапсулярного, внутрихрящевого, внутриполостного, интрацелиального, интрацеребеллярного,
интрацеребровентрикулярного, введения внутрь толстой/ободочной кишки, интрацервикального, внутрижелудочного, внутрипеченочного, интрамиокардиального, внутрикостного, внутритазового, интраперикардиального, внутрибрюшинного, внутриплеврального, внутрипростатического, внутрилегочного, интраректального, интраренального, интраретинального, интраспинального, интрасиновиального, внутригрудного, внутриматочного, интравезикулярного, болюсного, вагинального, ректального, буккального, сублингвального, интраназального и трансдермального способов введения.
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