Dual Variable Domain Immunoglobulin and Uses Thereof

Abstract

The present invention relates to engineered multivalent and multispecific binding proteins, methods of making, and specifically to their uses in the prevention and/or treatment of acute and chronic inflammatory and other diseases.

1 - 75 . (canceled) 
     
     
         76 . A binding protein comprising first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-(X2)n, wherein
 VD1 is a first variable domain;   VD2 is a second variable domain;   C is a constant domain;   X1 is a linker;   X2 is an Fc region; and   n is 0 or 1;   wherein the VD1 domains on the first and second polypeptide chains form a functional target binding site and the VD2 domains on the first and second polypeptide-chains form a functional target binding site, and wherein at least one functional target site binds to TNF.   
     
     
         77 . The binding protein of  claim 76 , wherein the variable domains that form the functional target binding site for TNF comprise variable domains from adalimumab (HUMIRA®), infliximab (REMICADE®), HUMICADE®, CNTO 148 (Medarex/Centocor) or etenercept (ENBREL®). 
     
     
         78 . The binding protein of  claim 76 , wherein the binding protein also binds to a cytokine, cytokine receptor, or a cytokine related protein. 
     
     
         79 . The binding protein of  claim 76 , wherein the binding protein also binds to a target selected from the group consisting of ABCF1, ACVRI, ACVR1B, ACVR2, ACVR2B, ACVRL1, AMH, AMHR2, BMPR1A, BMPR1B, BMPR2, BCL6, C19orf10 (IL27w), C3, C4A, C5, CNR1, CRP, CTLA4, CYSLTR1, BLR1, CCL1 (1-309), CCL2 (mcp-1), CCL3 (MIP-1a), CCL4 (MIP-1b), CCL5 (RANTES), CCL7 (mcp-3), CCL8 (mcp-2), CCL11 (eotaxin), CCL13 (mcp-4), CCL15 (MIP-Id),CCL16 (HCC-4), CCL17 (TARC), CCL18 (PARC), CCL19, CCL20 (MIP-3a), CCL21 (MIP-2), CCL22, CCL23 (MPIF-1), CCL24 (MPIF-2/eotaxin2), CCL25 (TECK), CCL26, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD28, CD3E, CD3G, CD3Z, CD69, CD80, CD86, CEBPB, CER1, CSF1, CSF2, CSF3, CX3CL1, CX3CR1, CXCL1, CXCL2, CXCL3, CXCL5 (ENA-78/L1X), CXCL6 (GCP-2), CXCL9, CXCL10 (IP-10), CXCL11 (l-TAC/IP-9), CXCL12 (SDF1), CXCL13, CXCL14, CXCR4, DKFZp451J0118, FADD, FCER1A, FCER2, FCGR3A, FGF2, GFI1, GPR2, GPR44, HAVCR2, ICEBERG, IFNA1, IFNA2, IFNB1, IFNG, IGF1, IL1A, IL1B, IL1F10, IL1F5, IL1F6, IL1F7, IL1F8, IL1F9, IL1R1, IL1R2, IL1RN, IL2, IL2RA, IL2RB, IL2RG, IL3, IL4, IL4R, IL5, IL5RA, IL6, IL6R, IL6ST, IL7, IL8, IL8RA, IL8RB, IL9, IL9R, IL10, MORA, IL10RB, IL11, IL11RA, IL12A, IL12B, IL12RB1, IL12RB2, IL13, IL13RA1, IL13RA2, IL15, IL15RA, IL16, IL17, IL17R, IL17C, IL18, IL18RI, IL19, IL20, IL22, IRAK1, IRAK2, KITLG, LEP, LTA, LTB, LTB4R, LTB4R2, LTBR, MIF, MYD88, NCK2, NPPB, OPRD1, P2RX7, PDGFB, SCYEI (endothelial Monocyte-activating cytokine ), SDF2, SPPI, TBX21 , TDGF1, TGFA, TNFAIP3, TGFB1, TGFB111, TGFB2, TGFB3, TGFBR1, TGFBR2, TGFBR3, THIL, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLRS, TLR9, TLR10, TOLLIP, TNF, TNFRSF1A, TNFRSF1B, TNFRSF7, TNFRSF8, TNFRSF9, TNFRSF11A, TNFRSF21, TNFSF4, TNFSF5, TNFSF6, TNFSF11, TRADD, TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, VEGF, XCL1, XCL2, XCR1 (CCXCR1), ZFPM2, and ZNF144 (RNF110). 
     
     
         80 . The binding protein of  claim 76 , wherein the binding protein also binds to a target selected from the group consisting of BMPI, BMP2, BMP3B (GDF10), BMP4, BMP6, BMP8, CSF1(M-CSF), CSF2 (GM-CSF), CSF3 (G-CSF), EPO, FGFI (aFGF), FGF2 (bFGF), FGF3 (int-2), FGF4 (HST), FGF5, FGF6 (HST-2), FGF7 (KGF), FGF9, FGF10, FGF11, FGF12, FGF12B, FGF14, FGF16, FGF17, FGF19, FGF20, FGF21, FGF23, IGF1, IGF2, IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNB1, IFNG, IFNW1, FIL1, FIL1 (EPSILON), FIL1 (ZETA), IL1A, IL1B, IL2, IL3, IL4, IL5, IL6, IL7, IL8, IL9, IL10, IL11, IL12A, IL12B, IL13, IL14, IL15, IL16, IL17, IL17B, IL18, IL19, IL20, IL22, IL23, IL24, IL25, IL26, IL27, IL28A, IL28B, IL29, IL30, PDGFA, PDGFB, TGFA, TGFB1, TGFB2, TGFB3, LTA (TNF-b), LTB, TNF (TNFa), TNFSF4 (OX40 ligand), TNFSF5 (CD40 ligand), TNFSF6 (FasL), TNFSF7 (C027 ligand), TNFSF8 (CD30 ligand), TNFSF9 (4-1BB ligand), TNFSF10(TRAIL), TNFSF11 (TRANCE), TNFSFI2 (AP03L), TNFSF13 (April), TNFSF13B, TNFSF14 (HVEM-L), TNFSF15 (VEGI), TNFSF18, FIGF (VEGFD), VEGF, VEGFB, VEGFC, IL1RI, IL1R2, IL1RL1, IL1RL2, IL2RA, IL2RB, IL2RG, IL3RA, IL4R, IL5RA, IL6R, IL7R, IL8RA, IL8RB, IL9R, IL10RA, IL10RB, IL11RA, IL12RBI, IL12RB2, IL13RA1, IL13RA2, IL15RA, IL17R, IL18R1, IL20RA, IL21R, IL22R, IL1HY1, IL1RAP, IL1RAPL1, ILIRAPL2, IL1RN, IL6ST, IL18BP, IL18RAP, IL22RA2, AIF1, HGF, LEP (leptin), PTN, and THPO. 
     
     
         81 . The binding protein of  claim 76 , wherein the binding protein also binds to TNF, IL-12, IL-12p40, IL-18, C5, CBL, CD147, gpl20, VLA4, CD11a, CD18, VEGF, CD40L, Id, ICAM-1, CXCL13, CD2, EGFR, TGF-beta 2, E-selectin, Factor VII, Her2/neu, F gp, CD11/18, CD14, ICAM-3, CD80, CD4, CD3, CD23, beta2-integrin, alpha4beta7, CD52, HLA DR, CD22, CD20, MIF, CD64 (FcR), TCR alpha beta, CD2, Hepatitis B antigen, CA 125, EpCAM, gp120, CMV, gpIIbIIIa, IgE, CD25, CD33, HLA, VNR-integrin, IL-I alpha, IL-I beta, IL-I receptor, IL-2 receptor, IL-4, IL4 receptor, IL5, IL- 5 receptor, IL-6, IL-8, IL-9, IL-13, IL-13 receptor, IL-17, and IL-23. 
     
     
         82 . The binding protein of  claim 76 , wherein the binding protein also binds to a target selected from the group consisting of IL-12, TWEAK, IL-23, CXCL13, CD40, CD40L, IL-18, VEGF, VLA4, TNF, CD45RB, CD200, IFNgamma, GM-CSF, FGF, C5, CD52, and CCR2. 
     
     
         83 . The binding protein of  claim 76 , wherein the binding protein also binds to a target selected from the group consisting of TNF, 1-1, MIF, IL-1B, IL-6, IL-8, IL-10, IL-18, IL-12, IL-23, FasL, LPS, Toll-like receptors, TLR-4, tissue factor, MIP-2 ,ADORA2A, CASPI, CASP4, NFKB1, NFKB2, PROC, TNFRSF1A, CSF3, CCR3, IL-1RN, PTAFR, TLR2, TLR4, GPR44, HMOX1, midkine, IRAK1, SERPINA1, SERPINE1, and TREM1. 
     
     
         84 . The binding protein of  claim 76 , wherein the binding protein also binds to VEGF. 
     
     
         85 . The binding protein of  claim 81 , wherein the variable domains that form the functional target binding site for VEGF comprise variable domains from bevacizumab (AVASTIN®). 
     
     
         86 . A binding protein comprising first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-(X2)n, wherein
 VD1 is a first variable domain;   VD2 is a second variable domain;   C is a constant domain;   X1 is a linker;   X2 is an Fc region; and   n is 0 or 1;   wherein the VD1 domains on the first and second polypeptide chains form a functional target binding site and the VD2 domains on the first and second polypeptide chains form a functional target binding site, and wherein at least one functional target site binds to VEGF.   
     
     
         87 . The binding protein of  claim 86 , wherein the wherein the variable domains that form the functional target binding site for VEGF comprise variable domains from bevacizumab (AVASTIN®). 
     
     
         88 . The binding protein of  claim 86 , wherein the binding protein also binds to a cytokine, cytokine receptor, or a cytokine related protein. 
     
     
         89 . The binding protein of  claim 86 , wherein the binding protein also binds to a target selected from the group consisting of BMPI, BMP2, BMP3B (GDF10), BMP4, BMP6, BMP8, CSF1(M-CSF), CSF2 (GM-CSF), CSF3 (G-CSF), EPO, FGFI (aFGF), FGF2 (bFGF), FGF3 (int-2), FGF4 (HST), FGF5, FGF6 (HST-2), FGF7 (KGF), FGF9, FGF10, FGF11, FGF12, FGF12B, FGF14, FGF16, FGF17, FGF19, FGF20, FGF21, FGF23, IGF1, IGF2, IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNB1, IFNG, IFNW1, FIL1, FIL1 (EPSILON), FIL1 (ZETA), IL1A, IL1B, IL2, IL3, IL4, IL5, IL6, IL7, IL8, IL9, IL10, IL11, IL12A, IL12B, IL13, IL14, IL15, IL16, IL17, IL17B, IL18, IL19, IL20, IL22, IL23, IL24, IL25, IL26, IL27, IL28A, IL28B, IL29, IL30, PDGFA, PDGFB, TGFA, TGFB1, TGFB2, TGFB3, LTA (TNF-b), LTB, TNF (TNFa), TNFSF4 (OX40 ligand), TNFSF5 (CD40 ligand), TNFSF6 (FasL), TNFSF7 (C027 ligand), TNFSF8 (CD30 ligand), TNFSF9 (4-1BB ligand), TNFSF10 (TRAIL), TNFSF11 (TRANCE), TNFSFI2 (AP03L), TNFSF13 (April), TNFSF13B, TNFSF14 (HVEM-L), TNFSF15 (VEGI), TNFSF18, FIGF (VEGFD), VEGF, VEGFB, VEGFC, IL1RI, IL1R2, IL1RL1, IL1RL2, IL2RA, IL2RB, IL2RG, IL3RA, IL4R, IL5RA, IL6R, IL7R, IL8RA, IL8RB, IL9R, MORA, IL10RB, IL11RA, IL12RBI, IL12RB2, IL13RA1, IL13RA2, IL15RA, IL17R, IL18R1, IL20RA, IL21R, IL22R, IL1HY1, IL1RAP, IL1RAPL1, ILIRAPL2, IL1RN, IL6ST, IL18BP, IL18RAP, IL22RA2, AIF1, HGF, LEP (leptin), PTN, and THPO. 
     
     
         90 . The binding protein of  claim 86 , wherein the binding protein also binds to TNF, IL-12, IL-12p40, IL-18, C5, CBL, CD147, gpl20, VLA4, CD11a, CD18, VEGF, CD40L, Id, ICAM-1, CXCL13, CD2, EGFR, TGF-beta 2, E-selectin, Factor VII, Her2/neu, F gp, CD11/18, CD14, ICAM-3, CD80, CD4, CD3, CD23, beta2-integrin, alpha4beta7, CD52, HLA DR, CD22, CD20, MIF, CD64 (FcR), TCR alpha beta, CD2, Hepatitis B antigen, CA 125, EpCAM, gp120, CMV, gpIIbIIIa, IgE, CD25, CD33, HLA, VNR-integrin, IL-I alpha, IL-I beta, IL-I receptor, IL-2 receptor, IL-4, IL4 receptor, IL5, IL- 5 receptor, IL-6, IL-8, IL-9, IL-13, IL-13 receptor, IL-17, and IL-23. 
     
     
         91 . The binding protein of  claim 86 , wherein the binding protein also binds to a target selected from the group consisting of IL-12, TWEAK, IL-23, CXCL13, CD40, CD40L, IL-18, VEGF, VLA4, TNF, CD45RB, CD200, IFNgamma, GM-CSF, FGF, C5, CD52, and CCR2. 
     
     
         92 . A binding protein comprising first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-(X2)n, wherein
 VD1 is a first variable domain;   VD2 is a second variable domain;   C is a constant domain;   X1 is a linker;   X2 is an Fc region; and   n is 0 or 1;   wherein the VD1 domains on the first and second polypeptide chains form a functional target binding site and the VD2 domains on the first and second polypeptide chains form a functional target binding site, and wherein at least one functional target site binds to a cytokine, cytokine receptor, or a cytokine related protein.   
     
     
         93 . The binding protein of  claim 92 , wherein the cytokine is an interleukin. 
     
     
         94 . The binding protein of  claim 93 , wherein the interleukin is selected from IL-1A, IL-1B, IL-1R1, IL-1R2, IL-1RN, IL-2, IL-2RA, IL-2RB, IL-2RG, IL-3, IL-4, IL-4R, IL-5, IL-5RA, IL-6, IL-6R, IL-6ST, IL-7, IL-8, IL-8RA, IL-8RB, IL-9, IL-9R, IL-10, IL-10RA, IL-10RB, IL-11, IL-11RA, IL-12A, IL-12B, IL-12RB1, IL-12RB2, IL-13, IL-13RA1, IL-13RA2, IL-14, IL-15, IL-15RA, IL-16, IL-17, IL-17B, IL-17C, IL-17R, IL-18, IL-18R1, IL-19, IL-20, IL-20RA, IL-21R IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28A, IL-28B, IL-29, IL-30, IL-1F10, IL-1F5, IL-1F6, IL-1F7, IL-1F8, IL-1F9. 
     
     
         95 . The binding protein of  claim 93 , wherein the interleukin is IL-1B. 
     
     
         96 . The binding protein of  claim 93 , wherein the interleukin is IL-1A. 
     
     
         97 . The binding protein of  claim 93 , wherein the interleukin is IL-4. 
     
     
         98 . The binding protein of  claim 93 , wherein the interleukin is IL-6. 
     
     
         99 . The binding protein of  claim 93 , wherein the interleukin is IL-13. 
     
     
         100 . The binding protein of  claim 93 , wherein the interleukin is IL-17. 
     
     
         101 . The binding protein of  claim 93 , wherein the interleukin is IL-17B. 
     
     
         102 . The binding protein of  claim 93 , wherein the interleukin is IL-18. 
     
     
         103 . The binding protein of  claim 93 , wherein the interleukin is IL-22. 
     
     
         104 . The binding protein of  claim 93 , wherein the interleukin is IL-23. 
     
     
         105 . The binding protein of  claim 93 , wherein the binding protein binds to IL-13 and IL-4. 
     
     
         106 . The binding protein of  claim 99 , wherein the binding protein also binds to a target selected from TNFα, IL-5, IL-9, IL-25, TARC, MDC, MIF, TGF-β, LHR agonist, CL25, SPRR2a, SPRR2b, ADAM8, PDE2, and IL-1β. 
     
     
         107 . The binding protein of  claim 93 , wherein the variable domains that form the functional target binding site for the interleukin comprise variable domains selected from the group consisting of J695 (Cambridge Antibody Technology), ABX-IL8 (Abgenix) and HuMax-IL-15 (Genmab).