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 EGFR. 
     
     
         77 . The binding protein of  claim 76 , wherein the variable domains that form the functional target binding site for EGFR comprise variable domains from an anti-EGFR antibody selected from cetuximab (ERBITUX® Imclone), ABX-EGF (Abgenix-Immunex-Amgen), HUMAX-EGFR™ (Genmab), EMD55900 (Merck), EMD62000 (Merck), and EMD72000 (Merck). 
     
     
         78 . The binding protein of  claim 76 , wherein the binding protein also binds to a target selected from the group consisting of ABCF1; ACVR1; ACVR1B; ACVR2; ACVR2B; ACVRL1; ADORA2A; Aggrecan; AGR2; AICDA; AIF1; AIG1; AKAP1; AKAP2; AMH; AMHR2; ANGPT1; ANGPT2; ANGPTL3; ANGPTL4; ANPEP; APC; APOC1; AR; AZGP1 (zinc-a-glycoprotein); 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 (plectin); BRCA1; C19orf10 (IL27w); C3; C4A; C5; C5R1; CANT1; CASP1; CASP4; CAV1; CCBP2 (D6/JAB61); CCL1 (1-309); CCL11 (eotaxin); 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; exodus-2; CCL22 (MDC/STC-1); CCL23 (MPIF-1); CCL24 (MPIF-2/eotaxin-2); CCL25 (TECK); CCL26 (eotaxin-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/STRL 22/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; CDHI(E-cadherin); CDH10; CDH12; CDH13; CDH18; CDH19; CDH20; CDH5; CDH7; CDH8; CDH9; CDK2; CDK3; CDK4; CDK5; CDK6; CDK7; CDK9; CDKN1A (p21 Wap1/Cip1); CDKN1B (p27Kip1); CDKN1C; CDKN2A (p16INK4a); CDKN2B; CDKN2C; CDKN3; CEBPB; CER1; CHGA; CHGB; Chitinase; CHST10; CKLFSF2; CKLFSF3; CKLFSF4; CKLFSF5; CKLFSF6; CKLFSF7; CKLFSF8; CLDN3; CLDN7 (claudin-7); CLN3; CLU (clusterin); CMKLR1; CMKOR1 (RDC1); CNR1; COL18A1; COL1A1; COL4A3; COL6A1; CR2; CRP; CSF1(M-CSF); CSF2 (GM-CSF); CSF3 (GCSF); CTLA4; CTNNB1 (b-catenin); CTSB (cathepsin B); CX3CL1 (SCYD1); CX3CR1 (V28); CXCL1 (GR01); CXCL10 (IP-10); CXCL11 (I-TAC/IP-9); CXCL12 (SDF1); CXCL13; CXCL14; CXCL16; CXCL2 (GR02); CXCL3 (GR03); CXCL5 (ENA-78/LIX); CXCL6 (GCP-2); CXCL9 (MIG); CXCR3 (GPR9/CKR-L2); CXCR4; CXCR6 (TYMSTR/STRL33/Bonzo); CYB5; CYC1; CYSLTR1; DAB21P; DES; DKFZp451 J0118; 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; FGF1; 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 (fibronectin); FLT1; FOS; FOSL1 (FRA-1); FY (DARC); GABRP (GABAa); GAGEB1; GAGEC1; GALNAC4S-6ST; GAT A3; GDF5; GFI1; GGT1; GM-CSF; GNAS1; GNRH1; GPR2 (CCR10); GPR31; GPR44; GPR81 (FKSG80); GRCC10 (C10); GRP; GSN (Gelsolin); GSTP1; HAVCR2; HDAC4; HDAC5; HDAC7A; HDAC9; HGF; HIF1A; HIP1; histamine and histamine receptors; HLA-A; HLA-DRA; HM74; HMOX1; HUMCYT2A; ICEBERG; ICOSL; ID2; IFN-a; IFNA1; IFNA2; IFNA4; IFNA5; IFNA6; IFNA7; IFNB1; IFNgamma; 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 (glycoprotein 130); IL7; IL7R; IL8; IL8RA; IL8RB; IL9; IL9R; ILK; INHA; INHBA; INSL3; INSL4; IRAKI; IRAK2; ITGA1; ITGA2; ITGA3; ITGA6 (a6 integrin); ITGAV; ITGB3; ITGB4 (b 4 integrin); JAG1; JAK1; JAK3; JUN; K6HF; KAI1; KDR; KITLG; KLF5 (GC Box BP); KLF6; KLK10; KLK12; KLK13; KLK14; KLK15; KLK3; KLK4; KLK5; KLK9; KRT1; KRT19 (Keratin 19); KRT2A; KRTHB6 (hair-specific type II keratin); LAMA5; LEP (leptin); Lingo-p75; Lingo-Troy; LPS; LTA (TNF-b); LTB; LTB4R (GPR16); LTB4R2; LTBR; MACMARCKS; MAG or Omgp; MAP2K7 (c-Jun); MDK; MIB1; midkine; MIF; MIP-2; MKI67 (Ki-67); MMP2; MMP9; MS4A1; MSMB; MT3 (metallothionectin-III); MTSS1; MUC1 (mucin); MYC; MYD88; NCK2; neurocan; 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; phosphacan; 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 (lipophilin B); SCGB2A1 (mammaglobin 2); SCGB2A2 (mammaglobin 1); SCYE1 (endothelial Monocyte-activating cytokine); SDF2; SERPINA1; SERPINA3; SERPINB5 (maspin); 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; TGFB111; TGFB2; TGFB3; TGFBR1; TGFBR2; TGFBR3; TH1L; THBS1 (thrombospondin-1); THBS2; THBS4; THPO; TIE (Tie-1); TIMP3; tissue factor; 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 ligand); TNFSF5 (CD40 ligand); TNFSF6 (FasL); TNFSF7 (CD27 ligand); TNFSF8 (CD30 ligand); TNFSF9 (4-1BB ligand); TOLLIP; Toll-like receptors; TOP2A (topoisomerase lia); TP53; TPM1; TPM2; TRADD; TRAF1; TRAF2; TRAF3; TRAF4; TRAF5; TRAF6; TREM1; TREM2; TRPC6; TSLP; TWEAK; VEGF; VEGFB; VEGFC; versican; VHL C5; VLA-4; XCL1 (lymphotactin); XCL2 (SCM-1b); XCR1 (GPR5/CCXCR1); YY1; and ZFPM2. 
     
     
         79 . The binding protein of  claim 76 , wherein the binding protein also binds to a target selected from the group consisting of CD52, CD20, CD19, CD3, CD4, CD8, BMP6, IL12A, IL1A, IL1B, IL2, IL24, INHA, TNF, TNFSF10, EGF, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, GRP, IGF1, IGF2, TGFA, TGFB1, TGFB2, TGFB3, VEGF, CDK2, IGF1R, BCL2, CD164, CDKN1C, CDKN2B, CDKN2C, CDKN3, GNRH1, IGFBP6, ODZ1, PAWR, PLG, TGFB1I1, AR, BRCA1, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, E2F1, EGFR, ENO1, ERBB2, ESR1, ESR2, IGFBP3, INSL4, MYC, NOX5, NR6A1, PAP, PCNA, PRKCQ, PRKD1, PRL, TP53, KLK6, CHGB, INSL3, SHBG, NR1D1, NR1H3, NR1I3, NR2F6, NR4A3, NR0B1, NR0B2, NR1D2, NR1H2, NR1H4, NR1I2, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR3C1, NR3C2, NR4A1, NR4A2, NR5A1, NR5A2, PGR, RARB, KLK3, KRT1, APOC1, CHGA, COL1A1, COL6A1, ERK8, KLK10, KLK12, KLK13, KLK14, KLK15, KLK4, KLK5, KLK9, MMP2, MMP9, MSMB, NTN4, PSAP, SERPINA3, TIMP3, CD44, CDH20, CDH10, CDH13, CDH18, CDH19, CDH7, CDH8, CDH9, ROBO2, ILK, ITGA1, APC, MTSS1, AGR2, AIG1, AKAP1, AKAP2, CANT1, CAV1, CDH12, CLDN3, CLN3, CYB5, CYC1, DAB21P, DES, DNCL1, ELAC2, ENO2, ENO3, FASN, FLJ12584, FLJ25530, GAGEB1, GAG EC 1, GGT1, GSTP1, HIP1, HUMCYT2A, IL29, K6HF, KAI1, KRT2A, MIB1, PART1, PATE, PCA3, PIAS2, PIK3CG, PPID, PR1, PSCA, SLC2A2, SLC33A1, SLC43A1, STEAP, STEAP2, TPM1, TPM2, TRPC6, ANGPT1, ANGPT2, ANPEP, ECGF1, EREG, FIGF, FLT1, JAG1, KDR, LAMA5, NRP1, NRP2, PGF, PLXDC1, STAB1, VEGFC, ANGPTL3, BAI1, COL4A3, IL8, ANGPTL4, PECAM1, PF4, PROK2, SERPINF1, CCL11, CCL2, CXCL1, CXCL10, CXCL3, CXCL5, CXCL6, CXCL9, IFNA1, IFNB1, IFNG, IL6, MDK, EDG1, EFNA1, EFNA3, EFNB2, EPHB4, FGFR3, HGF, ITGB3, PDGFA, TEK, TGFBR1, CDH5, COL18A1, ENG, ITGAV, BAD, BAG1, CCNA1, CCNA2, CCND1, CCNE1, CCNE2, CDH1 (E-cadherin), CDKN1B (p27Kip1), CDKN2A (p16INK4a), CTNNB1 (b-catenin), CTSB (cathepsin B), F3 (TF), FOSL1 (FRA-1), GAT A3, GSN (Gelsolin), IGFBP2, IL2RA, IL6R, IL6ST (glycoprotein 130), ITGA6 (a6 integrin), JUN, MAP2K7 (c-Jun), MKI67 (Ki-67), NGFB (NGF), NGFR, NME1 (NM23A), PLAU (uPA), PTEN, SERPINB5 (maspin), SERPINE1 (PAI-1), THBS1 (thrombospondin-1), TIE (Tie-1), TNFRSF6 (Fas), TNFSF6 (FasL), TOP2A (topoisomerase lia), AZGP1 (zinc-a-glycoprotein), BPAG1 (plectin), CDKN1A (p21Wap1/Cip1), CLDN7 (claudin-7), CLU (clusterin), ERBB2 (Her-2), FLRT1 (fibronectin), GABRP (GABAa), GNAS1, ID2, ITGB4 (b 4 integrin), KLF5 (GC Box BP), KRT19 (Keratin 19), KRTHB6 (hair-specific type II keratin), MACMARCKS, MT3 (metallothionectin-III), MUC1 (mucin), PTGS2 (COX-2), RAC2 (p21Rac2), S100A2, SCGB1D2 (lipophilin B), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SPRR1B (Spr1), THBS2, THBS4, and TNFAIP2 (B94). 
     
     
         80 . The binding protein of  claim 76 , wherein the binding protein also binds to TNF, IL-12, IL-12p40, IL-18, C5, CBL, CD147, gp120, 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-1 alpha, IL-1 beta, IL-1 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. 
     
     
         81 . The binding protein of  claim 76 , wherein the binding protein also binds to VEGFR. 
     
     
         82 . The binding protein of  claim 76 , wherein the binding protein also binds to a member of the Erb-2 or Erb-3 family. 
     
     
         83 . The binding protein of  claim 82 , wherein the member of the Erb-2 family is ErbB2 (HER-2). 
     
     
         84 . The binding protein of  claim 83 , wherein the wherein the variable domains that form the functional target binding site for HER-2 comprise variable domains from trastuzumab (HERCEPTIN®) or pertuzumab (OMNITARG®). 
     
     
         85 . 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 HER2/neu (ErbB2). 
     
     
         86 . The binding protein of  claim 85 , wherein the wherein the variable domains that form the functional target binding site for HER-2 comprise variable domains from trastuzumab (HERCEPTIN®) or pertuzumab (OMNITARG®). 
     
     
         87 . The binding protein of  claim 85 , wherein the binding protein also binds to a target selected from the group consisting of ABCF1; ACVR1; ACVR1B; ACVR2; ACVR2B; ACVRL1; ADORA2A; Aggrecan; AGR2; AICDA; AIF1; AIG1; AKAP1; AKAP2; AMH; AMHR2; ANGPT1; ANGPT2; ANGPTL3; ANGPTL4; ANPEP; APC; APOC1; AR; AZGP1 (zinc-a-glycoprotein); 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 (plectin); BRCA1; C19orf10 (IL27w); C3; C4A; C5; C5R1;CANT1; CASP1; CASP4; CAV1; CCBP2 (D6/JAB61); CCL1 (1-309); CCL11 (eotaxin); 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; exodus-2; CCL22 (MDC/STC-1); CCL23 (MPIF-1); CCL24 (MPIF-2/eotaxin-2); CCL25 (TECK); CCL26 (eotaxin-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/STRL 22/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; CDHI(E-cadherin); CDH10; CDH12; CDH13; CDH18; CDH19; CDH20; CDH5; CDH7; CDH8; CDH9; CDK2; CDK3; CDK4; CDK5; CDK6; CDK7; CDK9; CDKN1A (p21 Wap1/Cip1); CDKN1B (p27Kip1); CDKN1C; CDKN2A (p16INK4a); CDKN2B; CDKN2C; CDKN3; CEBPB; CER1; CHGA; CHGB; Chitinase; CHST10; CKLFSF2; CKLFSF3; CKLFSF4; CKLFSF5; CKLFSF6; CKLFSF7; CKLFSF8; CLDN3; CLDN7 (claudin-7); CLN3; CLU (clusterin); CMKLR1; CMKOR1 (RDC1); CNR1; COL18A1; COL1A1; COL4A3; COL6A1; CR2; CRP; CSFI(M-CSF); CSF2 (GM-CSF); CSF3 (GCSF); CTLA4; CTNNB1 (b-catenin); CTSB (cathepsin B); CX3CL1 (SCYD1); CX3CR1 (V28); CXCL1 (GR01); CXCL10 (IP-10); CXCL11(I-TAC/IP-9); CXCL12 (SDF1); CXCL13; CXCL14; CXCL16; CXCL2 (GR02); CXCL3 (GR03); CXCL5 (ENA-78/LIX); CXCL6 (GCP-2); CXCL9 (MIG); CXCR3 (GPR9/CKR-L2); CXCR4; CXCR6 (TYMSTR/STRL33/Bonzo); CYB5; CYC1; CYSLTR1; DAB21P; 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; FGF1; 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 (fibronectin); FLT1; FOS; FOSL1 (FRA-1); FY (DARC); GABRP (GABAa); GAGEB1; GAGEC1; GALNAC4S-6ST; GAT A3; GDF5; GFI1; GGT1; GM-CSF; GNAS1; GNRH1; GPR2 (CCR10); GPR31; GPR44; GPR81 (FKSG80); GRCC10 (C10); GRP; GSN (Gelsolin); GSTP1; HAVCR2; HDAC4; HDAC5; HDAC7A; HDAC9; HGF; HIF1A; HIP1; histamine and histamine receptors; HLA-A; HLA-DRA; HM74; HMOX1; HUMCYT2A; ICEBERG; ICOSL; ID2; IFN-a; IFNA1; IFNA2; IFNA4; IFNA5; IFNA6; IFNA7; IFNB1; IFNgamma; 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 (glycoprotein 130); IL7; IL7R; IL8; IL8RA; IL8RB; IL9; IL9R; ILK; INHA; INHBA; INSL3; INSL4; IRAKI; IRAK2; ITGA1; ITGA2; ITGA3; ITGA6 (a6 integrin); ITGAV; ITGB3; ITGB4 (b 4 integrin); JAG1; JAK1; JAK3; JUN; K6HF; KAI1; KDR; KITLG; KLF5 (GC Box BP); KLF6; KLK10; KLK12; KLK13; KLK14; KLK15; KLK3; KLK4; KLK5; KLK9; KRT1; KRT19 (Keratin 19); KRT2A; KRTHB6 (hair-specific type II keratin); LAMA5; LEP (leptin); Lingo-p75; Lingo-Troy; LPS; LTA (TNF-b); LTB; LTB4R (GPR16); LTB4R2; LTBR; MACMARCKS; MAG or Omgp; MAP2K7 (c-Jun); MDK; MIB1; midkine; MIF; MIP-2; MKI67 (Ki-67); MMP2; MMP9; MS4A1; MSMB; MT3 (metallothionectin-III); MTSS1; MUC1 (mucin); MYC; MYD88; NCK2; neurocan; 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; phosphacan; 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 (lipophilin B); SCGB2A1(mammaglobin 2); SCGB2A2 (mammaglobin 1); SCYE1 (endothelial Monocyte-activating cytokine); SDF2; SERPINA1; SERPINA3; SERPINB5 (maspin); 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; TGFB111; TGFB2; TGFB3; TGFBR1; TGFBR2; TGFBR3; TH1L; THBS1 (thrombospondin-1); THBS2; THBS4; THPO; TIE (Tie-1); TIMP3; tissue factor; 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 ligand); TNFSF5 (CD40 ligand); TNFSF6 (FasL); TNFSF7 (CD27 ligand); TNFSF8 (CD30 ligand); TNFSF9 (4-1BB ligand); TOLLIP; Toll-like receptors; TOP2A (topoisomerase lia); TP53; TPM1; TPM2; TRADD; TRAF1; TRAF2; TRAF3; TRAF4; TRAF5; TRAF6; TREM1; TREM2; TRPC6; TSLP; TWEAK; VEGF; VEGFB; VEGFC; versican; VHL C5; VLA-4; XCL1 (lymphotactin); XCL2 (SCM-1b); XCR1 (GPR5/CCXCR1); YY1; and ZFPM2. 
     
     
         88 . The binding protein of  claim 85 , wherein the binding protein also binds to CD52, CD20, CD19, CD3, CD4, CD8, BMP6, IL12A, IL1A, IL1B, IL2, IL24, INHA, TNF, TNFSF10, EGF, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, GRP, IGF1, IGF2, TGFA, TGFB1, TGFB2, TGFB3, VEGF, CDK2, IGF1R, BCL2, CD164, CDKN1C, CDKN2B, CDKN2C, CDKN3, GNRH1, IGFBP6, ODZ1, PAWR, PLG, TGFB1I1, AR, BRCA1, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, E2F1, EGFR, ENO1, ERBB2, ESR1, ESR2, IGFBP3, INSL4, MYC, NOX5, NR6A1, PAP, PCNA, PRKCQ, PRKD1, PRL, TP53, KLK6, CHGB, INSL3, SHBG, NR1D1, NR1H3, NR1I3, NR2F6, NR4A3, NR0B1, NR0B2, NR1D2, NR1H2, NR1H4, NR1I2, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR3C1, NR3C2, NR4A1, NR4A2, NR5A1, NR5A2, PGR, RARB, KLK3, KRT1, APOC1, CHGA, COL1A1, COL6A1, ERK8, KLK10, KLK12, KLK13, KLK14, KLK15, KLK4, KLK5, KLK9, MMP2, MMP9, MSMB, NTN4, PSAP, SERPINA3, TIMP3, CD44, CDH20, CDH10, CDH13, CDH18, CDH19, CDH7, CDH8, CDH9, ROBO2, ILK, ITGA1, APC, MTSS1, AGR2, AIG1, AKAP1, AKAP2, CANT1, CAV1, CDH12, CLDN3, CLN3, CYB5, CYC1, DAB21P, DES, DNCL1, ELAC2, ENO2, ENO3, FASN, FLJ12584, FLJ25530, GAGEB1, GAGEC1, GGT1, GSTP1, HIP1, HUMCYT2A, IL29, K6HF, KAI1, KRT2A, MIB1, PART1, PATE, PCA3, PIAS2, PIK3CG, PPID, PR1, PSCA, SLC2A2, SLC33A1, SLC43A1, STEAP, STEAP2, TPM1, TPM2, TRPC6, ANGPT1, ANGPT2, ANPEP, ECGF1, EREG, FIGF, FLT1, JAG1, KDR, LAMA5, NRP1, NRP2, PGF, PLXDC1, STAB1, VEGFC, ANGPTL3, BAI1, COL4A3, IL8, ANGPTL4, PECAM1, PF4, PROK2, SERPINF1, CCL11, CCL2, CXCL1, CXCL10, CXCL3, CXCL5, CXCL6, CXCL9, IFNA1, IFNB1, IFNG, IL6, MDK, EDG1, EFNA1, EFNA3, EFNB2, EPHB4, FGFR3, HGF, ITGB3, PDGFA, TEK, TGFBR1, CDH5, COL18A1, ENG, ITGAV, BAD, BAG1, CCNA1, CCNA2, CCND1, CCNE1, CCNE2, CDH1 (E-cadherin), CDKN1B (p27Kip1), CDKN2A (p16INK4a), CTNNB1 (b-catenin), CTSB (cathepsin B), F3 (TF), FOSL1 (FRA-1), GAT A3, GSN (Gelsolin), IGFBP2, IL2RA, IL6R, IL6ST (glycoprotein 130), ITGA6 (a6 integrin), JUN, MAP2K7 (c-Jun), MKI67 (Ki-67), NGFB (NGF), NGFR, NME1 (NM23A), PLAU (uPA), PTEN, SERPINB5 (maspin), SERPINE1 (PAI-1), THBS1 (thrombospondin-1), TIE (Tie-1), TNFRSF6 (Fas), TNFSF6 (FasL), TOP2A (topoisomerase lia), AZGP1 (zinc-a-glycoprotein), BPAG1 (plectin), CDKN1A (p21Wap1/Cip1), CLDN7 (claudin-7), CLU (clusterin), ERBB2 (Her-2), FLRT1 (fibronectin), GABRP (GABAa), GNAS1, ID2, ITGB4 (b 4 integrin), KLF5 (GC Box BP), KRT19 (Keratin 19), KRTHB6 (hair-specific type II keratin), MACMARCKS, MT3 (metallothionectin-III), MUC1 (mucin), PTGS2 (COX-2), RAC2 (p21Rac2), S100A2, SCGB1D2 (lipophilin B), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SPRR1B (Spr1), THBS2, THBS4, and TNFAIP2 (B94). 
     
     
         89 . The binding protein of  claim 85 , wherein the binding protein also binds to a target selected from the group consisting of TNF, IL-12, IL-12p40, IL-18, C5, CBL, CD147, gp120, 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-1 alpha, IL-1 beta, IL-1 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. 
     
     
         90 . The binding protein of  claim 85 , wherein the binding protein also binds to a member of the EGF or Erb-3 family. 
     
     
         91 . 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 an insulin-like growth factor. 
     
     
         92 . The binding protein of  claim 91 , wherein the insulin-like growth factor is selected from IGF1, IGF2, IGF1/2, and IGF1R. 
     
     
         93 . The binding protein of  claim 91 , wherein the binding protein also binds to CD52, CD20, CD19, CD3, CD4, CD8, BMP6, IL12A, IL1A, IL1B, IL2, IL24, INHA, TNF, TNFSF10, EGF, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, GRP, IGF1, IGF2, TGFA, TGFB1, TGFB2, TGFB3, VEGF, CDK2, IGF1R, BCL2, CD164, CDKN1C, CDKN2B, CDKN2C, CDKN3, GNRH1, IGFBP6, ODZ1, PAWR, PLG, TGFB1I1, AR, BRCA1, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, E2F1, EGFR, ENO1, ERBB2, ESR1, ESR2, IGFBP3, INSL4, MYC, NOX5, NR6A1, PAP, PCNA, PRKCQ, PRKD1, PRL, TP53, KLK6, CHGB, INSL3, SHBG, NR1D1, NR1H3, NR1I3, NR2F6, NR4A3, NR0B1, NR0B2, NR1D2, NR1H2, NR1H4, NR1I2, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR3C1, NR3C2, NR4A1, NR4A2, NR5A1, NR5A2, PGR, RARB, KLK3, KRT1, APOC1, CHGA, COL1A1, COL6A1, ERK8, KLK10, KLK12, KLK13, KLK14, KLK15, KLK4, KLK5, KLK9, MMP2, MMP9, MSMB, NTN4, PSAP, SERPINA3, TIMP3, CD44, CDH20, CDH10, CDH13, CDH18, CDH19, CDH7, CDH8, CDH9, ROBO2, ILK, ITGA1, APC, MTSS1, AGR2, AIG1, AKAP1, AKAP2, CANT1, CAV1, CDH12, CLDN3, CLN3, CYB5, CYC1, DAB21P, DES, DNCL1, ELAC2, ENO2, ENO3, FASN, FLJ12584, FLJ25530, GAGEB1, GAGEC1, GGT1, GSTP1, HIP1, HUMCYT2A, IL29, K6HF, KAI1, KRT2A, MIB1, PART1, PATE, PCA3, PIAS2, PIK3CG, PPID, PR1, PSCA, SLC2A2, SLC33A1, SLC43A1, STEAP, STEAP2, TPM1, TPM2, TRPC6, ANGPT1, ANGPT2, ANPEP, ECGF1, EREG, FIGF, FLT1, JAG1, KDR, LAMA5, NRP1, NRP2, PGF, PLXDC1, STAB1, VEGFC, ANGPTL3, BAI1, COL4A3, IL8, ANGPTL4, PECAM1, PF4, PROK2, SERPINF1, CCL11, CCL2, CXCL1, CXCL10, CXCL3, CXCL5, CXCL6, CXCL9, IFNA1, IFNB1, IFNG, IL6, MDK, EDG1, EFNA1, EFNA3, EFNB2, EPHB4, FGFR3, HGF, ITGB3, PDGFA, TEK, TGFBR1, CDH5, COL18A1, ENG, ITGAV, BAD, BAG1, CCNA1, CCNA2, CCND1, CCNE1, CCNE2, CDH1 (E-cadherin), CDKN1B (p27Kip1), CDKN2A (p16INK4a), CTNNB1 (b-catenin), CTSB (cathepsin B), F3 (TF), FOSL1 (FRA-1), GAT A3, GSN (Gelsolin), IGFBP2, IL2RA, IL6R, IL6ST (glycoprotein 130), ITGA6 (a6 integrin), JUN, MAP2K7 (c-Jun), MKI67 (Ki-67), NGFB (NGF), NGFR, NME1 (NM23A), PLAU (uPA), PTEN, SERPINB5 (maspin), SERPINE1 (PAI-1), THBS1 (thrombospondin-1), TIE (Tie-1), TNFRSF6 (Fas), TNFSF6 (FasL), TOP2A (topoisomerase lia), AZGP1 (zinc-a-glycoprotein), BPAG1 (plectin), CDKN1A (p21Wap1/Cip1), CLDN7 (claudin-7), CLU (clusterin), ERBB2 (Her-2), FLRT1 (fibronectin), GABRP (GABAa), GNAS1, ID2, ITGB4 (b 4 integrin), KLF5 (GC Box BP), KRT19 (Keratin 19), KRTHB6 (hair-specific type II keratin), MACMARCKS, MT3 (metallothionectin-III), MUC1 (mucin), PTGS2 (COX-2), RAC2 (p21Rac2), S100A2, SCGB1D2 (lipophilin B), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SPRR1B (Spr1), THBS2, THBS4, and TNFAIP2 (B94). 
     
     
         94 . The binding protein of  claim 91 , wherein the binding protein binds to IGF1 and IGF2. 
     
     
         95 . The binding protein of  claim 91 , wherein the binding protein binds to IGF1/2 and ErbBr (HER-2). 
     
     
         96 . 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 cluster of differentiation (CD) protein. 
     
     
         97 . The binding protein of  claim 96 , wherein the CD protein is selected from CD3, CD4, CD8, CD11, CD14, CD18, CD19, CD20, CD22, CD23, CD24, CD25, CD28, CD33, CD37, CD38, CD40, CD44, CD52, CD54, CD64, CD72, CD74, CD80, CD81, CD83, CD86, CD138 and/or CD164. 
     
     
         98 . The binding protein of  claim 96 , wherein the CD protein is CD3. 
     
     
         99 . The binding protein of  claim 98 , wherein the CD3 is muromonab-CD3 (Orthoclone IKT3®). 
     
     
         100 . The binding protein of  claim 96 , wherein the CD protein is CD4. 
     
     
         101 . The binding protein of  claim 96 , wherein the CD protein is CD19. 
     
     
         102 . The binding protein of  claim 96 , wherein the CD protein is CD20. 
     
     
         103 . The binding protein of  claim 102 , wherein the CD20 is selected from RITUXAN® (Idec/Genentech/Roche), HUMAX-CD-20® (Genmab), ibritumomab tiuxetan (ZEVALIN® Idec/Schering AG) and hA20 (Immunomedics). 
     
     
         104 . The binding protein of  claim 96 , wherein the variable domains that form the functional target binding site for the CD protein comprise variable domains from ABX-CBL (Abgenix), Efalizumab (RAPTIVA®), HUMAX CD4® (Genmab), IDEC-114 (IDEC Pharmaceuticals), IDEC-131 (IDEC Pharmaceuticals), IDEC151 (Clenoliximab, IDEC Pharmaceuticals), IDEC152 (IDEC Pharmaceuticals), Epratuzumab (LYMPHOCIDE®), MDX-060 (Medarex), MOR101 and MOR102 (MorphoSys). 
     
     
         105 . The binding protein of any one of  claims 98 - 102 , wherein the binding protein also binds to CD52, CD20, CD19, CD3, CD4, CD8, BMP6, IL12A, IL1A, IL1B, IL2, IL24, INHA, TNF, TNFSF10, EGF, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, GRP, IGF1, IGF2, TGFA, TGFB1, TGFB2, TGFB3, VEGF, CDK2, IGF1R, BCL2, CD164, CDKN1C, CDKN2B, CDKN2C, CDKN3, GNRH1, IGFBP6, ODZ1, PAWR, PLG, TGFB1I1, AR, BRCA1, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, E2F1, EGFR, ENO1, ERBB2, ESR1, ESR2, IGFBP3, INSL4, MYC, NOX5, NR6A1, PAP, PCNA, PRKCQ, PRKD1, PRL, TP53, KLK6, CHGB, INSL3, SHBG, NR1D1, NR1H3, NR1I3, NR2F6, NR4A3, NR0B1, NR0B2, NR1D2, NR1H2, NR1H4, NR1I2, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR3C1, NR3C2, NR4A1, NR4A2, NR5A1, NR5A2, PGR, RARB, KLK3, KRT1, APOC1, CHGA, COL1A1, COL6A1, ERK8, KLK10, KLK12, KLK13, KLK14, KLK15, KLK4, KLK5, KLK9, MMP2, MMP9, MSMB, NTN4, PSAP, SERPINA3, TIMP3, CD44, CDH20, CDH10, CDH13, CDH18, CDH19, CDH7, CDH8, CDH9, ROB02, ILK, ITGA1, APC, MTSS1, AGR2, AIG1, AKAP1, AKAP2, CANT1, CAV1, CDH12, CLDN3, CLN3, CYB5, CYC1, DAB21P, DES, DNCL1, ELAC2, ENO2, ENO3, FASN, FLJ12584, FLJ25530, GAGEB1, GAGEC1, GGT1, GSTP1, HIP1, HUMCYT2A, IL29, K6HF, KAI1, KRT2A, MIB1, PART1, PATE, PCA3, PIAS2, PIK3CG, PPID, PR1, PSCA, SLC2A2, SLC33A1, SLC43A1, STEAP, STEAP2, TPM1, TPM2, TRPC6, ANGPT1, ANGPT2, ANPEP, ECGF1, EREG, FIGF, FLT1, JAG1, KDR, LAMA5, NRP1, NRP2, PGF, PLXDC1, STAB1, VEGFC, ANGPTL3, BAI1, COL4A3, IL8, ANGPTL4, PECAM1, PF4, PROK2, SERPINF1, CCL11, CCL2, CXCL1, CXCL10, CXCL3, CXCL5, CXCL6, CXCL9, IFNA1, IFNB1, IFNG, IL6, MDK, EDG1, EFNA1, EFNA3, EFNB2, EPHB4, FGFR3, HGF, ITGB3, PDGFA, TEK, TGFBR1, CDH5, COL18A1, ENG, ITGAV, BAD, BAG1, CCNA1, CCNA2, CCND1, CCNE1, CCNE2, CDH1 (E-cadherin), CDKN1B (p27Kip1), CDKN2A (p16INK4a), CTNNB1 (b-catenin), CTSB (cathepsin B), F3 (TF), FOSL1 (FRA-1), GAT A3, GSN (Gelsolin), IGFBP2, IL2RA, IL6R, IL6ST (glycoprotein 130), ITGA6 (a6 integrin), JUN, MAP2K7 (c-Jun), MKI67 (Ki-67), NGFB (NGF), NGFR, NME1 (NM23A), PLAU (uPA), PTEN, SERPINB5 (maspin), SERPINE1 (PAI-1), THBS1 (thrombospondin-1), TIE (Tie-1), TNFRSF6 (Fas), TNFSF6 (FasL), TOP2A (topoisomerase lia), AZGP1 (zinc-a-glycoprotein), BPAG1 (plectin), CDKN1A (p21Wap1/Cip1), CLDN7 (claudin-7), CLU (clusterin), ERBB2 (Her-2), FLRT1 (fibronectin), GABRP (GABAa), GNAS1, ID2, ITGB4 (b 4 integrin), KLF5 (GC Box BP), KRT19 (Keratin 19), KRTHB6 (hair-specific type II keratin), MACMARCKS, MT3 (metallothionectin-III), MUC1 (mucin), PTGS2 (COX-2), RAC2 (p21Rac2), S100A2, SCGB1D2 (lipophilin B), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SPRR1B (Spr1), THBS2, THBS4, and TNFAIP2 (B94). 
     
     
         106 . The binding protein of  claim 102 , wherein the binding protein binds to CD20 and CD3. 
     
     
         107 . The binding protein of  claim 102 , wherein the binding protein binds to CD20 and CD138. 
     
     
         108 . The binding protein of  claim 102 , wherein the binding protein binds to CD20 and CD38. 
     
     
         109 . The binding protein of  claim 102 , wherein the binding protein binds to CD20 and CD40. 
     
     
         110 . The binding protein of  claim 96 , wherein the binding protein binds to CD38 and CD138. 
     
     
         111 . The binding protein of  claim 96 , wherein the binding protein binds to CD38 and CD40. 
     
     
         112 . The binding protein of  claim 96 , wherein the binding protein binds to CD138 and CD40. 
     
     
         113 . 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 the variable domains for at least one functional target site are derived from an anti-EpCAM antibody. 
     
     
         114 . 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 angiopoietin2 (ANGPT2). 
     
     
         115 . The binding protein of  claims 114 , wherein the binding protein also binds to CD52, CD20, CD19, CD3, CD4, CD8, BMP6, IL12A, IL1A, IL1B, IL2, IL24, INHA, TNF, TNFSF10, EGF, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, GRP, IGF1, IGF2, TGFA, TGFB1, TGFB2, TGFB3, VEGF, CDK2, IGF1R, BCL2, CD164, CDKN1C, CDKN2B, CDKN2C, CDKN3, GNRH1, IGFBP6, ODZ1, PAWR, PLG, TGFB1I1, AR, BRCA1, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, E2F1, EGFR, ENO1, ERBB2, ESR1, ESR2, IGFBP3, INSL4, MYC, NOX5, NR6A1, PAP, PCNA, PRKCQ, PRKD1, PRL, TP53, KLK6, CHGB, INSL3, SHBG, NR1D1, NR1H3, NR1I3, NR2F6, NR4A3, NR0B1, NR0B2, NR1D2, NR1H2, NR1H4, NR1I2, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR3C1, NR3C2, NR4A1, NR4A2, NR5A1, NR5A2, PGR, RARB, KLK3, KRT1, APOC1, CHGA, COL1A1, COL6A1, ERK8, KLK10, KLK12, KLK13, KLK14, KLK15, KLK4, KLK5, KLK9, MMP2, MMP9, MSMB, NTN4, PSAP, SERPINA3, TIMP3, CD44, CDH20, CDH10, CDH13, CDH18, CDH19, CDH7, CDH8, CDH9, ROBO2, ILK, ITGA1, APC, MTSS1, AGR2, AIG1, AKAP1, AKAP2, CANT1, CAV1, CDH12, CLDN3, CLN3, CYB5, CYC1, DAB21P, DES, DNCL1, ELAC2, ENO2, ENO3, FASN, FLJ12584, FLJ25530, GAGEB1, GAGEC1, GGT1, GSTP1, HIP1, HUMCYT2A, IL29, K6HF, KAI1, KRT2A, MIB1, PART1, PATE, PCA3, PIAS2, PIK3CG, PPID, PR1, PSCA, SLC2A2, SLC33A1, SLC43A1, STEAP, STEAP2, TPM1, TPM2, TRPC6, ANGPT1, ANGPT2, ANPEP, ECGF1, EREG, FIGF, FLT1, JAG1, KDR, LAMA5, NRP1, NRP2, PGF, PLXDC1, STAB1, VEGFC, ANGPTL3, BAI1, COL4A3, IL8, ANGPTL4, PECAM1, PF4, PROK2, SERPINF1, CCL11, CCL2, CXCL1, CXCL10, CXCL3, CXCL5, CXCL6, CXCL9, IFNA1, IFNB1, IFNG, IL6, MDK, EDG1, EFNA1, EFNA3, EFNB2, EPHB4, FGFR3, HGF, ITGB3, PDGFA, TEK, TGFBR1, CDH5, COL18A1, ENG, ITGAV, BAD, BAG1, CCNA1, CCNA2, CCND1, CCNE1, CCNE2, CDH1 (E-cadherin), CDKN1B (p27Kip1), CDKN2A (p16INK4a), CTNNB1 (b-catenin), CTSB (cathepsin B), F3 (TF), FOSL1 (FRA-1), GATA3,GSN (Gelsolin), IGFBP2, IL2RA, IL6R, IL6ST (glycoprotein 130), ITGA6 (a6 integrin), JUN, MAP2K7 (c-Jun), MKI67 (Ki-67), NGFB (NGF), NGFR, NME1 (NM23A), PLAU (uPA), PTEN, SERPINB5 (maspin), SERPINE1 (PAI-1), THBS1 (thrombospondin-1), TIE (Tie-1), TNFRSF6 (Fas), TNFSF6 (FasL), TOP2A (topoisomerase lia), AZGP1 (zinc-a-glycoprotein), BPAG1 (plectin), CDKN1A (p21Wap1/Cip1), CLDN7 (claudin-7), CLU (clusterin), ERBB2 (Her-2), FLRT1 (fibronectin), GABRP (GABAa), GNAS1, ID2, ITGB4 (b 4 integrin), KLF5 (GC Box BP), KRT19 (Keratin 19), KRTHB6 (hair-specific type II keratin), MACMARCKS, MT3 (metallothionectin-III), MUC1 (mucin), PTGS2 (COX-2), RAC2 (p21Rac2), S100A2, SCGB1D2 (lipophilin B), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SPRR1B (Spr1), THBS2, THBS4, and TNFAIP2 (B94).