Dual variable domain immunoglobulin and uses thereof

• US 7,612,181 B2
• Filed: 08/18/2006
• Issued: 11/03/2009
• Est. Priority Date: 08/19/2005
• Status: Expired due to Fees

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Dixon, Richard W., Wu, Chengbin, Salfeld, Jochen G., Ghayur, Tariq
• Primary Examiner(s): Blanchard; David J.
• Assistant Examiner(s): GUSSOW, ANNE
• Application Number:
  US11/507,050
• Publication Number:
  US 20070071675A1
• Time in Patent Office: 1,173 Days
• Field of Search: None
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 51/1093 conjugates with carriers being antibodies
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/22 : against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/24 : against cytokines, lymphokines or interferons
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 16/244 : Interleukins [IL]
• CPC Class Codes: C07K 16/245 : IL-1
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/40 : against enzymes
• CPC Class Codes: C07K 16/46 : Hybrid immunoglobulins hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00
• CPC Class Codes: C07K 16/467 : Igs with modifications in the FR-residues only
• CPC Class Codes: C07K 16/468 : Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/51 : Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/522 : CH1 domain
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/64 : comprising a combination of variable region and constant region components
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

1. A binding protein comprising four polypeptide chains, wherein two polypeptide chains comprise VD1-(X1)n-VD2-C-(X2)n, wherein VD1 is a first heavy chain variable domain, VD2 is a second heavy chain variable domain, C is a heavy chain constant domain, X1 is a linker with the proviso that it is not CH1, and X2 is an Fc region;

and two polypeptide chains comprise VD1-(X1)n-VD2-C-(X2)n, wherein VD1 is a first light chain variable domain, VD2 is a second light chain variable domain, C is a light chain constant domain, X1 is a linker with the proviso that it is not CH1, and X2 does not comprise an Fc region; and

n is 0 or 1;

wherein said four polypeptide chains of said binding protein form four functional antigen binding sites.

2. The binding protein according to claim 1, wherein said binding protein is capable of binding one or more targets.

3. The binding protein according to claim 2, wherein said one or more targets is 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/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-cadherin);

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;

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 (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 (fibronectin);

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 (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;

IL8RB;

IL9;

IL9R;

ILK;

INHA;

INHBA;

INSL3;

INSL4;

IRAK1;

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;

KLK6;

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;

NRII2;

NRII3;

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;

SI00A2;

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;

TGFBI;

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 Iia);

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.

4. The binding protein according to claim 1, wherein said binding protein is capable of binding a two targets, wherein the two targets are selected from the group consisting of CD138 and CD20;

CD138 and CD40;

CD20 and CD3;

CD38 &

CD138;

CD38 and CD20;

CD38 and CD40;

CD40 and CD20;

CD19 and CD20;

CD-8 and IL-6;

PDL-1 and CTLA-4;

CTLA-4 and BTNO2;

CSPGs and RGM A;

IGF1 and IGF2;

IGF1/2 and Erb2B;

IL-12 and IL-18;

IL-12 and TWEAK;

IL-13 and ADAM8;

IL-13 and CL25;

IL-13 and IL-1beta;

IL-13 and IL-25;

IL-13 and IL-4;

IL-13 and IL-5;

IL-13 and IL-9;

IL-13 and LHR agonist;

IL-13 and MDC;

IL-13 and MIF;

IL-13 and PED2;

IL-13 and SPRR2a;

IL-13 and SPRR2b;

IL-13 and TARC;

IL-13 and TGF-β

;

IL-1α and

IL-1β

;

MAG and RGM A;

NgR and RGM A;

NogoA and RGM A;

OMGp and RGM A;

RGM A and RGM B;

Te38 and TNFα

;

TNFα and

IL-12;

TNFα and

IL-12p40;

TNFα and

IL-13;

TNFα and

IL-15;

TNFα and

IL-17;

TNFα and

IL-18;

TNFα and

IL-1beta;

TNFα and

IL-23;

TNFα and

MIF;

TNFα and

PEG2;

TNFα and

PGE4;

TNFα and

VEGF; and

VEGFR and EGFR;

TNFα and

RANK ligand;

TNFα and

Blys;

TNFα and

GP130;

TNFα and

CD-22; and

TNFα and

CTLA-4.

5. The binding protein according to claim 2, wherein the binding protein is capable of modulating a biological function of one or more targets.

6. The binding protein according to claim 2, wherein the binding protein is capable of neutralizing one or more targets.

7. The binding protein according to claim 2, wherein said one or more targets is selected from the group consisting of cytokine, chemokine, cell surface protein, enzyme and receptor.

8. The binding protein according to claim 7 wherein the cytokine is selected from the group consisting of lymphokines, monokines, and polypeptide hormones.

9. The binding protein according to claim 8, wherein said cytokines are IL-1α

and IL-1β

.

10. The binding protein according to claim 9, wherein the binding protein comprises a DVD heavy chain amino acid sequence selected from the group consisting of 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, and SEQ ID NO. 59;

and a DVD light chain amino acid sequence selected from the group consisting of 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, and SEQ ID NO. 60.

11. The binding protein according to claim 8, wherein said cytokines are TNF-α

and IL-13.

12. The binding protein according to claim 8, wherein said cytokines are IL-12 and IL-18.

13. The binding protein according to claim 12, wherein the binding protein comprises a DVD heavy chain amino acid sequence selected from the group consisting of SEQ ID NO. 83, SEQ ID NO. 90, SEQ ID NO. 93, SEQ ID NO. 95, and SEQ ID NO. 114;

and a DVD light chain amino acid sequence selected from the group consisting of SEQ ID NO. 86, SEQ ID NO. 91, SEQ ID NO. 94, SEQ ID NO. 46, SEQ ID NO. 96, and SEQ ID NO. 116.

14. The binding protein according to claim 7 wherein the chemokine is selected from the group consisting of CCR2, CCR5 and CXCL-13.

15. The binding protein according to claim 7 wherein the cell surface protein is an integrin.

16. The binding protein according to claim 7 wherein the cell surface proteins are CD-20 and CD3.

17. The binding protein according to claim 16, wherein the binding protein comprises a DVD heavy chain amino acid sequence is SEQ ID NO. 97, and a DVD light chain SEQ ID NO. 101.

18. The binding protein according to claim 7 wherein the enzyme is selected from the group consisting of kinases and proteases.

19. The binding protein according to claim 7 wherein the receptor is selected from the group consisting of lymphokine receptor, monokine receptor, and polypeptide hormone receptor.

20. The binding protein according to claim 7, wherein said binding protein has an on rate constant(Kon) to said one or more targets selected from the group consisting of:

at least about 10²M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10³M<sup>−

1</sup>s<sup>−

1</sup>, at least about 10⁴M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10⁵M<sup>−

1</sup>s<sup>−

1</sup>; and

at least about 10⁶M<sup>−

1</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

21. The binding protein according to claim 7, wherein said binding protein has an off rate constant(Koff) to said one or more targets selected from the group consisting of:

at most about 10<sup>−

3</sup>s<sup>−

1</sup>;

at most about 10<sup>−

4</sup>s<sup>−

1</sup>;

at most about 10<sup>−

5</sup>s<sup>−

1</sup>; and

at most about 10<sup>−

6</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

22. The binding protein according to claim 7, wherein said binding protein has a dissociation constant (K_D) to said one or more targets selected from the group consisting of:

at most about 10<sup>−

7</sup> M;

at most about 10<sup>−

8</sup> M;

at most about 10<sup>−

9</sup> M;

at most about 10<sup>−

10</sup> M;

at most about 10<sup>−

11</sup> M;

at most about 10<sup>−

12</sup> M; and

at most 10<sup>−

13</sup> M.

23. A binding protein conjugate comprising a binding protein described in any one of claims 1-8, 12, and 13, said binding protein conjugate further comprising an agent selected from the group consisting of;

an immunoadhension molecule, an imaging agent, a therapeutic agent, and a cytotoxic agent.

24. The binding protein conjugate according to claim 23, wherein said agent is an imaging agent selected from the group consisting of a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin.

25. The binding protein conjugate according to claim 24, wherein said imaging agent is a radiolabel selected from the group consisting of:

³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁶Ho, and ¹⁵³Sm.

26. The binding protein conjugate according to claim 23, wherein said agent is a therapeutic or cytotoxic agent selected from the group consisting of;

an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, toxin, and an apoptotic agent.

27. The binding protein according to claim 1, wherein said binding protein is a crystallized binding protein.

28. The crystallized binding protein according to claim 27, wherein said crystal is a carrier-free pharmaceutical controlled release crystal.

29. The crystallized binding protein according to claim 27, wherein said binding protein has a greater half life in vivo than the soluble counterpart of said binding protein.

30. The crystallized binding protein according to claim 27, wherein said binding protein retains biological activity.

31. A binding protein described in claim 1 produced according to a method comprising culturing a host cell in culture medium under conditions sufficient to produce said binding protein, wherein said host cell comprises a vector, said vector comprising a nucleic acid encoding said binding protein.

32. A pharmaceutical composition comprising a binding protein of any one of claims 1-8, 12, 13, 27-30, and 31, and a pharmaceutically acceptable carrier.

33. The pharmaceutical composition of claim 32 further comprising at least one additional therapeutic agent.

34. The binding protein according to any one of claims 1-6, wherein the linker XI is selected from the group consisting of AKTTPKLEEGEFSEAR (SEQ ID NO:

118);

AKTTPKLEEGEFSEARV (SEQ ID NO;

119);

AKTTPKLGG (SEQ ID NO;

     120);

SAKTTPKLGG (SEQ ID NO;

121);

SAKTTP (SEQ ID NO;

122);

RADAAP (SEQ ID NO;

123);

RADAAPTVS (SEQ ID NO;

124);

RADAAAAGGPGS (SEQ ID NO;

125);

RADAAAA(G4S)4 (SEQ ID NO;

126);

SAKTTPKLEEGEFSEARV (SEQ ID NO;

     127);

ADAAP (SEQ ID NO;

40);

ADAAPTVSIFPP (SEQ ID NO;

103);

TVAAP (SEQ ID NO;

44);

TVAAPSVFIFPP (SEQ ID NO;

50);

QPKAAP (SEQ ID NO;

88);

QPKAAPSVTLFPP (SEQ ID NO;

92);

AKTTPP (SEQ ID NO;

38);

AKTTPPSVTPLAP (SEQ ID NO;

128);

AKTTAP (SEQ ID NO;

129);

AKTTAPSVYPLAP (SEQ ID NO;

99);

ASTKGP (SEQ ID NO;

42);

ASTKGPSVFPLAP (SEQ ID NO;

48);

GGGGSGGGGSGGGGS (SEQ ID NO;

130);

GENKVEYAPALMALS (SEQ ID NO;

131);

GPAKELTPLKEAKVS (SEQ ID NO;

132); and

GHEAAAVMQVQYPAS (SEQ ID NO;

133).

35. The pharmaceutical composition according to claim 33, wherein said additional agent is a therapeutic or imaging agent.

36. The pharmaceutical composition of claim 35, wherein said additional agent is selected from the group consisting of:

Therapeutic agent, imaging agent, cytotoxic agent, angiogenesis inhibitors;

kinase inhibitors;

co-stimulation molecule blockers;

adhesion molecule blockers;

anti-cytokine antibody or functional fragment thereof;

methotrexate;

cyclosporin;

rapamycin;

FK506;

detectable label or reporter;

a TNF antagonist;

an antirheumatic;

a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, and a cytokine antagonist.

37. A pharmaceutical composition comprising a binding protein conjugate according to claim 23 and a pharmaceutically acceptable carrier.

38. The pharmaceutical composition according to claim 37, wherein said binding protein congjugate comprises an imaging agent selected from the group consisting of a radiolabel, an enxyme, a fluorescent labe, a luminescent label, a bioluminescent label, a magnetic label, and biotin.

39. The pharmaceutical composition according to claim 38, wherein said imaging agent is a radiolabel selected from the group consisting of:

³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹In, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁶Ho, and ¹⁵³Sm.

40. The pharamaceutical composition according to claim 37, wherein said binding protein conjugate comprises a therapeutic or cytotoxic agent selected from the group consisting of an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, a toxin, and an apoptotic agent.

41. The pharmaceutical composition of claim 37 further comprising a second agent.

42. The pharmaceutical composition of claim 41, wherein said second agent is a therapeutic or imaging agent.

43. The pharmaceutical composition of claim 42, wherein said therapeutic or imaging agent is selected from the group:

cytotoxic agent, angiogenesis inhibitors, kinase inhibitors;

co-stimulation molecule blockers;

adhesion molecule blockers;

anti-cytokine antibody or functional fragment thereof;

methotrexate;

cyclosporin;

rapamycin;

FK506;

detectable label or reportor;

a TNF antagonist;

an antiheumatic;

a muscle relaxant, a narcotic, anon-steroid anti-inflammatory dug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppresive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, ³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁶Ho, ¹⁵³Sm, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, biotin, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, and a cytokine antagonist.