What is claimed is:
1. A binding protein comprising an antigen binding domain capable of binding human IL-
17, said antigen binding domain comprises at least one CDR comprising an amino acid
sequence selected from the group consisting of:
CDR-H1. X1-X2-X3-X4-X5 (SEQ ID NO:919), wherein;
X1 is D or S;
X2 is Y;
X3 is E or G;
X4 is I, M, V, or F;
X5 is H; CDR-H2 . X1-X2—X3—X4—X5—X6—X7—X8—X9—X10-X11-X12—X13—X14—X15—X16—X17
(SEQ ID NO:920), wherein;
X1 is V;
X2 is T, I, or N;
X3 is D, H, or W;
X4 is P or is not present;
X5 is E, G, or S;
X6 is S, N, or D;
X7 is G;
X8 is G or T;
X9 is T;
X10 is L, A, T, or F;
X11 is H or Y;
X12 is N;
X13 is P, Q, or S;
X14 is K, A, or N;
X15 is F or L;
X16 is D, K, or R; and
X17 is G, D, or S; CDR-H3. X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 (SEQ ID NO: 921) ,
wherein;
X1 is Y, F, or D;
X2 is Y, L, S, or G;
X3 is K, T, R, or Y;
X4 is Y or W;
X5 is E, D, or I;
X6 is S, G, or Y;
X7 is F, Y, or T;
X8 is Y, F, or M;
4. The binding protein according to claim 3, wherein said at least 3 CDRs comprises a
variable domain CDR set selected from the group consisting of:
(Table Removed)
5. The binding protein according to claim 4, comprising at least two variable domain CDR
sets.
6. The binding protein according to claim 5, wherein said at least two variable domain CDR
sets are selected from a group consisting of:
VH 7D7 CDR Set and VL 7D7 CDR Set; VH 6C6 CDR Set and VL 6C6 CDR Set; VH 1D8 CDR Set and VL 1D8 CDR Set; VH 8B12 CDR Set and VL 8B12 CDR Set; VH 10F7 CDR Set and VL 10F7 CDR Set; and VH 5C5 CDR Set and VL 5C5 CDR Set; and VH 10G9 CDR Set and VL 10G9 Set.
7. The binding protein according to claim 6, further comprising a human acceptor
framework.
8. The binding protein according to claim 7, wherein said human acceptor framework
comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO.:7 SEQ ID NO.:17
SEQ ID NO.:8 SEQ ID NO.:18
SEQ ID NO.:9 SEQ ID NO.:19
SEQ ID NO.:10 SEQ ID NO.:20
SEQ ID NO.:ll SEQ ID NO.:21
SEQ ID NO.:12 SEQ ID NO.:22
SEQ ID NO.:13 SEQ ID NO.:23
SEQ ID NO.:14 SEQ ID NO.:24 AND
SEQ ID NO.:15 SEQ ID NO.:25.
SEQ ID NO.:16
9. The binding protein according to claim 7 or 8, wherein said human acceptor framework
comprises at least one framework region amino acid substitution, wherein the amino acid
sequence of the framework is at least 65% identical to the sequence of said human
acceptor framework and comprises at least 70 amino acid residues identical to said human
acceptor framework.
10. The binding protein according to claim 8, wherein said human acceptor framework
comprises at least one framework region amino acid substitution at a key residue, said key
residue selected from the group consisting of:
a residue adjacent to a CDR; a glycosylation site residue; a rare residue;
a residue capable of interacting with human IL-17; a residue capable of interacting with a CDR; a canonical residue;
a contact residue between heavy chain variable region and light chain variable region; a residue within a Vernier zone; and
a residue in a region that overlaps between a Chothia-defined variable heavy chain CDR1 and a Rabat-defined first heavy chain framework.
11. The binding protein according to claim 10, wherein key residue selected from the group consisting of: 2H, 4H, 24H, 26H, 27H, 29H, 34H, 35H, 37H, 39H, 44H, 45H, 47H, 48H, 49H, 50H, 51H, 58H, 59H, 60H, 63H, 67H, 69H, 71H, 73H, 76H, 78H, 91H, 93H, 94H, 2L, 4L, 25L, 29L, 27bL, 33L, 34L, 36L, 38L, 43L, 44L, 46L, 47L, 48L, 49L, 55L, 58L, 62L, 64L, 71L, 87L, 89L, 90L, 91L, 94L, 95L.
12. The binding protein according to claim 11, wherein the binding protein is a consensus human variable domain.
13. The binding protein according to claim 1, wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of:
SEQ ID NO:60 SEQ ID NO:71
SEQ ID NO:61 SEQ ID NO:72
SEQ ID NO:62 SEQ ID NO:73
SEQ ID NO:63 SEQ ID NO:74
SEQ ID NO:64 SEQ ID NO:75
SEQ ID NO:65 SEQ ID NO:76
SEQ ID NO:66 SEQ ID NO:931
SEQ ID NO:67 SEQ ID NO:932 AND
SEQ ID NO:68 SEQ ID NO:933.
SEQ ID NO:69
SEQ ID NO:70
14. The binding protein according to claim 13, wherein said binding protein comprises two
variable domains, wherein said two variable domains have amino acid sequences selected
from the group consisting of:
SEQ ID NO:60 & SEQ ID NO:62,
SEQ ID NO:60 & SEQ ID NO:63,
SEQ ID NO:60 & SEQ ID NO:64,
SEQ ID NO:60 & SEQ ID NO:65,
SEQ ID NO:60 & SEQ ID NO:66
SEQ ID NO:60 & SEQ ID NO:67,
SEQ ID NO:60 & SEQ ID NO:68,
SEQ ID NO:61 & SEQ ID NO:62,
SEQ ID NO:61 & SEQ ID NO:63,
SEQ ID NO:61 & SEQ ID NO:64,
SEQ ID NO:61 & SEQ ID NO:65,
SEQ ID NO:61 & SEQ ID NO:66,
SEQ ID NO:61 & SEQ ID NO:67, AND
SEQ ID NO:61 & SEQ ID NO:68.
15. The binding protein according to claim 11, wherein said binding protein comprises at
least one variable domain having an amino acid sequence selected from the group
consisting of:
SEQ ID NO:60 SEQ ID N0.:71
SEQ ID N0:61 SEQ ID NO.:72
SEQ ID NO:62 SEQ ID NO.:73
SEQ ID NO:63 SEQ ID NO.:74
SEQ ID NO:64 SEQ ID NO.:75
SEQ ID NO:65 SEQ ID NO.:76
SEQ ID NO:66 SEQ ID NO:931
SEQ ID NO:67 SEQ ID NO:932 AND
SEQ ID NO:68 SEQ ID NO:933.
SEQ ID NO:69
SEQ ID NO:70
16. The binding protein according to claim 1, wherein the binding protein binds IL-17.
17. The binding protein according to claim 14, wherein the binding protein binds IL-17.
18. The binding protein according to claim 17, wherein the binding protein is capable of modulating a biological function of IL-17.
19. The binding protein according to claim 17, wherein the binding protein is capable of neutralizing IL-17.
20. The binding protein according to claim 17, wherein said binding protein has an on rate constant (Kon) to said target selected from the group consisting of: at least about 102M-ls-1; at least about 103M-1s-1; at least about 104M-1s-1; at least about 105M-1s-1, and at least about 106M-1s-1; as measured by surface plasmon resonance.
21. The binding protein according to claim 17, wherein said binding protein has an off rate constant (Koff) to said target selected from the group consisting of: at most about 10-3s-1; at most about 10-4s-1; at most about 10-5s-1; and at most about 10-6s-1, as measured by surface plasmon resonance.
22. The binding protein according to claim 17, wherein said binding protein has a dissociation constant (KD) to said target selected from the group consisting of: at most about 10-7 M; at most about 10-8 M; at most about 10-9 M; at most about 10-10 M; at most about 10-11 M; at most about 10-12 M; and at most 10-13 M.
23. An IL-17 binding protein construct comprising a binding protein described in claim 1, said IL-17 binding protein construct further comprising a linker polypeptide or an immunoglobulin constant domain.
24. The IL-17 binding protein construct according to claim 23, wherein said binding protein is selected from the group consisting of;
an immunoglobulin molecule, a disulfide linked Fv,
a monoclonal antibody, a scFv,
a chimeric antibody, a single domain antibody,
a CDR-grafted antibody, a diabody,
a humanized antibody, a multispecific antibody,
a Fab, a dual specific antibody,a Fab',
a bispecific antibody, and
aF(ab')2, aDVD-Ig™.
aFv,
25. The IL-17 binding protein construct according to claim 23, wherein said binding protein
comprises a heavy chain immunoglobulin constant domain selected from the group
consisting of;
a human IgM constant domain, a human IgG4 constant domain,
a human IgGl constant domain, a human IgE constant domain,
a human IgG2 constant domain, and
a human IgG3 constant domain, a human IgA constant domain.
26. The IL-17 binding protein construct according to claim 23, comprising an
immunoglobulin constant domain having an amino acid sequence selected from the group
consisting of:
SEQ ID NO:3 SEQ ID NO:4 SEQ ID NO:5 and SEQ ID NO.6.
27. An IL-17 binding protein conjugate comprising an IL-17 binding protein construct of claim 24, said IL-17 binding protein conjugate further comprising an agent selected from the group consisting of; an immunoadhesion molecule, an imaging agent, a therapeutic agent, and a cytotoxic agent.
28. The IL-17 binding protein conjugate according to claim 27, 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.
29. The IL-17 binding protein conjugate according to claim 27, wherein said imaging agent is a radiolabel selected from the group consisting of: 3H, 14C, 35S, 90Y, 99Tc, l11In, 1251,131I, 177Lu,166Ho,andl53Sm.
30. The IL-17 binding protein conjugate according to claim 27, 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.
31. The IL-17 binding protein construct according to claim 24, wherein said binding protein possesses a human glycosylation pattern.
32. The binding protein according to claim 1, wherein said binding protein is a crystallized binding protein.
33. The IL-17 binding protein construct according to claim 23, wherein said IL-17 binding protein construct is a crystallized IL-17 binding protein construct.
34. The IL-17 binding protein construct according to claim 33, wherein said crystallized IL-17 binding protein construct is a carrier-free pharmaceutical controlled release crystallized IL-17 binding protein construct.
35. The IL-17 binding protein construct according to claim 34, wherein said IL-17 binding protein construct has a greater half life in vivo than the soluble counterpart of said IL-17 binding protein construct.
36. The IL-17 binding protein construct according to claim 34, wherein said IL-17 binding protein construct retains biological activity.
37. An isolated nucleic acid encoding a binding protein amino acid sequence of claim 1.
38. An isolated nucleic acid encoding an IL-17 binding protein construct amino acid sequence of claim 23.
39. A vector comprising an isolated nucleic acid according to claim 37 or 38.
40. The vector of claim 39, wherein said vector is selected from the group consisting of pcDNA, pTT, pTT3, pEFBOS, pBV, pJV, and pBJ.
41. A host cell comprising a vector according to claim 39.
42. The host cell according to claim 41, wherein said host cell is a prokaryotic cell.
43. The host cell according to claim 42, wherein said host cell is E. coli.
44. The host cell according to claim 41, wherein said host cell is a eukaryotic cell.
45. The host cell according to claim 44, wherein said eukaryotic cell is selected from the group consisting of protist cell, animal cell, plant cell, and fungal cell.
46. The host cell according to claim 44, wherein said eukaryotic cell is an animal cell selected from the group consisting of a mammalian cell, an avian cell, and an insect cell.
47. The host cell according to claim 44, wherein said host cell is a CHO cell.
48. The host cell according to claim 44, wherein said host cell is COS.
49. The host cell according to claim 44, wherein said host cell is a yeast cell.
50. The host cell according to claim 49, wherein said yeast cell is Saccharomyces cerevisiae.
51. The host cell according to claim 44, wherein said host cell is an insect Sf9 cell.
52. A method of producing a protein capable of binding IL-17, comprising culturing a host cell of claim 41 in culture medium under conditions sufficient to produce a binding protein capable of binding IL-17.
53. A protein produced according to the method of claim 52.
54. A composition for the release of a binding protein said composition comprising:

(a) a formulation, wherein said formulation comprises a crystallized binding protein, according to claim 33, and an ingredient; and
(b) at least one polymeric carrier.

55. The composition according to claim 54, wherein said polymeric carrier is a polymer selected from one or more of the group consisting of: poly (acrylic acid), poly (cyanoacrylates), poly (amino acids), poly (anhydrides), poly (depsipeptide), poly (esters), poly (lactic acid), poly (lactic-co-glycolic acid) or PLGA, poly (b-hydroxybutryate), poly (caprolactone), poly (dioxanone); poly (ethylene glycol), poly ((hydroxypropyl) methacrylamide, poly [(organo) phosphazene], poly (ortho esters), poly (vinyl alcohol), poly (vinylpyrrolidone), maleic anhydride- alkyl vinyl ether copolymers, pluronic polyols, albumin, alginate, cellulose and cellulose derivatives, collagen, fibrin, gelatin, hyaluronic acid, oligosaccharides, glycaminoglycans, sulfated polysaccharides, blends and copolymers thereof.
56. The composition according to claim 54, wherein said ingredient is selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-ß-cyclodextrin, methoxypolyethylene glycol and polyethylene glycol.
57. A method for treating a mammal comprising the step of administering to the mammal an effective amount of the composition according to claim 54.
58. A pharmaceutical composition comprising the binding protein of claim 1, and a pharmaceutically acceptable carrier.
59. The pharmaceutical composition of claim 58, wherein said pharmaceutically acceptable carrier functions as adjuvant useful to increase the absorption or dispersion of said binding protein.
60. The pharmaceutical composition of claim 59, wherein said adjuvant is hyaluronidase.
61. The pharmaceutical composition of claim 58 further comprising at least one additional therapeutic agent for treating a disorder in which IL-17 activity is detrimental.
62. The pharmaceutical composition of claim 61, 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 corticosteroid, 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 oral steroid, an epinephrine or analog, a cytokine, and a cytokine antagonist.
63. A method for reducing human IL-17 activity comprising contacting human IL-17 with the binding protein of claim 1 such that human IL-17 activity is reduced.
64. A method for reducing human IL-17 activity in a human subject suffering from a disorder in which IL-17 activity is detrimental, comprising administering to the human subject the binding protein of claim 1 such that human IL-17 activity in the human subject is reduced.
65. A method for treating a subject for a disease or a disorder in which IL-17 activity is detrimental by administering to the subject the binding protein of claim 1 such that treatment is achieved.
66. The method of claim 65, wherein said disorder is selected from the group consisting of respiratory disorders; asthma; allergic and nonallergic asthma; asthma due to infection; asthma due to infection with respiratory syncytial virus (RSV); chronic obstructive pulmonary disease (COPD); other conditions involving airway inflammation; eosinophilia; fibrosis and excess mucus production; cystic fibrosis; pulmonary fibrosis; atopic disorders; atopic dermatitis; urticaria; eczema; allergic rhinitis; and allergic
enterogastritis; inflammatory and/or autoimmune conditions of the skin; inflammatory and/or autoimmune conditions of gastrointestinal organs; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn's disease; inflammatory and/or autoimmune conditions of the liver; liver cirrhosis; liver fibrosis; liver fibrosis caused by hepatitis B and/or C virus; scleroderma; tumors or cancers; hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; viral infections; HTLV-1 infection (e.g., from HTLV-1); suppression of expression of protective type 1 immune responses, and suppression of expression of protective type 1 immune responses during vaccination.
67. The method of claim 64, wherein said disorder is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, spondyloarthropathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis B, Hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure,
premature ovarian failure, fibrotic lung disease, cryptogenic fibrosing alveolitis, postinflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polyrnyositis associated lung disease, Sjogren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, fibrosis, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasculitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sj5rgren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, choleosatatis, idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci (GBS) infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Thl Type mediated diseases, acute and chronic pain (different forms of pain), and cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma) Abetalipoproteinemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced
hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1- antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti-CD3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, Burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chronic myelocytic leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes, diabetes mellitus, diabetic arteriosclerotic disease, Diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's Syndrome in middle age, drug- induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallervorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis (A), His bundle arrhythmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza a, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular
atrophy, Kaposi's sarcoma, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of the corticospinal system, lipedema, liver transplant rejection, lymphedema, malaria, malignant Lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi-system disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine- Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodysplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, non-Hodgkins lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, OKT3® therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, Pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynaud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, senile chorea, Senile Dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, solid tumors, specific arrhythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, viral encephalitis/aseptic meningitis, viral-associated hemaphagocytic syndrome, Wernicke- Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, acute coronary syndromes, acute idiopathic polyneuritis, acute inflammatory
demyelinating polyradiculoneuropathy, acute ischemia, adult Still's disease, alopecia areata, anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia, arteriosclerosis, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure, blepharitis, bronchiectasis, bullous pemphigoid, cardiovascular disease, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinically isolated syndrome (cis) with risk for multiple sclerosis, conjunctivitis, childhood onset psychiatric disorder, chronic obstructive pulmonary disease (COPD), dacryocystitis, dermatomyositis, diabetic retinopathy, diabetes mellitus, disk herniation, disk prolapse, drug induced immune hemolytic anemia, endocarditis, endometriosis, endophthalmitis, episcleritis, erythema multiforme, erythema multiforme major, gestational pemphigoid, Guillain-Barre syndrome (GBS), hay fever, Hughes syndrome, idiopathic Parkinson's disease, idiopathic interstitial pneumonia, IgE-mediated allergy, immune hemolytic anemia, inclusion body myositis, infectious ocular inflammatory disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis, keratojunctivitis sicca, Kussmaul disease or Kussmaul-Meier disease, Landry's paralysis, Langerhan's cell histiocytosis, livedo reticularis, macular degeneration, microscopic polyangiitis, morbus bechterev, motor neuron disorders, mucous membrane pemphigoid, multiple organ failure, myasthenia gravis, myelodysplastic syndrome, myocarditis, nerve root disorders, neuropathy, non-A non-B hepatitis, optic neuritis, osteolysis, ovarian cancer, pauciarticular JRA, peripheral artery occlusive disease (PAOD), peripheral vascular disease (PVD), peripheral artery, disease (PAD), phlebitis, polyarteritis nodosa (or periarteritis nodosa), polychondritis, polymyalgia rheumatica, poliosis, polyarticular JRA, polyendocrine deficiency syndrome, polymyositis, polymyalgia rheumatica (PMR), post-pump syndrome, primary Parkinsonism, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), prostatitis, pure red cell aplasia, primary adrenal insufficiency, recurrent neuromyelitis optica, restenosis, rheumatic heart disease, sapho (synovitis, acne, pustulosis, hyperostosis, and osteitis), scleroderma, secondary amyloidosis, shock lung, scleritis, sciatica, secondary adrenal insufficiency, silicone associated connective tissue disease, sneddon-wilkinson dermatosis, spondylitis ankylosans, Stevens-Johnson syndrome (SJS), systemic inflammatory response syndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, transverse myelitis, TRAPS (tumor necrosis factor receptor, type 1 allergic reaction, type II diabetes, urticaria, usual
interstitial pneumonia (UIP), vasculitis, vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome), wet macular degeneration, wound healing, yersinia and salmonella associated arthropathy.
68. A method of treating a patient suffering from a disorder in which IL-17 is detrimental
comprising the step of administering the binding protein of claim 1 before, concurrent, or after the administration of a second agent, wherein the second agent is selected from the group consisting of inhaled steroids; beta-agonists; short-acting or long-acting beta-agonists; antagonists of leukotrienes or leukotriene receptors; ADVAIR; IgE inhibitors; anti-IgE antibodies; XOLAIR; phosphodiesterase inhibitors; PDE4 inhibitors; xanthines; anticholinergic drugs; mast cell-stabilizing agents; Cromolyn; IL-4 inhibitors; IL-5 inhibitors; eotaxin/CCR3 inhibitors; antagonists of histamine or its receptors including HI, H2, H3, and H4; antagonists of prostaglandin D or its receptors DP1 and CRTH2; TNF antagonists; a soluble fragment of a TNF receptor; ENBREL; TNF enzyme antagonists; TNF converting enzyme (TACE) inhibitors; muscarinic receptor antagonists; TGF-beta antagonists; interferon gamma; perfenidone; chemotherapeutic agents, methotrexate; leflunomide; sirolimus (rapamycin) or an analog thereof, CCI-779; COX2 or cPLA2 inhibitors; NSAIDs; immunomodulators; p38 inhibitors; TPL-2, MK-2 and NFkB inhibitors; budenoside; epidermal growth factor; corticosteroids; cyclosporine; sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-1ß antibodies; anti-IL-6 antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies or agonists of TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, EMAP-II, GM-CSF, FGF, or PDGF; antibodies of CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; FK506; rapamycin; mycophenolate mofetil; ibuprofen; prednisolone; phosphodiesterase inhibitors; adensosine agonists; antithrombotic agents; complement inhibitors; adrenergic agents; IRAK, NIK, IKK, p38, or MAP kinase inhibitors; IL-1ß converting enzyme inhibitors; TNF-α converting enzyme inhibitors; T-cell signaling inhibitors; metalloproteinase inhibitors; 6-mercaptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors; soluble p55 TNF receptor; soluble p75 TNF receptor; sIL-1RI; sIL-1RII; sIL-6R; anti-inflammatory cytokines; IL-4; IL-10; IL-ll;and TGF-ß.
69. The method according to claim 65, wherein said administering to the subject is by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.
70. A binding protein comprising an antigen binding domain capable of binding human IL-17, said antigen binding domain comprises at least one CDR comprising an amino acid sequence selected from the group consisting of:
CDR-H1. X1-X2-X3-X4-X5 (SEQ ID NO:925), wherein;
X1 is N, A, D, or S;
X2 is Y, F, or L;
X3 is G, D, or A;
X4 is M or I; and
X5 is H, D, or S; CDR-H2 . X1-X2-X3-X4-X5—X6_X7-X8-X9-X10_X11-X12-X13—X14-X15-X16-X17 (SEQ ID NO:926), wherein;
X1 is V, W, or G;
X2 is I, T, M, or F;
X3 is S, N, T, or D;
X4 is Y or P;
X5 is D, N, or I;
X6 is G, S, L, or E;
X7 is S or G;
X8 is N, T, or E;
X9 is K, T, or A;
X10 is Y, G, N, or V;
X11 is Y or V;
X12 is A;
X13 is D, P, or Q; X14 is S, K, or N; X15 is V or F; X16 is K, R, or Q; and X17 is G; CDR-H3 . X1-X2-X3-X4-X5—X6-X7-X8-X9-X10_X11-X12—X13—X14-X15-X16-X17 (SEQ ID NO:927), wherein; 303
X1 is V, S, E, or I;
X2 is G, S, P, or R;
X3 is A, E, N, or P;
X4 is S, D, or W;
Xb is G, E, F, or L;
X6 is D, G, or W;
X7 is Y, I, N, or G;
X8 is Y, T, G, or A;
X9 is Y or I;
X10 is S, G, or Y;
X11 is Y, F, or T;
X12 is G, T, or is not present;
X13 is L, H, or is not present;
X14 is H or is not present;
X15 is F or is not present;
X16 is D; and
X17 is V, N, or Y; CDR-L1. X1-X2-X3-X4-X5—X6_X7-X8-X9-X10_X11-X12-X13 (SEQ ID
NO:928), wherein;
X1 is S, R, or K;
X2 is G or A;
X1 is S or D;
X4 is N, K, or Q;
X5 is S or is not present;
X6 is N or is not present;
X7 is I, L, N, or D;
X8 is G or I;
X9 is S, N, G, or D;
X10 is H, R, S, or D;
X11 is S, Y, A, or D;
X12 is V, A, L, or M; and
X13 is N, C, or H; CDR-L2. X1-X2-X3-X4-X5-X6-X7 (SEQ ID NO.-929), wherein;
X1 is G, Q, Y, or E;
X2 is I, D, or A;
X3 is G, N, S, or T;
X4 is Q, K, or T;
X5 is R, S, or L;
X6 is P, I, or V; and
X7 is S or P;
and
CDR-L3. X1-X2-X3-X4-X5—X6_X7-X8-X9-X10_X11 (SEQ ID NO: 930 ) ,
wherein;
X1 is A, Q, H, or L;
X2 is T or Q;
X3 is W, S, or H;
X, is D or T;
X5 is D or S;
X6 is S, T, L, or F;
X7 is L, T, or P;
X8 is G, H, or Y;
X9 is G, S, or T;
X10 is Y or is not present; and
X11 is V or is not present; a CDR-H1, a CDR-H2, and a CDR-H3 of any variable heavy region (VH) in Table 21, Table 23, Table 24, or Table 27; and
a CDR-L1, a CDR-L2, and a CDR-L3 of any variable light region (VL) in Table 21, Table 23, Table 25, or Table 27.
71. The binding protein according to claim 70, wherein said at least one CDR comprises an amino acid sequence selected from the group consisting of: residues 31-35 of SEQ ID NO:40; residues 50-66 of SEQ ID NO.:40; residues 99-103 of SEQ ID NO.:40;
residues 23-35 of SEQ ID NO:41; residues 51-57 of SEQ ID NO.:41; residues 90-110 of SEQ ID NO.:41;
residues 31-35 of SEQ ID NO:42; residues 50-66 of SEQ ID NO.:42; residues 99-103 of SEQ ID NO.:42;
residues 23-35 of SEQ ID NO:43; residues 51-57 of SEQ ID NO.:43; residues 90-110 of SEQ ID NO.:43;
residues 31-35 of SEQ ID NO:44; residues 50-66 of SEQ ID NO.:44; residues 99-101 of SEQ ID NO.:44;
residues 23-35 of SEQ ID NO:45; residues 51-57 of SEQ ID N0..45; residues 90-110 of SEQ ID NO.:45;
residues 31-35 of SEQ ID NO:46; residues 50-66 of SEQ ID NO.:46; residues 99-115 of SEQ ID NO.:46;
residues 24-34 of SEQ ID NO:47; residues 50-56 of SEQ ID NO.:47; residues 89-97 of SEQ ID NO. :47;
residues 31 -35 of SEQ ID NO:48; residues 50-66 of SEQ ID NO.:48; residues 99-101
of SEQ ID NO.:48;
residues 24-34 of SEQ ID NO:49; residues 50-56 of SEQ ID NO.:49; and residues 89-
97 of SEQ ID NO.:49;
the amino acid sequence for a CDR-H1, a CDR-H2, and a CDR-H3 of a VH in Table 21,
Table 23, Table 24, or Table 27; and
the amino acid sequence for a CDR-L1, a CDR-L2, and a CDR-L3 of a VL in Table
21, Table 23, Table 25, or Table 27.
72. The binding protein according to claim 71, wherein said binding protein comprises at least 3 CDRs.
73. The binding protein according to claim 71 wherein said antigen binding domain comprises a VH.
74. The binding protein according to claim 73, wherein said VHcomprises an amino acid sequence selected from the group consisting of:
SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, and an amino acid sequence of a VH in Table 21, Table 23, Table 24, and Table 27.
75. The binding protein according to claim 71, wherein said antigen binding domain comprises a VL.
76. The binding protein according to claim 75, wherein said VL comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, and an amino acid sequence of a VL in Table 21, Table 23, Table 25, and Table 27.
77. The binding protein according to claim 71, wherein said antigen binding domain comprises a VH and a VL.
78. The binding protein according to claim 76, further comprising a VH, wherein said VH comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, and an amino acid sequence of a VH in Table 21, Table 23, Table 24, and Table 27.
79. The binding protein according to claim 77, wherein said VL comprises an amino acid sequence of a VL in Table 21, Table 23, Table 25, or Table 27 and said VH comprises an amino acid sequence of a VH in Table 21, Table 23, Table 24, or Table 27.
80. The binding protein according to claim 71, further comprising a heavy chain immunoglobulin constant domain selected from the group consisting of: a human IgM constant domain; a human IgGl constant domain; a human IgG2 constant domain; a human IgG3 constant domain; a human IgG4 constant domain; a human IgE constant domain and a human IgA constant domain.
81. The binding protein according to claim 80, wherein said heavy chain immunoglobulin constant region domain is a human IgGl constant domain.
82. The binding protein according to claim 81, wherein said human IgG 1 constant domain comprises amino acid sequence selected from the group consisting of SEQ ID NO:3 and SEQ ID NO:4.
83. The binding protein according to claim 71, further comprising a light chain immunoglobulin constant domain selected from the group consisting of: a human Ig kappa constant domain and a human Ig lambda constant domain.
84. The binding protein according to claim 83, wherein said light chain immunoglobulin constant region domain is a human Ig kappa constant domain comprising amino acid sequence SEQ ID NO:5.
85. The binding protein according to claim 83, wherein said light chain immunoglobulin constant region domain is a human Ig lambda constant domain comprising amino acid sequence SEQ ID NO:6.
86. The binding protein according to claim 71, wherein said binding protein is selected from the group consisting of: an immunoglobulin molecule; an scFv; a monoclonal antibody; a human antibody; a chimeric antibody; a humanized antibody; a single domain antibody; a Fab fragment; an Fab' fragment; an F(ab')2; an Fv; and a disulfide linked Fv.
87. The binding protein according to claim 86, wherein said binding protein is a human antibody.
88. A binding protein capable of binding human IL-17, said binding protein comprising:
an Ig constant heavy region having an amino acid sequence selected from the group
consisting of SEQ ID NO:3 and SEQ ID NO: 4;
an Ig constant-light region having an amino acid sequence selected from the group
consisting of SEQ ID NO:5 and SEQ ID NO: 6;
an Ig variable heavy region having an amino acid sequence of a VH in Table 21, Table
23, Table 24, or Table 27; and
an Ig variable light region having an amino acid sequence of a VL in Table 21, Table 23,
Table 25, or Table 27.
89. A binding protein capable of binding human IL-17, said binding protein comprising:
an Ig constant heavy region having an amino acid sequence of SEQ ID NO:3;
an Ig constant light region having an amino acid sequence of SEQ ID NO:5;
an Ig variable heavy region having an amino acid sequence of a VH in Table 21, Table
23, Table 24, or Table 27; and
an Ig variable light region having an amino acid sequence of a VL in Table 21, Table 23,
Table 25, or Table 27.
90. A neutralizing binding protein, wherein said neutralizing binding protein comprises a binding protein according to any one of claims 70-89, and wherein said neutralizing binding protein is capable of neutralizing IL-17.
91. The neutralizing binding protein according to claim 90, wherein said IL-17 is selected from the group consisting of pro-human IL-17; mature-human IL-17, and truncated-human IL-17.
92. The neutralizing binding protein according to claim 90, wherein said neutralizing binding protein diminishes the ability of IL-17 to bind to its receptor.
93. The neutralizing binding protein according to claim 92, wherein said neutralizing binding protein diminishes the ability of pro-human IL-17, mature-human IL-17, or truncated-human IL-17 to bind to its receptor.
94. The neutralizing binding protein according to claim 90, wherein said neutralizing binding protein is capable of reducing one or more of IL-17 biological activities selected from the
group consisting of: Thl modulation; Th2 modulation; Nk modulation; neutrophil modulation; monocyte-macrophage lineage modulation; neutrophil modulation; eosinophil modulation; B-cells modulation; cytokine modulation; chemokine modulation; adhesion molecule modulation; and cell recruitment modulation.
95. The neutralizing binding protein according to claim 90, wherein said neutralizing binding protein has a dissociation constant (KD) selected from the group consisting of: at most about 10-7 M; at most about 10-8 M; at most about 10-9 M; at most about 10-10 M; at most about 10-11 M; at most about 10-12 M; and at most 10-13 M.
96. The neutralizing binding protein according to claim 90, wherein said neutralizing binding protein has an on rate selected from the group consisting of: at least about 102M-1s-1; at least about 103M-1s-1; at least about 104M-1s-1; at least about 105M-1s-1; and at least about 106MV.
97. The neutralizing binding protein according to claim 90, wherein said neutralizing binding protein has an off rate selected from the group consisting of: at most about 10-3s-1; at most about 10-4s-1; at most about 10-5s-1; and at most about 10-6s-1.
98. A labeled binding protein comprising a binding protein of any one of claims 70-89, wherein said binding protein is conjugated to a detectable label.
99. The labeled binding protein of claim 98, wherein the detectable label is selected from the group consisting of a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin.
100. The labeled binding protein of claim 99, wherein said label is a radiolabel selected from the group consisting of: 3H, 14C, 35S, 90Y, 99Tc, 111In, 1251,131I,177Lu, 166Ho, and 153Sm.
101. A conjugate binding protein comprising a binding protein of any one of claims 70-89, wherein said binding protein is conjugated to a therapeutic or cytotoxic agent.
102. The conjugate binding protein of claim 101, wherein said therapeutic or cytotoxic agent is 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.
103. An isolated nucleic acid encoding a binding protein amino acid sequence of any one of claims 70-89.
104. A vector comprising an isolated nucleic acid according to claim 103.
105. The vector of claim 104, wherein said vector is selected from the group consisting of; pcDNA, pTT, pTT3, pEFBOS, pBV, pJV, and pBJ.
106. A host cell comprising a vector according to any one of claims 104 or 105.
107. The host cell according to claim 106, wherein said host cell is a prokaryotic cell.
108. The host cell according to claim 107, wherein said host cell is E. coli.
109. The host cell according to claim 106, wherein said host cell is a eukaryotic cell.
110. The host cell according to claim 109, wherein said eukaryotic cell is selected from the group consisting of protist cell, animal cell, plant cell and fungal cell.
111. The host cell according to claim 110, wherein said eukaryotic cell is an animal cell selected from the group consisting of; a mammalian cell, an avian cell, and an insect cell.
112. The host cell according to claim 111, wherein said animal cell is a CHO cell.
113. The host cell according to claim 111, wherein said host cell is COS.
114. The host cell according to claim 110, wherein said eukaryotic cell is Saccharomyces cerevisiae.
115 The host cell according to claim 111, wherein said animal cell is an insect Sf9 cell.
116. A method of producing a binding protein that binds human IL-17, comprising culturing
the host cell of any one of claims 106-115 in a culture medium under conditions sufficient to produce a binding protein that binds human IL-17.
117. A binding protein produced according to the method of claim 116.
118. A crystallized binding protein comprising a binding protein according to any one of claims 70-97, wherein said binding protein exists as a crystal.
119. The crystallized binding protein according to claim 118, wherein said crystal is a carrier-free pharmaceutical controlled release crystal.
120. The crystallized binding protein according to claim 118, wherein said binding protein has a greater half life in vivo than the soluble counterpart of said binding protein.
121. The crystallized binding protein according to claim 118, wherein said binding protein retains biological activity.
122. A composition for the release of a binding protein said composition comprising:

(a) a formulation, wherein said formulation comprises a crystallized binding protein, according to any one of claims 118-121, and an ingredient; and
(b) at least one polymeric carrier.

123. The composition according to claim 122, wherein said polymeric carrier is a polymer selected from one or more of the group consisting of: poly (acrylic acid), poly (cyanoacrylates), poly (amino acids), poly (anhydrides), poly (depsipeptide), poly (esters), poly (lactic acid), poly (lactic-co-glycolic acid) or PLGA, poly (b-hydroxybutryate), poly (caprolactone), poly (dioxanone); poly (ethylene glycol), poly ((hydroxypropyl) methacrylamide, poly [(organo)phosphazene], poly (ortho esters), poly (vinyl alcohol), poly (vinylpyrrolidone), maleic anhydride- alkyl vinyl ether copolymers, pluronic polyols, albumin, alginate, cellulose and cellulose derivatives, collagen, fibrin, gelatin, hyaluronic acid, oligosaccharides, glycaminoglycans, sulfated polysaccharides, blends and copolymers thereof.
124. The composition according to claim 122, wherein said ingredient is selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-ß-cyclodextrin, methoxypolyethylene glycol and polyethylene glycol.
125. A method for treating a mammal comprising the step of administering to the mammal an effective amount of the composition according to claim 122.
126. A pharmaceutical composition comprising the binding protein of any one of claims 70-97, and a pharmaceutically acceptable carrier.
127. The pharmaceutical composition of claim 126 which further comprises at least one additional therapeutic agent for treating a disorder in which IL-17 activity is detrimental.
128. The pharmaceutical composition of claim 127, wherein said additional agent is selected from the group consisting of: angiogenesis inhibitors; kinase inhibitors; co-stimulation molecule blockers; adhesion molecule blockers; anti-cytokine antibody or functional fragment thereof; methotrexate; corticosteroids; cyclosporin; rapamycin; FK506; and non-steroidal anti-inflammatory agents.
129. A method for reducing human IL-17 activity comprising contacting human IL-17 with the binding protein of any one of claims 70-97 such that human IL-17 activity is reduced.
130. A method for reducing human IL-17 activity in a human subject suffering from a disorder in which IL-17 activity is detrimental, comprising administering to the human subject the binding protein of any one of claims 70-97 such that human IL-17 activity in the human subject is reduced.
131. A method for treating a subject for a disease or a disorder in which IL-17 activity is detrimental by administering to the subject the binding protein of any one of claims 70-97 such that treatment is achieved.
132. The method of claim 131, wherein said disorder is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein
purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, spondyloarthropathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis B, Hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, cryptogenic fibrosing alveolitis, postinflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjogren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, fibrosis, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with OTgan transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasculitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS,
sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjorgren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, choleosatatis, idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci (GBS) infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Thl Type mediated diseases, acute and chronic pain (different forms of pain), and cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma) Abetalipoproteinemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1- antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti-CD3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, Burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chronic myelocytic -leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes, diabetes mellitus, diabetic arteriosclerotic disease, Diffuse Lewy
body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's Syndrome in middle age, drug- induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallervorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis (A), His bundle arrhythmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza a, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of the corticospinal system, lipedema, liver transplant rejection, lymphedema, malaria, malignant Lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi-system disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine- Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodysplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies , neutropenic fever, non-Hodgkins lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, OKT3® therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, Pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome),
post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynaud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, senile chorea, Senile Dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, solid tumors, specific arrhythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, viral encephalitis/aseptic meningitis, viral-associated hemaphagocytic syndrome, Wernicke- Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, acute coronary syndromes, acute idiopathic polyneuritis, acute inflammatory demyelinating polyradiculoneuropathy, acute ischemia, adult Still's disease, alopecia areata, anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia, arteriosclerosis, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure, blepharitis, bronchiectasis, bullous pemphigoid, cardiovascular disease, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinically isolated syndrome (cis) with risk for multiple sclerosis, conjunctivitis, childhood onset psychiatric disorder, chronic obstructive pulmonary disease (COPD), dacryocystitis, dermatomyositis, diabetic retinopathy, diabetes mellitus, disk herniation, disk prolapse, drug induced immune hemolytic anemia, endocarditis, endometriosis, endophthalmitis, episcleritis, erythema multiforme, erythema multiforme major, gestational pemphigoid, Guillain-Barre syndrome (GBS), hay fever, Hughes syndrome, idiopathic Parkinson's disease, idiopathic interstitial pneumonia, IgE-mediated allergy, immune hemolytic anemia, inclusion body myositis, infectious ocular inflammatory disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis, keratojunctivitis sicca, Kussmaul disease or Kussmaul-Meier
disease, Landry's paralysis, Langerhan's cell histiocytosis, livedo reticularis, macular degeneration, microscopic polyangiitis, morbus bechterev, motor neuron disorders, mucous membrane pemphigoid, multiple organ failure, myasthenia gravis, myelodysplastic syndrome, myocarditis, nerve root disorders, neuropathy, non-A non-B hepatitis, optic neuritis, osteolysis, ovarian cancer, pauciarticular JRA, peripheral artery occlusive disease (PAOD), peripheral vascular disease (PVD), peripheral artery, disease (PAD), phlebitis, polyarteritis nodosa (or periarteritis nodosa), polychondritis, polymyalgia rheumatica, poliosis, polyarticular IRA, polyendocrine deficiency syndrome, polymyositis, polymyalgia rheumatica (PMR), post-pump syndrome, primary Parkinsonism, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), prostatitis, pure red cell aplasia, primary adrenal insufficiency, recurrent neuromyelitis optica, restenosis, rheumatic heart disease, sapho (synovitis, acne, pustulosis, hyperostosis, and osteitis), scleroderma, secondary amyloidosis, shock lung, scleritis, sciatica, secondary adrenal insufficiency, silicone associated connective tissue disease, sneddon-wilkinson dermatosis, spondylitis ankylosans, Stevens-Johnson syndrome (SJS), systemic inflammatory response syndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, transverse myelitis, TRAPS (tumor necrosis factor receptor, type 1 allergic reaction, type II diabetes, urticaria, usual interstitial pneumonia (UIP), vasculitis, vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome), wet macular degeneration, wound healing, yersinia and salmonella associated arthropathy.
133. A method of treating a patient suffering from a disorder in which IL-17 is detrimental comprising the step of administering the binding protein of any one of claims 70-97 before, concurrent, or after the administration of a second agent, wherein the second agent is selected from the group consisting of an antibody, or fragment thereof, capable of binding human IL-12; methotrexate; an antibody, or fragment thereof, capable of binding human TNF; corticosteroids, cyclosporin, rapamycin, FK506, and non-steroidal antiinflammatory agents.
134. A binding protein comprising a polypeptide chain, wherein said polypeptide chain comprises VDl-(Xl)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; XI is a linker with the proviso that it is not CH1;
X2 is an Fc region; and n is 0 or 1;
wherein the binding protein is capable of binding human IL-17 and TNF-α;
wherein VD1 comprises an amino acid sequence of a variable heavy region (VH) of an anti-TNF-α antibody wherein said amino acid sequence is any of SEQ ID NOs:563, 573, 578, 593, 628, 638, 648, 658, 668, 678, 688, 698,708,718,728, 738,748,758,763, 773, 783, 793, 803, 813, 823, 833, 843, 853, 863, 873, and 883; and
wherein VD2 comprises the amino acid sequence of a VH region of anti-IL-17 antibody wherein said amino acid sequence is any of SEQ ID NOs:565, 575, 580, 595, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 765, 775, 795, 805, 815, 825, 835, 845, 855, 865, 875, and 885.
135. The binding protein according to claim 134, wherein VD1 and VD2 comprise an amino acid sequence of any of SEQ ID NOs: 562, 572, 577, 592, 627, 637, 647, 657, 667, 677, 687, 697, 707, 717, 727, 737, 747, 757, 762, 772, 782, 792, 802, 812, 822, 832, 842, 852, 862, 872, and 882.
136. A binding protein comprising a polypeptide chain, wherein said polypeptide chain comprises VDl-(Xl)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; X2 does not comprise an Fc region; and n is 0 or 1; wherein the binding protein is capable of binding human IL-17 and TNF-α; wherein VD1 comprises an amino acid sequence of a variable light region (VL) of an anti-TNF-α antibody wherein said amino acid sequence is any of SEQ ID NOs:568, 583, 588, 598, 603, 608, 613, 618, 623, 633, 643, 653, 663, 673,683, 693, 703, 713, 723, 733,743,753,768, 778,788,798,808, 818, 828, 848, 858,868, and 878; and
wherein VD2 comprises an amino acid sequence of a VL region of anti-IL-17 antibody wherein said amino acid sequence is any of SEQ ID NOs:570, 585, 590, 600, 605, 610, 615, 620, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 735, 745, 755, 770, 780, 790, 800, 810, 820, 830, 850, 860, 870, and 880.
137. The binding protein according to claim 136, wherein the VD1 and VD2 light chain variable domains comprise an amino acid sequence of any of SEQ ID NOs:567, 582, 587, 597, 602, 607, 612, 617, 622, 632, 642, 652,662,672, 682, 692, 702, 712,722,732, 742, 752, 767, 777, 787, 797, 807, 817, 827, 847, 857, 867, and 877.
138. The binding protein according to claim 134 or 136, wherein n is 0.
139. A binding protein comprising first and second polypeptide chains, wherein said first polypeptide chain comprises a first VDl-(Xl)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 wherein said second polypeptide chain comprises a second VDl-(Xl)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;
X2 does not comprise an Fc region; and
n is 0 or 1; wherein the binding protein is capable of binding human IL-17 and TNF-α; wherein said VD1 and VD2 heavy chain variable domains comprise an amino acid sequence of any of SEQ ID NOs: 562, 572,577, 592, 627, 637, 647, 657, 667, 677, 687, 697, 707, 717, 727, 737, 747,757, 762,772,782,792, 802, 812, 822, 832, 842,852, 862, 872, and 882; and
wherein said VD 1 and VD2 light chain variable domains comprise an amino acid sequence selected from the group consisting of SEQ ID NOs:567, 582, 587,597, 602, 607, 612, 617, 622, 632, 642, 652,662, 672, 682,692, 702, 712, 722, 732, 742, 752, 767, 777, 787, 797, 807, 817, 827, 847, 857, 867, and 877.
140. The binding protein according to claim 134, 136, or 139, wherein X1 or X2 is an amino
acid sequence selected from the group consisting of SEQ ID NOs:888-918.
141. The binding protein according to claim 139, wherein the binding protein comprises two first polypeptide chains and two second polypeptide chains.
142. The binding protein according to claim 134, 136, or 139, wherein the Fc region is selected from the group consisting of native sequence Fc region and a variant sequence Fc region.
143. The binding protein according to claim 142, wherein the Fc region is selected from the group consisting of an Fc region from an IgGl, IgG2, IgG3, IgG4, IgA, IgM, IgE, and IgD.
144. The binding protein according to claim 134, 136, or 139, wherein said VD1 of the first polypeptide chain and said VD1 of the second polypeptide chain are obtained from the same first and second parent antibody, respectively, or antigen binding portion thereof.
145. The binding protein according to any one of claims 134-144, wherein said anti-TNF-α antibody binds TNF-α with a potency different from the potency with which said anti-IL-17 antibody binds human IL-17.
146. The binding protein according to any one of claims 134-144, wherein said anti-TNF-α antibody binds TNF-α with an affinity different from the affinity with which said anti-IL-17 antibody binds human IL-17.
147. The binding protein according to any one of claims 134-144, wherein said anti-TNF-α antibody and said anti-IL-17 antibody are selected from the group consisting of a human antibody, a CDR grafted antibody, and a humanized antibody.
148. The binding protein according to claim 134, 136, or 139, wherein said binding protein possesses at least one desired property exhibited by said anti-TNF-α antibody or said anti-IL-17 antibody.
149. The binding protein according to claim 148, wherein said desired property is selected from one or more antibody parameters.
150. The binding protein according to claim 149, wherein said antibody parameters are selected from the group consisting of antigen specificity, affinity to antigen, potency, biological function, epitope recognition, stability, solubility, production efficiency,
immunogenicity, pharmacokinetics, bioavailability, tissue cross reactivity, and orthologous antigen binding.
151. A binding protein capable of binding two antigens comprising four polypeptide chains,
wherein two polypeptide chains comprise VDl-(Xl)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 CHI; and
X2 is an Fc region; and wherein two polypeptide chains comprise VDl-(Xl)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;
X2 does not comprise an Fc region; and
n is 0 or 1; wherein the VD1 and VD2 heavy chain variable domains comprise an amino acid sequence of any of SEQ ID NOs: 562, 572, 577, 592, 627, 637, 647, 657, 667, 677, 687, 697, 707, 717, 727, 737, 747, 757, 762, 772, 782, 792, 802, 812, 822, 832, 842, 852, 862, 872, and 882; and
wherein the VD1 and VD2 light chain variable domains comprise an amino acid sequence selected from the group consisting of SEQ ID NOs:567, 582, 587, 597, 602, 607, 612, 617, 622,632, 642, 652, 662, 672,682, 692, 702, 712, 722, 732, 742, 752, 767, 777, 787, 797, 807, 817, 827, 847, 857, 867, and 877.
152. The binding protein according to claim 134, 136, 139, or 151, 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-1s-1; at least about 103M-1s-1; at least about 104M-1s-1; at least about 105M-1s-1; and at least about 106M-1s-1, as measured by surface plasmon resonance.
153. The binding protein according to claim 134, 136, 139, or 151, 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 10-3s-1; at most about 10-4s-1; at most about 10-4s-1; and at most about 10-6s-1, as measured by surface plasmon resonance.
154. The binding protein according to claim 134, 136, 139, or 151, wherein said binding protein has a dissociation constant (KD) to said one or more targets selected from the group consisting of: at most about 10-7 M; at most about 10-8 M; at most about 10-9 M; at most about 10-10 M; at most about 10-11 M; at most about 10-12 M; and at most 10-13 M.
155. A binding protein conjugate comprising a binding protein according to any one of claims 134, 136, 139, or 151, said binding protein conjugate further comprising an agent selected from the group consisting of; an immunoadhesion molecule, an imaging agent, a therapeutic agent, and a cytotoxic agent.
156. The binding protein conjugate according to claim 155, 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.
157. The binding protein conjugate according to claim 156, wherein said imaging agent is a radiolabel selected from the group consisting of: 3H 14C 35S, 90Y, 99Tc, 111In, 1251,131I, 177Lu,166Ho,and153Sm.
158. The binding protein conjugate according to claim 156, 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.
159. The binding protein according to claim 134,136, 139, or 151, wherein said binding protein is a crystallized binding protein.
160. The binding protein according to claim 159, wherein said crystal is a carrier-free pharmaceutical controlled release crystal.
161. The binding protein according to claim 159, wherein said binding protein has a greater half life in vivo than the soluble counterpart of said binding protein.
162. The binding protein according to claim 159, wherein said binding protein retains biological activity.
163. An isolated nucleic acid encoding a binding protein amino acid sequence according to any one of claims 134, 136, 139, or 151.
164. A vector comprising an isolated nucleic acid according to claim 163.
165. The vector according to claim 164, wherein said vector is selected from the group consisting of pcDNA, pTT, pTT3, pEFBOS, pBV, pJV, pcDNA3.1 TOPO, pEF6 TOPO, and pBJ.
166. A host cell comprising a vector according to claim 164.
167. The host cell according to claim 166, wherein said host cell is a prokaryotic cell.
168. The host cell according to claim 167, wherein said host cell is E. coli.
169. The host cell according to claim 166, wherein said host cell is a eukaryotic cell.
170. The host cell according to claim 166, wherein said eukaryotic cell is selected from the group consisting of protist cell, animal cell, plant cell, and fungal cell.
171. The host cell according to claim 169, wherein said eukaryotic cell is an animal cell selected from the group consisting of a mammalian cell, an avian cell, and an insect cell.
172. The host cell according to claim 171, wherein said host cell is a CHO cell.
173. The host cell according to claim 171, wherein said host cell is COS.
174. The host cell according to claim 166, wherein said host cell is a yeast cell.
175. The host cell according to claim 174, wherein said yeast cell is Saccharomyces cerevisiae.
176. The host cell according to claim 171, wherein said host cell is an insect Sf9 cell.
177. A method of producing a binding protein, comprising culturing a host cell described in any one of claims 166-176 in culture medium under conditions sufficient to produce the binding protein.
178. The method according to claim 177, wherein 50%-75% of the binding protein produced is a dual specific tetravalent binding protein.
179. The method according to claim 177, wherein 75%-90% of the binding protein produced is a dual specific tetravalent binding protein.
180. The method according to claim 177, wherein 90%-95% of the binding protein produced is a dual specific tetravalent binding protein.
181. A protein produced according to the method of claim 177.
182. A pharmaceutical composition comprising the binding protein of any one of claims 134-162 and 181, and a pharmaceutically acceptable carrier.
183. The pharmaceutical composition of claim 182 further comprising at least one additional therapeutic agent.
184. The pharmaceutical composition of claim 183, wherein said additional therapeutic 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 antiinflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteroid, 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.
185. A method for treating a subject for a disease or a disorder by administering to the subject the binding protein of any one of claims 134-162 and 181 such that treatment is achieved.
186. The method of claim 185, wherein said disorder is selected from the group comprising rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme
arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, spondyloarthropathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis B, Hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, cryptogenic fibrosing alveolitis, postinflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjogren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, fibrosis, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid
hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasculitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjorgren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, choleosatatis, idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci (GBS) infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Thl Type mediated diseases, acute and chronic pain (different forms of pain), and cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma) Abetalipoproteinemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1- antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti-CD3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, Burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chronic myelocytic
leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes, diabetes mellitus, diabetic arteriosclerotic disease, Diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's Syndrome in middle age, drug- induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallervorden-Spate disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis (A), His bundle arrhythmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza a, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of the corticospinal system, lipedema, liver transplant rejection, lymphedema, malaria, malignant Lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi-system disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine- Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodysplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, non-Hodgkins lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial
disorders, OKT3® therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, Pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynaud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, senile chorea, Senile Dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, solid tumors, specific arrhythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, viral encephalitis/aseptic meningitis, viral-associated hemaphagocytic syndrome, Wernicke- Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, acute coronary syndromes, acute idiopathic polyneuritis, acute inflammatory demyelinating polyradiculoneuropathy, acute ischemia, adult Still's disease, alopecia areata, anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia, arteriosclerosis, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure, blepharitis, bronchiectasis, bullous pemphigoid, cardiovascular disease, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinically isolated syndrome (cis) with risk for multiple sclerosis, conjunctivitis, childhood onset psychiatric disorder, chronic obstructive pulmonary disease (COPD), dacryocystitis, dermatomyositis, diabetic retinopathy, diabetes mellitus, disk herniation, disk prolapse,
drug induced immune hemolytic anemia, endocarditis, endometriosis, endophthalmitis, episcleritis, erythema multiforme, erythema multiforme major, gestational pemphigoid, Guillain-Barre syndrome (GBS), hay fever, Hughes syndrome, idiopathic Parkinson's disease, idiopathic interstitial pneumonia, IgE-mediated allergy, immune hemolytic anemia, inclusion body myositis, infectious ocular inflammatory disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis, keratojunctivitis sicca, Kussmaul disease or Kussmaul-Meier disease, Landry's paralysis, Langerhan's cell histiocytosis, livedo reticularis, macular degeneration, microscopic polyangiitis, morbus bechterev, motor neuron disorders, mucous membrane pemphigoid, multiple organ failure, myasthenia gravis, myelodysplastic syndrome, myocarditis, nerve root disorders, neuropathy, non-A non-B hepatitis, optic neuritis, osteolysis, ovarian cancer, pauciarticular JRA, peripheral artery occlusive disease (PAOD), peripheral vascular disease (PVD), peripheral artery, disease (PAD), phlebitis, polyarteritis nodosa (or periarteritis nodosa), polychondritis, polymyalgia rheumatica, poliosis, polyarticular JRA, polyendocrine deficiency syndrome, polymyositis, polymyalgia rheumatica (PMR), post-pump syndrome, primary Parkinsonism, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), prostatitis, pure red cell aplasia, primary adrenal insufficiency, recurrent neuromyelitis optica, restenosis, rheumatic heart disease, sapho (synovitis, acne, pustulosis, hyperostosis, and osteitis), scleroderma, secondary amyloidosis, shock lung, scleritis, sciatica, secondary adrenal insufficiency, silicone associated connective tissue disease, sneddon-wilkinson dermatosis, spondylitis ankylosans, Stevens-Johnson syndrome (SJS), systemic inflammatory response syndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, transverse myelitis, TRAPS (tumor necrosis factor receptor, type 1 allergic reaction, type II diabetes, urticaria, usual interstitial pneumonia (UIP), vasculitis, vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome), wet macular degeneration, wound healing, yersinia and salmonella associated arthropathy.
187. The method according to claim 186, wherein said administering to the subject is by at
least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal,
intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.
188. A method for generating a DVD-Ig binding protein capable of binding two antigens comprising the steps of
a) obtaining a first parent antibody or antigen binding portion thereof, capable of binding TNF-α;
b) obtaining a second parent antibody or antigen binding portion thereof, capable of binding human IL-17;
c) constructing first and third polypeptide chains comprising VDl-(Xl)n-VD2-C-(X2)n, wherein
VD1 is a first heavy chain variable domain obtained from said first parent
antibody or antigen binding portion thereof;
VD2 is a second heavy chain variable domain obtained from said second
parent antibody or antigen binding portion thereof;
C is a heavy chain constant domain;
X1 is a linker with the proviso that it is not CH1;
X2 is an Fc region; and
n is 0 or l;and
d) constructing second and fourth polypeptide chains comprising VDl-(Xl)n-
VD2-C-(X2)n, wherein
VD1 is a first light chain variable domain obtained from said first parent
antibody or antigen binding portion thereof;
VD2 is a second light chain variable domain obtained from said second
parent antibody or antigen binding thereof;
C is a light chain constant domain;
X1 is a linker with the proviso that it is not CH1;
X2 does not comprise an Fc region; and
n is 0 or l;and
e) expressing said first, second, third and fourth polypeptide chains;
such that a DVD-Ig binding protein capable of binding TNF-α and human IL-17 is
generated, wherein the binding protein is capable of binding TNF-α and human IL-17;
wherein VD1 and VD2 heavy chain variable domains comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: of SEQ ID NOs: 562, 572, 577, 592, 627, 637, 647, 657, 667, 677, 687, 697, 707, 717, 727, 737, 747, 757, 762, 772, 782, 792, 802, 812, 822, 832, 842, 852, 862, 872, and 882; and

wherein the VD1 and VD2 light chain variable domains comprise an amino acid sequence selected from the group consisting of SEQ ID NOs:567, 582, 587, 597, 602, 607, 612, 617, 622, 632, 642, 652, 662, 672, 682, 692, 702, 712, 722, 732, 742, 752, 767, 777, 787, 797, 807, 817, 827, 847, 857, 867, and 877.
189. The method of claim 188, wherein said first parent antibody or antigen binding portion thereof, and said second parent antibody or antigen binding portion thereof, are selected from the group consisting of a human antibody, a CDR grafted antibody, and a humanized antibody.
190. The method of claim 188, wherein said first parent antibody or antigen binding portion thereof, and said second parent antibody or antigen binding portion thereof, are selected from the group consisting of a Fab fragment, a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, a dAb fragment, an isolated complementarity determining region (CDR), a single chain antibody, and diabodies.
191. The method of claim 188, wherein said first parent antibody or antigen binding portion thereof possesses at least one desired property exhibited by the DVD-Ig binding protein.
192. The method of claim 188, wherein said second parent antibody or antigen binding portion thereof possesses at least one desired property exhibited by the DVD-Ig binding protein.
193. The method of claim 188, wherein the Fc region is selected from the group consisting of a native sequence Fc region and a variant sequence Fc region.
194. The method of claim 193, wherein the Fc region is selected from the group consisting of an Fc region from an IgGl, IgG2, IgG3, IgG4, IgA, IgM, IgE, and IgD.
195. The method of claim 191, wherein said desired property is selected from one or more antibody parameters.
196. The method of claim 192, wherein said desired property is selected from one or more antibody parameters.
197. The method of claim 195, wherein said antibody parameters are selected from the group consisting of antigen specificity, affinity to antigen, potency, biological function, epitope recognition, stability, solubility, production efficiency, immunogenicity, pharmacokinetics, bioavailability, tissue cross reactivity, and orthologous antigen binding.
198. The method of claim 196, wherein said antibody parameters are selected from the group consisting of antigen specificity, affinity to antigen, potency, biological function, epitope recognition, stability, solubility, production efficiency, immunogenicity, pharmacokinetics, bioavailability, tissue cross reactivity, and orthologous antigen binding.
199. The method of claim 188, wherein said first parent antibody or antigen binding portion thereof, binds said first antigen with a different affinity than the affinity with which said second parent antibody or antigen binding portion thereof, binds said second antigen.
200. The method of claim 188, wherein said first parent antibody or antigen binding portion thereof, binds said first antigen with a different potency than the potency with which said second parent antibody or antigen binding portion thereof, binds said second antigen.
201. A method for generating a DVD-Ig binding protein capable of binding TNF-α and human IL-17 with desired properties comprising the steps of

a) obtaining a first parent antibody or antigen binding portion thereof, capable of binding TNF-α and possessing at least one desired property exhibited by the Dual Variable Domain Immunoglobulin;
b) obtaining a second parent antibody or antigen binding portion thereof, capable of binding human IL-17 and possessing at least one desired property exhibited by the Dual Variable Domain Immunoglobulin;
c) constructing first and third polypeptide chains comprising VDl-(Xl)n-VD2-C-(X2)n, wherein;
VD1 is a first heavy chain variable domain obtained from said first parent
antibody or antigen binding portion thereof;
VD2 is a second heavy chain variable domain obtained from said second
parent antibody or antigen binding portion thereof;
C is a heavy chain constant domain;
X1 is a linker with the proviso that it is not CH1;
X2 is an Fc region; and n is 0 or 1;
d) constructing second and fourth polypeptide chains comprising VDl-(Xl)n-
VD2-C-(X2)n, wherein;
VD1 is a first light chain variable domain obtained from said first parent
antibody or antigen binding portion thereof;
VD2 is a second light chain variable domain obtained from said second
parent antibody or antigen binding portion thereof;
C is a light chain constant domain;
X1 is a linker with the proviso that it is not CH1;
X2 does not comprise an Fc region; and
n is 0 or 1;
e) expressing said first, second, third, and fourth polypeptide chains;
such that a DVD-Ig binding capable of binding said TNF-α and human IL-17 with
desired properties is generated,
wherein VD1 and VD2 heavy chain variable domains comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: of SEQ ID NOs: 562, 572, 577,592, 627, 637, 647, 657, 667, 677, 687, 697, 707, 717, 727, 737, 747, 757, 762, 772, 782, 792, 802, 812, 822, 832, 842, 852, 862, 872, and 882; and
wherein the VD1 and VD2 light chain variable domains comprise an amino acid sequence selected from the group consisting of SEQ ID NOs:567, 582, 587,597,602, 607,612, 617, 622, 632, 642, 652, 662, 672, 682, 692, 702, 712, 722, 732, 742, 752, 767, 777, 787, 797, 807, 817, 827, 847, 857, 867, and 877.