US2017058027A1PendingUtilityA1
Il-1 binding proteins
Est. expiryMay 14, 2030(~3.8 yrs left)· nominal 20-yr term from priority
A61P 37/08A61P 37/04A61P 9/06A61P 7/08A61P 37/06A61P 3/08A61P 5/18A61P 7/10A61P 9/00A61P 9/08A61P 7/04A61P 5/16A61P 3/10A61P 5/48A61P 9/10A61P 37/02A61P 9/14A61P 7/06A61P 5/00A61P 37/00A61P 3/06A61P 5/50A61P 5/14A61P 9/04A61P 9/12A61P 39/02A61P 7/02A61P 43/00A61P 33/06A61P 25/04A61P 3/02A61P 25/16A61P 25/30A61P 31/04A61P 31/06A61P 35/02A61P 27/02A61P 25/24A61P 35/00A61P 33/08A61P 31/20A61P 3/00A61P 33/02A61P 27/14A61P 29/00A61P 31/08A61P 25/22A61P 31/18A61P 25/28A61P 31/14A61P 25/06A61P 31/16A61P 3/14A61P 31/12A61P 31/00A61P 25/18A61P 25/32A61P 33/00A61P 25/14A61P 31/10A61P 19/06A61P 17/02A61P 11/16A61P 17/08A61P 13/12A61P 21/04A61P 25/00A61P 19/10A61P 17/04A61P 15/02A61P 1/18A61P 15/08A61P 13/08A61K 47/6879A61P 13/02A61P 19/02A61P 17/06A61P 11/02A61P 17/00A61P 17/14A61P 1/16A61P 1/14A61P 21/02A61P 1/00A61P 11/00A61P 21/00A61P 1/04A61P 11/04A61P 15/10A61P 11/06A61P 19/00C07K 16/245C07K 2317/92G01N 2800/00C07K 2317/76C07K 2317/565G01N 33/6869A61K 9/0043G01N 2333/545C07K 2317/33A61K 9/0085A61K 9/007C07K 2317/24C07K 2317/64C07K 2317/31A61K 9/0034A61K 9/0031A61K 9/0014A61K 45/06A61K 39/3955C07K 2317/56A61K 9/006A61K 2039/505A61K 38/00A61K 9/0053A61K 9/0019C07K 14/545C07K 2317/35C07K 16/468Y02A50/30
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Claims
Abstract
Proteins that bind IL-1α and IL-1β are described along with their use in compositions and methods for treating, preventing, and diagnosing IL-1-related disorders and for detecting IL-1α and IL-1β in cells, tissues, samples, and compositions.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A binding protein comprising first and second polypeptide chains, wherein said first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein:
VD1 is a first heavy chain variable domain; VD2 is a second heavy chain variable domain; C is a heavy chain constant domain; X1 is a linker with the proviso that it is not CH1; X2 is an Fc region; and n is independently 0 or 1; and wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein: VD1 is a first light chain variable domain; VD2 is a second light chain variable domain; C is a light chain constant domain; X1 is a linker with the proviso that it is not CH1; X2 does not comprise an Fc region; and n is independently 0 or 1; wherein, in said first polypeptide chain, VD1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 60-148, 196, 198, 200, 202, 204, 206, 208 and 210; and VD2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 213 and 227; wherein, in said second polypeptide chain, VD1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 149-189, 197, 199, 201, 203, 205, 207, 209 and 211; and VD2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 216 and 229; and wherein the binding protein binds human IL-1β and human IL-1α.
2 . A binding protein comprising first and second polypeptide chains, wherein said first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein:
VD1 is a first heavy chain variable domain; VD2 is a second heavy chain variable domain; C is a heavy chain constant domain; X1 is a linker with the proviso that it is not CH1; X2 is an Fc region; and n is independently 0 or 1; and wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein: VD1 is a first light chain variable domain; VD2 is a second light chain variable domain; C is a light chain constant domain; X1 is a linker with the proviso that it is not CH1; X2 does not comprise an Fc region; and n is independently 0 or 1; wherein, in said first polypeptide chain, VD1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 213 and 227; and VD2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 60-148, 196, 198, 200, 202, 204, 206, 208 and 210; wherein, in said second polypeptide chain, VD1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 216 and 229; and VD2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 149-189, 197, 199, 201, 203, 205, 207, 209 and 211; and wherein the binding protein binds human IL-1β and human IL-1α.
3 . The binding protein according to claim 1 , wherein:
said first polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 212, 217, 226, 230, 232, 234, and 236.
4 . The binding protein according to claim 1 , wherein:
said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 215, 218, 228, 231, 233, 235, and 237.
5 . The binding protein according to claim 2 , wherein:
said first polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 219 and 221.
6 . The binding protein according to claim 2 , wherein:
said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 220 and 222.
7 . The binding protein according to claim 1 or claim 2 , wherein:
when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:212, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 215, 228, 231, 233 and 235;
when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:217, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 218 and 237;
when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:219, then said second polypeptide chain comprises the amino acid sequence of SEQ ID NO:220;
when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:221, then said second polypeptide chain comprises SEQ ID NO:222;
when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:226, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 228, 215, 231, 233, and 235;
when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:230, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 231, 215, 228, 233, and 235;
when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:232, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 233, 215, 228, 231, and 235;
when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:234, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 235, 215, 228, 231, and 233; and
when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:236, then said second polypeptide chain comprises SEQ ID NO:237.
8 . The binding protein according to claim 7 , wherein:
said first polypeptide chain comprises SEQ ID NO:212, and said second polypeptide chain comprises SEQ ID NO:215; or said first polypeptide chain comprises SEQ ID NO:217, and said second polypeptide chain comprises SEQ ID NO:218; or said first polypeptide chain comprises SEQ ID NO:219, and said second polypeptide chain comprises SEQ ID NO:220; or said first polypeptide chain comprises SEQ ID NO:221, and said second polypeptide chain comprises SEQ ID NO:222; or said first polypeptide chain comprises SEQ ID NO:226, and said second polypeptide chain comprises SEQ ID NO:228; or said first polypeptide chain comprises SEQ ID NO:230, and said second polypeptide chain comprises SEQ ID NO:231; or said first polypeptide chain comprises SEQ ID NO:232, and said second polypeptide chain comprises SEQ ID NO:233; or said first polypeptide chain comprises SEQ ID NO:234, and said second polypeptide chain comprises SEQ ID NO:235; or said first polypeptide chain comprises SEQ ID NO:236, and said second polypeptide chain comprises SEQ ID NO:237.
9 . The binding protein according to claim 1 or claim 2 , wherein the binding protein comprises two first polypeptide chains and two second polypeptide chains.
10 . The binding protein according to claim 1 or claim 2 , wherein X1 or X2 is an amino acid sequence selected from the group consisting of SEQ ID NOs:26-57, 233, 224, and 225.
11 . The binding protein according to claim 1 or claim 2 , wherein the Fc region is selected from the group consisting of a native sequence Fc region and a variant sequence Fc region.
12 . The binding protein according to claim 1 or claim 2 , wherein the Fc region is selected from the group consisting of an Fc region from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, and IgD.
13 . A binding protein conjugate comprising a binding protein as described in claim 1 or claim 2 , 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.
14 . The binding protein conjugate according to claim 13 , 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.
15 . The binding protein conjugate according to claim 14 , wherein said imaging agent is a radiolabel selected from the group consisting of: 3 H, 14 C, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, and 153 Sm.
16 . The binding protein conjugate according to claim 13 , 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.
17 . The binding protein according to claim 1 or claim 2 , wherein said binding protein is a crystallized binding protein.
18 . The crystallized binding protein according to claim 17 , wherein said crystallized binding protein is a carrier-free pharmaceutical controlled release crystallized IL-1β binding protein.
19 . The crystallized binding protein construct according to claim 18 , wherein said crystallized binding protein has a greater half life in vivo than the soluble counterpart.
20 . The crystallized binding protein according to claim 17 , wherein said crystallized binding protein retains biological activity.
21 . A composition for the release of a crystallized binding protein, said composition comprising:
(a) a formulation, wherein said formulation comprises a crystallized binding protein, described in claim 17 , and an ingredient; and (b) at least one polymeric carrier.
22 . The composition according to claim 21 , 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.
23 . The composition according to claim 21 , wherein said ingredient is selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol and polyethylene glycol.
24 . A pharmaceutical composition comprising a binding protein as described in claim 1 or claim 2 , and a pharmaceutically acceptable carrier.
25 . The pharmaceutical composition according to claim 24 further comprising at least one additional agent.
26 . The pharmaceutical composition according to claim 25 , wherein said additional agent is selected from the group consisting of: a therapeutic agent; an imaging agent; a cytotoxic agent; an angiogenesis inhibitor; a kinase inhibitor; a co-stimulation molecule blocker; an adhesion molecule blockers; an anti-cytokine antibody or functional fragment thereof; methotrexate; cyclosporin; rapamycin; FK506; a 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 epinephrine or analog thereof; a cytokine; and a cytokine antagonist.
27 . A pharmaceutical composition comprising a binding protein conjugate as described in claim 13 and a pharmaceutically acceptable carrier.
28 . The pharmaceutical composition according to claim 27 , wherein the binding protein conjugate comprises 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 pharmaceutical composition according to claim 28 , wherein said imaging agent is a radiolabel selected from the group consisting of: 3 H, 14 C, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, and 153 Sm.
30 . The pharmaceutical composition according to claim 27 , wherein said binding protein conjugate comprises a therapeutic or cytotoxic agent selected from the group consisting of: an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, a toxin, and an apoptotic agent.
31 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding a polypeptide chain amino acid sequence of a binding protein described in claim 1 or claim 2 .
32 . A vector comprising one or more isolated nucleic acid molecules according to claim 31 .
33 . The vector according to claim 32 , wherein said vector is selected from the group consisting of: pcDNA, pTT, pTT3, pEFBOS, pBV, pcDNA3.1 TOPO, pEF6 TOPO, and pBJ.
34 . A host cell comprising a vector according to claim 32 .
35 . The host cell according to claim 34 , wherein said host cell is a prokaryotic cell.
36 . The host cell according to claim 35 , wherein said prokaryotic host cell is Escherichia coli.
37 . The host cell according to claim 34 , wherein said host cell is a eukaryotic cell.
38 . The host cell according to claim 37 , wherein said eukaryotic cell is selected from the group consisting of: a protist cell, an animal cell, a plant cell, and a fungal cell.
39 . The host cell according to claim 38 , wherein said fungal cell is a yeast cell.
40 . The host cell according to claim 39 , wherein said yeast cell is Saccharomyces cerevisiae.
41 . The host cell according to claim 38 , wherein said animal cell is selected from the group consisting of: a mammalian cell, an avian cell, and an insect cell.
42 . The host cell according to claim 41 , wherein said mammalian cell is a CHO cell or a COS cell.
43 . The host cell according to claim 41 , wherein said insect host cell is an insect Sf9 cell.
44 . A method of producing a binding protein, comprising culturing a host cell described in claim 34 in culture medium under conditions sufficient to produce the binding protein.
45 . A binding protein produced according to the method of claim 44 .
46 . A method for reducing human IL-1 activity comprising contacting a human IL-1 protein with the binding protein as described in claim 1 or claim 2 such that human IL-1 protein activity is reduced.
47 . A method for reducing human IL-1 activity in a human subject suffering from a disorder in which IL-1 activity is detrimental, comprising administering to the human subject the binding protein as described in claim 1 or claim 2 or a crystal thereof, such that human IL-1 activity in the human subject is reduced.
48 . A method for treating a subject for a disorder in which IL-1 activity is detrimental comprising administering to the subject a binding protein as described in claim 1 or claim 2 or a crystal thereof such that treatment is achieved.
49 . The method of claim 48 , wherein said disorder is selected from the group consisting of: diabetes; uveitis; neuropathic pain; osteoarthritic pain; inflammatory pain; rheumatoid arthritis; osteoarthritis; juvenile chronic arthritis; septic arthritis; Lyme arthritis; psoriatic arthritis; reactive arthritis; spondyloarthropathy; systemic lupus erythematosus (SLE); Crohn's disease; ulcerative colitis; inflammatory bowel disease; autoimmune diabetes; insulin dependent diabetes mellitus; thyroiditis; asthma; allergic diseases; psoriasis; dermatitis; scleroderma; graft versus host disease; organ transplant rejection; acute immune disease associated with organ transplantation; chronic immune disease associated with organ transplantation; sarcoidosis; atherosclerosis; disseminated intravascular coagulation (DIC); 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; autoimmune uveitis; septic shock; toxic shock syndrome; sepsis syndrome; cachexia; infectious diseases; parasitic diseases; 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; polyglandular deficiency type II (Schmidt's syndrome); acute respiratory distress syndrome (ARDS); 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 (GCA); primary sclerosing hepatitis; cryptogenic autoimmune hepatitis; acquired immunodeficiency syndrome (AIDS); 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; post-inflammatory 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; Sjögren'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; 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; idiopathic male infertility; nitric oxide-associated male infertility; sperm autoimmunity; multiple sclerosis (all subtypes, including primary progressive, secondary progressive, relapsing remitting); 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; Sjörgren's syndrome; Takayasu's disease/arteritis; autoimmune thrombocytopaenia (AITP); 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 disease; alcoholic cirrhosis; alcohol-induced liver injury; cholestasis; idiosyncratic liver disease; drug-induced hepatitis; non-alcoholic steatohepatitis; allergy; group B Streptococci (GBS) infection; mental disorders (e.g., depression and schizophrenia); Th2 Type and Th1 Type mediated diseases; acute and chronic pain (different forms of pain); cancer (such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate, and rectal cancer); hematopoietic malignancies; leukemia; lymphoma; abetalipoproteinemia; acrocyanosis; acute and chronic parasitic or infectious processes; acute leukemia; acute lymphoblastic leukemia (ALL); T-cell ALL; FAB ALL; acute myeloid leukemia (AML); acute or chronic bacterial infection; acute pancreatitis; acute renal failure; adenocarcinomas; atrial 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 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 hemophagocytic 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; hemochromatosis; 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 (IPF); 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 syndrome migraine headache; idiopathic migraine headache; mitochondrial multisystem disorder; mixed connective tissue disease; monoclonal gammopathy; multiple myeloma; multiple systems degenerations (Menzel; Dejerine-Thomas; Shy-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-Hodgkin's lymphoma; occlusion of the abdominal aorta and its branches; occlusive arterial disorders; OKT3® therapy; orchitis/epididymitis; 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; Raynaud's disease; Refsum's disease; regular narrow QRS tachycardia; renovascular hypertension; reperfusion injury; restrictive cardiomyopathy; sarcomas; 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; 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 hemophagocytic 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; dacryocystitis; dermatomyositis; diabetic retinopathy; disk herniation; disk prolapse; drug induced immune hemolytic anemia; endocarditis; endometriosis; endophthalmitis; episcleritis; erythema multiforme; erythema multiforme major; gestational pemphigoid; Guillain-Barré 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; 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; 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; secondary Parkinsonism; prostatitis; pure red cell aplasia; primary adrenal insufficiency; recurrent neuromyelitis optica; restenosis; rheumatic heart disease; SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis); 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 (TNFR)-associated periodic syndrome); type B insulin resistance with acanthosis nigricans ; type 1 allergic reaction; type II diabetes; urticaria; usual interstitial pneumonia (UIP); vernal conjunctivitis; viral retinitis; Vogt-Koyanagi-Harada syndrome (VKH syndrome); wet macular degeneration; wound healing; Yersinia and Salmonella associated arthropathy.
50 . The method according to claim 48 , wherein said administering to the subject is by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intra-articular, 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.
51 . A method of treating a patient suffering from a disorder in which IL-1 is detrimental comprising the step of administering a binding protein as described in claim 1 or claim 2 or a crystal thereof before, concurrently with, 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-1β; an antibody, or fragment thereof, capable of binding human IL-1α; methotrexate; a corticosteroid; a beta-agonist; an antagonist of a leukotriene; an antagonist of ar leukotriene receptor; ADVAIR; an IgE inhibitor; an anti-IgE antibody; XOLAIR; a phosphodiesterase inhibitor; a PDE4 inhibitor; a xanthine; an anticholinergic drug; a mast cell-stabilizing agent; Cromolyn; an IL-4 inhibitor; an IL-5 inhibitor; an eotaxin/CCR3 inhibitor; an antagonist of histamine; an antagonist of a histamine receptor, an antagonist of prostaglandin D; an inhibitor of receptor DP1; an inhibitor of CRTH2; a TNF antagonist; a soluble fragment of a TNF receptor; ENBREL; a TNF enzyme antagonist; a TNF converting enzyme (TACE) inhibitor; a muscarinic receptor antagonist; a TGF-beta antagonist; interferon gamma; perfenidone; a chemotherapeutic agent, leflunomide; sirolimus (rapamycin) or an analog thereof, CCI-779; a COX2 or cPLA2 inhibitor; a non-steroidal anti-inflammatory drug (NSAID); an immunomodulator; a p38 inhibitor; a TPL-2 inhibitor; an MK-2 inhibitor; an NFκB inhibitor; budenoside; epidermal growth factor; cyclosporine; sulfasalazine; an aminosalicylate; 6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor; mesalamine; olsalazine; balsalazide; an antioxidant; a thromboxane inhibitor; an IL-1 receptor antagonist; a growth factor; an elastase inhibitor; a pyridinyl-imidazole compound; an antibody or agonists of TNF, LT, 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; an antibody to CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90; FK506; mycophenolate mofetil; ibuprofen; prednisolone; an adensosine agonist; an antithrombotic agent; a complement inhibitor; an adrenergic agent; a kinase inhibitor; an IL-1β converting enzyme inhibitors; a T-cell signaling inhibitor; a metalloproteinase inhibitor; an angiotensin converting enzyme inhibitor; soluble cytokine receptor; soluble p55 TNF receptor; soluble p75 TNF receptor; soluble IL-1RI; soluble IL-1RII; soluble IL-6R; an anti-inflammatory cytokine; IL-4; IL-10; IL-11; and TGF-β.
52 . A binding protein comprising an antigen binding domain, said binding protein capable of binding human IL-1β, said antigen binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, as defined below:
CDR-H1:
(SEQ ID NO: 190)
X 1 -Y-D-M-S, wherein;
X 1 is S, K or R;
CDR-H2:
(SEQ ID NO: 191)
Y-X 2 -S-X 4 -G-G-X 7 -G-T-Y-Y-P-D-X 14 -X 15 -K-G, wherein;
X 2 is I or V;
X 4 is S or H;
X 7 is G or A;
X 14 is T or S; and
X 15 is V or A;
CDR-H3:
(SEQ ID NO: 192)
G-G-V-X 4 -K-G-X 7 -F-D-X 10 , wherein;
X 4 is T or Y;
X 7 is Y or C; and
X 10 is V, E, L, M, Q, or Y;
CDR-L1:
(SEQ ID NO: 193)
R-A-S-G-N-I-X 7 -X 8 -X 9 -L-X 11 , wherein;
X 7 is H, Y, or W;
X 8 is N, G, T, Q, E, H, D, or K;
X 9 is Y or W; and
X 11 is T, A, or N;
CDR-L2:
(SEQ ID NO: 194)
X 1 -A-K-X 4 -L-X 6 -X 7 , wherein;
X 1 is N, Q, or D;
X 4 is T, N, I, E, or S;
X 6 is A, M, or E; and
X 7 is D, E, S, or A;
and
CDR-L3:
(SEQ ID NO: 195)
Q-X 2 -F-W-X 5 -X 6 -P-X 8 -X 9 , wherein;
X 2 is H or Q;
X 5 is S, N, T, K, R, or M;
X 6 is I or L;
X 8 is Y or A; and
X 9 is T, I, and N;
except that when CDR-H1 is S-Y-D-M-S (SEQ ID
NO: 17), then: CDR-H2 cannot be Y-I-S-S-G-G-G-
G-T-Y-Y-P-D-T-V-K-G (SEQ ID NO: 18);
CDR-H3 cannot be G-G-V-T-K-G-Y-F-D-V (SEQ ID
NO: 19);
CDR-L1 cannot be R-A-S-G-N-I-H-N-Y-L-T (SEQ ID
NO: 20);
CDR-L2 cannot be N-A-K-T-L-A-D (SEQ ID NO:
21); and
CDR-L3 cannot be Q-H-F-W-S-I-P-Y-T (SEQ ID
NO: 22).
53 . The binding protein according to claim 52 , wherein at least one CDR comprises an amino acid sequence selected from the group consisting of:
residues 31-35 of SEQ ID
residues 31-35 of SEQ ID NO: 63
NO: 60 (CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 60
residues 50-66 of SEQ ID NO: 63
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 60
residues 99-108 of SEQ ID NO: 63
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 149
residues 24-34 of SEQ ID NO: 150
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 149
residues 50-56 of SEQ ID NO: 150
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 149
residues 89-97 of SEQ ID NO: 150
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 69
residues 31-35 of SEQ ID NO: 97
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 69
residues 50-66 of SEQ ID NO: 97
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 69
residues 99-108 of SEQ ID NO: 97
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 173
residues 24-34 of SEQ ID NO: 187
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 173
residues 50-56 of SEQ ID NO: 187
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 173
residues 89-97 of SEQ ID NO: 187
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 67
residues 31-35 of SEQ ID NO: 90
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 67
residues 50-66 of SEQ ID NO: 90
(CDR-H2)
(CDR-H2)
residues 99-108 of SEQ ID NO: 67
residues 99-108 of SEQ ID NO: 90
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 151
residues 24-34 of SEQ ID NO: 156
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 151
residues 50-56 of SEQ ID NO: 156
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 151
residues 89-97 of SEQ ID NO: 156
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 88
residues 31-35 of SEQ ID NO: 92
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 88
residues 50-66 of SEQ ID NO: 92
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 88
residues 99-108 of SEQ ID NO: 92
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 159
residues 24-34 of SEQ ID NO: 153
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 159
residues 50-56 of SEQ ID NO: 153
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 159
residues 89-97 of SEQ ID NO: 153
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 96
residues 31-35 of SEQ ID NO: 94
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 96
residues 50-66 of SEQ ID NO: 94
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 96
residues 99-108 of SEQ ID NO: 94
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 155
residues 24-34 of SEQ ID NO: 166
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 155
residues 50-56 of SEQ ID NO: 166
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 155
residues 89-97 of SEQ ID NO: 166
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 90
residues 31-35 of SEQ ID NO: 82
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 90
residues 50-66 of SEQ ID NO: 82
(CDR-H2)
(CDR-H2)
residues 99-108 of SEQ ID NO: 90
residues 99-108 of SEQ ID NO: 82
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 182
residues 24-34 of SEQ ID NO: 159
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 182
residues 50-56 of SEQ ID NO: 159
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 182
residues 89-97 of SEQ ID NO: 159
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 90
residues 31-35 of SEQ ID NO: 101
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 90
residues 50-66 of SEQ ID NO: 101
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 90
residues 99-108 of SEQ ID NO: 101
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 167
residues 24-34 of SEQ ID NO: 158
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 167
residues 50-56 of SEQ ID NO: 158
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 167
residues 89-97 of SEQ ID NO: 158
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 90
residues 31-35 of SEQ ID NO: 96
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 90
residues 50-66 of SEQ ID NO: 96
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 90
residues 99-108 of SEQ ID NO: 96
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 164
residues 24-34 of SEQ ID NO: 157
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 164
residues 50-56 of SEQ ID NO: 157
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 164
residues 89-97 of SEQ ID NO: 157
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 73
residues 31-35 of SEQ ID NO: 70
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 73
residues 50-66 of SEQ ID NO: 70
(CDR-H2);
(CDR-H2)
residues 99-108 of SEQ ID NO: 73
residues 99-108 of SEQ ID NO: 70
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 174
residues 24-34 of SEQ ID NO: 161
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 174
residues 50-56 of SEQ ID NO: 161
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 174
residues 89-97 of SEQ ID NO: 161
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 86
residues 31-35 of SEQ ID NO: 83
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 86
residues 50-66 of SEQ ID NO: 83
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 86
residues 99-108 of SEQ ID NO: 83
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 159
residues 24-34 of SEQ ID NO: 158
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 159
residues 50-56 of SEQ ID NO: 158
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 159
residues 89-97 of SEQ ID NO: 158
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 90
residues 31-35 of SEQ ID NO: 102
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 90
residues 50-66 of SEQ ID NO: 102
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 90
residues 99-108 of SEQ ID NO: 102
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 169
residues 24-34 of SEQ ID NO: 185
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 169
residues 50-56 of SEQ ID NO: 185
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 169
residues 89-97 of SEQ ID NO: 185
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 91
residues 31-35 of SEQ ID NO: 98
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 91
residues 50-66 of SEQ ID NO: 98
(CDR-H2)
(CDR-H2);
residues 99-108 of SEQ ID NO: 91
residues 99-108 of SEQ ID NO: 98
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 165
residues 24-34 of SEQ ID NO: 160
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 165
residues 50-56 of SEQ ID NO: 160
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 165
residues 89-97 of SEQ ID NO: 160
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 76
residues 31-35 of SEQ ID NO: 74
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 76
residues 50-66 of SEQ ID NO: 74
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 76
residues 99-108 of SEQ ID NO: 74
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 175
residues 24-34 of SEQ ID NO: 186
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 175
residues 50-56 of SEQ ID NO: 186
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 175
residues 89-97 of SEQ ID NO: 186
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 99
residues 31-35 of SEQ ID NO: 95
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 99
residues 50-66 of SEQ ID NO: 95
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 99
residues 99-108 of SEQ ID NO: 95
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 189
residues 24-34 of SEQ ID NO: 157
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 189
residues 50-56 of SEQ ID NO: 157
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 189
residues 89-97 of SEQ ID NO: 157
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 100
residues 31-35 of SEQ ID NO: 72
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 100
residues 50-66 of SEQ ID NO: 72
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 72
NO: 100 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 168
residues 24-34 of SEQ ID NO: 178
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 168
residues 50-56 of SEQ ID NO: 178
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 168
residues 89-97 of SEQ ID NO: 178
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 71
residues 31-35 of SEQ ID NO: 96
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 71
residues 50-66 of SEQ ID NO: 96
(CDR-H2)
(CDR-H2);
residues 99-108 of SEQ ID NO: 71
residues 99-108 of SEQ ID NO: 96
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 170
residues 24-34 of SEQ ID NO: 163
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 170
residues 50-56 of SEQ ID NO: 163
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 170
residues 89-97 of SEQ ID NO: 163
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 84
residues 31-35 of SEQ ID NO: 77
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 84
residues 50-66 of SEQ ID NO: 77
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 84
residues 99-108 of SEQ ID NO: 77
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 188
residues 24-34 of SEQ ID NO: 183
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 188
residues 50-56 of SEQ ID NO: 183
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 188
residues 89-97 of SEQ ID NO: 183
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 78
residues 31-35 of SEQ ID NO: 90
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 78
residues 50-66 of SEQ ID NO: 90
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 78
residues 99-108 of SEQ ID NO: 90
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 179
residues 24-34 of SEQ ID NO: 171
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 179
residues 50-56 of SEQ ID NO: 171
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 179
residues 89-97 of SEQ ID NO: 171
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 93
residues 31-35 of SEQ ID NO: 79
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 93
residues 50-66 of SEQ ID NO: 79
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 93
residues 99-108 of SEQ ID NO: 79
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 176
residues 24-34 of SEQ ID NO: 180
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 176
residues 50-56 of SEQ ID NO: 180
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 176
residues 89-97 of SEQ ID NO: 180
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 87
residues 31-35 of SEQ ID NO: 381
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 87
residues 50-66 of SEQ ID NO: 381
(CDR-H2)
(CDR-H2);
residues 99-108 of SEQ ID NO: 87
residues 99-108 of SEQ ID NO: 381
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 154
residues 24-34 of SEQ ID NO: 152
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 154
residues 50-56 of SEQ ID NO: 152
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 154
residues 89-97 of SEQ ID NO: 152
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 85
residues 31-35 of SEQ ID NO: 81
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 85
residues 50-66 of SEQ ID NO: 81
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 85
residues 99-108 of SEQ ID NO: 81
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 162
residues 24-34 of SEQ ID NO: 177
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 162
residues 50-56 of SEQ ID NO: 177
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 162
residues 89-97 of SEQ ID NO: 177
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 89
residues 31-35 of SEQ ID NO: 80
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 89
residues 50-66 of SEQ ID NO: 80
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 89
residues 99-108 of SEQ ID NO: 80
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 170
residues 24-34 of SEQ ID NO: 172
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 170
residues 50-56 of SEQ ID NO: 172
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 170
residues 89-97 of SEQ ID NO: 172
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 75
residues 31-35 of SEQ ID NO: 196
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 75
residues 50-66 of SEQ ID NO: 196
(CDR-H2)
(CDR-H2);
residues 99-108 of SEQ ID NO: 75
residues 99-108 of SEQ ID NO: 196
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 181
residues 24-34 of SEQ ID NO: 197
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 181
residues 50-56 of SEQ ID NO: 197
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 181
residues 89-97 of SEQ ID NO: 197
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 92
residues 31-35 of SEQ ID NO: 198
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 92
residues 50-66 of SEQ ID NO: 198
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID NO: 92
residues 99-108 of SEQ ID NO: 198
(CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 184
residues 24-34 of SEQ ID NO: 199
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 184
residues 50-56 of SEQ ID NO: 199
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 184
residues 89-97 of SEQ ID NO: 199
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 200
residues 31-35 of SEQ ID NO: 202
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 200
residues 50-66 of SEQ ID NO: 202
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 202
NO: 200 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 201
residues 24-34 of SEQ ID NO: 203
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 201
residues 50-56 of SEQ ID NO: 203
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 201
residues 89-97 of SEQ ID NO: 203
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 204
residues 31-35 of SEQ ID NO: 206
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 204
residues 50-66 of SEQ ID NO: 206
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 206
NO: 204 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 205
residues 24-34 of SEQ ID NO: 207
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 205
residues 50-56 of SEQ ID NO: 207
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 205
residues 89-97 of SEQ ID NO: 207
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 208
residues 31-35 of SEQ ID NO: 210
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 208
residues 50-66 of SEQ ID NO: 210
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 210
NO: 208 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 209
residues 24-34 of SEQ ID NO: 211
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 209
residues 50-56 of SEQ ID NO: 211
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 209
residues 89-97 of SEQ ID NO: 211
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 103
residues 31-35 of SEQ ID NO: 126
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 103
residues 50-66 of SEQ ID NO: 126
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 126
NO: 103 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 104
residues 31-35 of SEQ ID NO: 127
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 104
residues 50-66 of SEQ ID NO: 127
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 127
NO: 104 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 105
residues 31-35 of SEQ ID NO: 128
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 105
residues 50-66 of SEQ ID NO: 128
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 128
NO: 105 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 106
residues 31-35 of SEQ ID NO: 129
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 106
residues 50-66 of SEQ ID NO: 129
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 129
NO: 106 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 107
residues 31-35 of SEQ ID NO: 130
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 107
residues 50-66 of SEQ ID NO: 130
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 130
NO: 107 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 108
residues 31-35 of SEQ ID NO: 131
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 108
residues 50-66 of SEQ ID NO: 131
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 131
NO: 108 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 109
residues 31-35 of SEQ ID NO: 132
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 109
residues 50-66 of SEQ ID NO: 132
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 132
NO: 109 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 110
residues 31-35 of SEQ ID NO: 133
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 110
residues 50-66 of SEQ ID NO: 133
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 133
NO: 110 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 111
residues 31-35 of SEQ ID NO: 134
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 111
residues 50-66 of SEQ ID NO: 134
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 134
NO: 111 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 112
residues 31-35 of SEQ ID NO: 135
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 112
residues 50-66 of SEQ ID NO: 135
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 135
NO: 112 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 113
residues 31-35 of SEQ ID NO: 136
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 113
residues 50-66 of SEQ ID NO: 136
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 136
NO: 113 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 114
residues 31-35 of SEQ ID NO: 137
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 114
residues 50-66 of SEQ ID NO: 137
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 137
NO: 114 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 115
residues 31-35 of SEQ ID NO: 138
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 115
residues 50-66 of SEQ ID NO: 138
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 138
NO: 115 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 116
residues 31-35 of SEQ ID NO: 139
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 116
residues 50-66 of SEQ ID NO: 139
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 139
NO: 116 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 117
residues 31-35 of SEQ ID NO: 140
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 117
residues 50-66 of SEQ ID NO: 140
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 140
NO: 117 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 118
residues 31-35 of SEQ ID NO: 141
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 118
residues 50-66 of SEQ ID NO: 141
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 141
NO: 118 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 119
residues 31-35 of SEQ ID NO: 142
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 119
residues 50-66 of SEQ ID NO: 142
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 142
NO: 119 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 120
residues 31-35 of SEQ ID NO: 143
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 120
residues 50-66 of SEQ ID NO: 143
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 143
NO: 120 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 121
residues 31-35 of SEQ ID NO: 144
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 121
residues 50-66 of SEQ ID NO: 144
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 144
NO: 121 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 122
residues 31-35 of SEQ ID NO: 145
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 122
residues 50-66 of SEQ ID NO: 145
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 145
NO: 122 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 123
residues 31-35 of SEQ ID NO: 146
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 123
residues 50-66 of SEQ ID NO: 146
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 146
NO: 123 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 124
residues 31-35 of SEQ ID NO: 147
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 124
residues 50-66 of SEQ ID NO: 147
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 147
NO: 124 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO: 125
residues 31-35 of SEQ ID NO: 148
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO: 125
residues 50-66 of SEQ ID NO: 148
(CDR-H2);
(CDR-H2);
residues 99-108 of SEQ ID
residues 99-108 of SEQ ID NO: 148
NO: 125 (CDR-H3);
(CDR-H3);
residues 24-34 of SEQ ID NO: 59
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
(CDR-L3).
54 . The binding protein according to claim 52 , wherein at least three CDRs are from a set of CDRs selected from the group of CDR sets consisting of:
CDR
Set
SEQ ID NO.
1
residues 31-35 of SEQ ID NO: 60
(CDR-H1);
residues 50-66 of SEQ ID NO: 60
(CDR-H2);
residues 99-108 of SEQ ID NO: 60
(CDR-H3);
2
residues 24-34 of SEQ ID NO: 149
(CDR-L1);
residues 50-56 of SEQ ID NO: 149
(CDR-L2);
residues 89-97 of SEQ ID NO: 149
(CDR-L3);
3
residues 31-35 of SEQ ID NO: 69
(CDR-H1);
residues 50-66 of SEQ ID NO: 69
(CDR-H2);
residues 99-108 of SEQ ID NO: 69
(CDR-H3);
4
residues 24-34 of SEQ ID NO: 173
(CDR-L1);
residues 50-56 of SEQ ID NO: 173
(CDR-L2);
residues 89-97 of SEQ ID NO: 173
(CDR-L3);
5
residues 31-35 of SEQ ID NO: 67
(CDR-H1);
residues 50-66 of SEQ ID NO: 67
(CDR-H2)
residues 99-108 of SEQ ID NO: 67
(CDR-H3);
6
residues 24-34 of SEQ ID NO: 151
(CDR-L1);
residues 50-56 of SEQ ID NO: 151
(CDR-L2);
residues 89-97 of SEQ ID NO: 151
(CDR-L3);
7
residues 31-35 of SEQ ID NO: 88
(CDR-H1);
residues 50-66 of SEQ ID NO: 88
(CDR-H2);
residues 99-108 of SEQ ID NO: 88
(CDR-H3);
8
residues 24-34 of SEQ ID NO: 159
(CDR-L1);
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residues 50-66 of SEQ ID NO: 109
(CDR-H2);
residues 99-108 of SEQ ID NO: 109
(CDR-H3);
122
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
123
residues 31-35 of SEQ ID NO: 110
(CDR-H1);
residues 50-66 of SEQ ID NO: 110
(CDR-H2);
residues 99-108 of SEQ ID NO: 110
(CDR-H3);
124
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
125
residues 31-35 of SEQ ID NO: 111
(CDR-H1);
residues 50-66 of SEQ ID NO: 111
(CDR-H2);
residues 99-108 of SEQ ID NO: 111
(CDR-H3);
126
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
127
residues 31-35 of SEQ ID NO: 112
(CDR-H1);
residues 50-66 of SEQ ID NO: 112
(CDR-H2);
residues 99-108 of SEQ ID NO: 112
(CDR-H3);
128
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
129
residues 31-35 of SEQ ID NO: 113
(CDR-H1);
residues 50-66 of SEQ ID NO: 113
(CDR-H2);
residues 99-108 of SEQ ID NO: 113
(CDR-H3);
130
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
131
residues 31-35 of SEQ ID NO: 114
(CDR-H1);
residues 50-66 of SEQ ID NO: 114
(CDR-H2);
residues 99-108 of SEQ ID NO: 114
(CDR-H3);
132
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
133
residues 31-35 of SEQ ID NO: 115
(CDR-H1);
residues 50-66 of SEQ ID NO: 115
(CDR-H2);
residues 99-108 of SEQ ID NO: 115
(CDR-H3);
134
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
135
residues 31-35 of SEQ ID NO: 116
(CDR-H1);
residues 50-66 of SEQ ID NO: 116
(CDR-H2);
residues 99-108 of SEQ ID NO: 116
(CDR-H3);
136
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
137
residues 31-35 of SEQ ID NO: 117
(CDR-H1);
residues 50-66 of SEQ ID NO: 117
(CDR-H2);
residues 99-108 of SEQ ID NO: 117
(CDR-H3);
138
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
139
residues 31-35 of SEQ ID NO: 118
(CDR-H1);
residues 50-66 of SEQ ID NO: 118
(CDR-H2);
residues 99-108 of SEQ ID NO: 118
(CDR-H3);
140
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
141
residues 31-35 of SEQ ID NO: 119
(CDR-H1);
residues 50-66 of SEQ ID NO: 119
(CDR-H2);
residues 99-108 of SEQ ID NO: 119
(CDR-H3);
142
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
143
residues 31-35 of SEQ ID NO: 120
(CDR-H1);
residues 50-66 of SEQ ID NO: 120
(CDR-H2);
residues 99-108 of SEQ ID NO: 120
(CDR-H3);
144
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
145
residues 31-35 of SEQ ID NO: 121
(CDR-H1);
residues 50-66 of SEQ ID NO: 121
(CDR-H2);
residues 99-108 of SEQ ID NO: 121
(CDR-H3);
146
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
147
residues 31-35 of SEQ ID NO: 122
(CDR-H1);
residues 50-66 of SEQ ID NO: 122
(CDR-H2);
residues 99-108 of SEQ ID NO: 122
(CDR-H3);
148
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
149
residues 31-35 of SEQ ID NO: 123
(CDR-H1);
residues 50-66 of SEQ ID NO: 123
(CDR-H2);
residues 99-108 of SEQ ID NO: 123
(CDR-H3);
150
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
151
residues 31-35 of SEQ ID NO: 124
(CDR-H1);
residues 50-66 of SEQ ID NO: 124
(CDR-H2);
residues 99-108 of SEQ ID NO: 124
(CDR-H3);
152
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
153
residues 31-35 of SEQ ID NO: 125
(CDR-H1);
residues 50-66 of SEQ ID NO: 125
(CDR-H2);
residues 99-108 of SEQ ID NO: 125
(CDR-H3);
154
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
155
residues 31-35 of SEQ ID NO: 126
(CDR-H1);
residues 50-66 of SEQ ID NO: 126
(CDR-H2);
residues 99-108 of SEQ ID NO: 126
(CDR-H3);
156
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
157
residues 31-35 of SEQ ID NO: 127
(CDR-H1);
residues 50-66 of SEQ ID NO: 127
(CDR-H2);
residues 99-108 of SEQ ID NO: 127
(CDR-H3);
158
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
159
residues 31-35 of SEQ ID NO: 128
(CDR-H1);
residues 50-66 of SEQ ID NO: 128
(CDR-H2);
residues 99-108 of SEQ ID NO: 128
(CDR-H3);
160
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
161
residues 31-35 of SEQ ID NO: 129
(CDR-H1);
residues 50-66 of SEQ ID NO: 129
(CDR-H2);
residues 99-108 of SEQ ID NO: 129
(CDR-H3);
162
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
163
residues 31-35 of SEQ ID NO: 130
(CDR-H1);
residues 50-66 of SEQ ID NO: 130
(CDR-H2);
residues 99-108 of SEQ ID NO: 130
(CDR-H3);
164
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
165
residues 31-35 of SEQ ID NO: 131
(CDR-H1);
residues 50-66 of SEQ ID NO: 131
(CDR-H2);
residues 99-108 of SEQ ID NO: 131
(CDR-H3);
166
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
167
residues 31-35 of SEQ ID NO: 132
(CDR-H1);
residues 50-66 of SEQ ID NO: 132
(CDR-H2);
residues 99-108 of SEQ ID NO: 132
(CDR-H3);
168
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
169
residues 31-35 of SEQ ID NO: 133
(CDR-H1);
residues 50-66 of SEQ ID NO: 133
(CDR-H2);
residues 99-108 of SEQ ID NO: 133
(CDR-H3);
170
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
171
residues 31-35 of SEQ ID NO: 134
(CDR-H1);
residues 50-66 of SEQ ID NO: 134
(CDR-H2);
residues 99-108 of SEQ ID NO: 134
(CDR-H3);
172
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
173
residues 31-35 of SEQ ID NO: 135
(CDR-H1);
residues 50-66 of SEQ ID NO: 135
(CDR-H2);
residues 99-108 of SEQ ID NO: 135
(CDR-H3);
174
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
175
residues 31-35 of SEQ ID NO: 136
(CDR-H1);
residues 50-66 of SEQ ID NO: 136
(CDR-H2);
residues 99-108 of SEQ ID NO: 136
(CDR-H3);
176
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
177
residues 31-35 of SEQ ID NO: 137
(CDR-H1);
residues 50-66 of SEQ ID NO: 137
(CDR-H2);
residues 99-108 of SEQ ID NO: 137
(CDR-H3);
178
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
179
residues 31-35 of SEQ ID NO: 138
(CDR-H1);
residues 50-66 of SEQ ID NO: 138
(CDR-H2);
residues 99-108 of SEQ ID NO: 138
(CDR-H3);
180
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
181
residues 31-35 of SEQ ID NO: 139
(CDR-H1);
residues 50-66 of SEQ ID NO: 139
(CDR-H2);
residues 99-108 of SEQ ID NO: 139
(CDR-H3);
182
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
183
residues 31-35 of SEQ ID NO: 140
(CDR-H1);
residues 50-66 of SEQ ID NO: 140
(CDR-H2);
residues 99-108 of SEQ ID NO: 140
(CDR-H3);
184
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
185
residues 31-35 of SEQ ID NO: 141
(CDR-H1);
residues 50-66 of SEQ ID NO: 141
(CDR-H2);
residues 99-108 of SEQ ID NO: 141
(CDR-H3);
186
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
187
residues 31-35 of SEQ ID NO: 142
(CDR-H1);
residues 50-66 of SEQ ID NO: 142
(CDR-H2);
residues 99-108 of SEQ ID NO: 142
(CDR-H3);
188
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
189
residues 31-35 of SEQ ID NO: 143
(CDR-H1);
residues 50-66 of SEQ ID NO: 143
(CDR-H2);
residues 99-108 of SEQ ID NO: 143
(CDR-H3);
190
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
191
residues 31-35 of SEQ ID NO: 144
(CDR-H1);
residues 50-66 of SEQ ID NO: 144
(CDR-H2);
residues 99-108 of SEQ ID NO: 144
(CDR-H3);
192
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
193
residues 31-35 of SEQ ID NO: 145
(CDR-H1);
residues 50-66 of SEQ ID NO: 145
(CDR-H2);
residues 99-108 of SEQ ID NO: 145
(CDR-H3);
194
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
195
residues 31-35 of SEQ ID NO: 146
(CDR-H1);
residues 50-66 of SEQ ID NO: 146
(CDR-H2);
residues 99-108 of SEQ ID NO: 146
(CDR-H3);
196
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
197
residues 31-35 of SEQ ID NO: 147
(CDR-H1);
residues 50-66 of SEQ ID NO: 147
(CDR-H2);
residues 99-108 of SEQ ID NO: 147
(CDR-H3);
198
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3);
199
residues 31-35 of SEQ ID NO: 148
(CDR-H1);
residues 50-66 of SEQ ID NO: 148
(CDR-H2);
residues 99-108 of SEQ ID NO: 148
(CDR-H3);
200
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3).
55 . The binding protein according to claim 54 , comprising CDRs from two CDR sets.
56 . The binding protein according to claim 55 , wherein said two CDR sets are selected from the group consisting of:
CDR Set 1 and CDR Set 2
CDR Set 3 and CDR Set 4
CDR Set 5 and CDR Set 6
CDR Set 7 and CDR Set 8
CDR Set 9 and CDR Set 10
CDR Set 11 and CDR Set 12
CDR Set 13 and CDR Set 14
CDR Set 15 and CDR Set 16
CDR Set 17 and CDR Set 18
CDR Set 19 and CDR Set 20
CDR Set 21 and CDR Set 22
CDR Set 23 and CDR Set 24
CDR Set 25 and CDR Set 26
CDR Set 27 and CDR Set 28
CDR Set 29 and CDR Set 30
CDR Set 31 and CDR Set 32
CDR Set 33 and CDR Set 34
CDR Set 35 and CDR Set 36
CDR Set 37 and CDR Set 38
CDR Set 39 and CDR Set 40
CDR Set 41 and CDR Set 42
CDR Set 43 and CDR Set 44
CDR Set 45 and CDR Set 46
CDR Set 47 and CDR Set 48
CDR Set 49 and CDR Set 50
CDR Set 51 and CDR Set 52
CDR Set 53 and CDR Set 54
CDR Set 55 and CDR Set 56
CDR Set 57 and CDR Set 58
CDR Set 59 and CDR Set 60
CDR Set 61 and CDR Set 62
CDR Set 63 and CDR Set 64
CDR Set 65 and CDR Set 66
CDR Set 67 and CDR Set 68
CDR Set 69 and CDR Set 70
CDR Set 71 and CDR Set 72
CDR Set 73 and CDR Set 74
CDR Set 75 and CDR Set 76
CDR Set 77 and CDR Set 78
CDR Set 79 and CDR Set 80
CDR Set 81 and CDR Set 82
CDR Set 83 and CDR Set 84
CDR Set 85 and CDR Set 86
CDR Set 87 and CDR Set 88
CDR Set 89 and CDR Set 90
CDR Set 91 and CDR Set 92
CDR Set 93 and CDR Set 94
CDR Set 95 and CDR Set 96
CDR Set 97 and CDR Set 98
CDR Set 99 and CDR Set 100
CDR Set 101 and CDR Set 102
CDR Set 103 and CDR Set 104
CDR Set 105 and CDR Set 106
CDR Set 107 and CDR Set 108
CDR Set 109 and CDR Set 110
CDR Set 111 and CDR Set 112
CDR Set 113 and CDR Set 114
CDR Set 115 and CDR Set 116
CDR Set 117 and CDR Set 118
CDR Set 119 and CDR Set 120
CDR Set 121 and CDR Set 122
CDR Set 123 and CDR Set 124
CDR Set 125 and CDR Set 126
CDR Set 127 and CDR Set 128
CDR Set 129 and CDR Set 130
CDR Set 131 and CDR Set 132
CDR Set 133 and CDR Set 134
CDR Set 135 and CDR Set 136
CDR Set 137 and CDR Set 138
CDR Set 139 and CDR Set 140
CDR Set 141 and CDR Set 142
CDR Set 143 and CDR Set 144
CDR Set 145 and CDR Set 146
CDR Set 147 and CDR Set 148
CDR Set 149 and CDR Set 150
CDR Set 151 and CDR Set 152
CDR Set 153 and CDR Set 154
CDR Set 155 and CDR Set 156
CDR Set 157 and CDR Set 158
CDR Set 159 and CDR Set 160
CDR Set 161 and CDR Set 162
CDR Set 163 and CDR Set 164
CDR Set 165 and CDR Set 166
CDR Set 167 and CDR Set 168
CDR Set 169 and CDR Set 170
CDR Set 171 and CDR Set 172
CDR Set 173 and CDR Set 174
CDR Set 175 and CDR Set 176
CDR Set 177 and CDR Set 178
CDR Set 179 and CDR Set 180
CDR Set 181 and CDR Set 182
CDR Set 183 and CDR Set 184
CDR Set 185 and CDR Set 186
CDR Set 187 and CDR Set 188
CDR Set 189 and CDR Set 190
CDR Set 191 and CDR Set 192
CDR Set 193 and CDR Set 194
CDR Set 195 and CDR Set 196
CDR Set 197 and CDR Set 198
CDR Set 199 and CDR Set 200
57 . The binding protein according to any one of claims 52 , 53 , and 56 , further comprising a human acceptor framework.
58 . The binding protein according to claim 57 , wherein said human acceptor framework comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 7-10, 13-16, 25, 240-316, and 317-381.
59 . The binding protein according to claim 57 , 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.
60 . The binding protein according to claim 57 , 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-1β; 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 Kabat-defined first heavy chain framework.
61 . The binding protein according to claim 60 , wherein the key residue by Kabat numbering is 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, and 95L.
62 . The binding protein according to claim 57 , wherein the binding protein comprises a consensus human variable domain.
63 . The binding protein according to any one of claims 52 , 53 , and 56 , wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of SEQ ID NO:60-189.
64 . The binding protein according to claim 63 , wherein said binding protein comprises two variable domains.
65 . The binding protein according to claim 64 , wherein said two variable domains comprise amino acid sequences selected from the group consisting of:
SEQ ID NO: 60 and SEQ ID NO: 149
SEQ ID NO: 198 and SEQ ID NO: 199
SEQ ID NO: 69 and SEQ ID NO: 173
SEQ ID NO: 202 and SEQ ID NO: 203
SEQ ID NO: 67 and SEQ ID NO: 151
SEQ ID NO: 206 and SEQ ID NO: 207
SEQ ID NO: 88 and SEQ ID NO: 159
SEQ ID NO: 210 and SEQ ID NO: 211
SEQ ID NO: 96 and SEQ ID NO: 155
SEQ ID NO: 103 and SEQ ID NO: 59
SEQ ID NO: 90 and SEQ ID NO: 182
SEQ ID NO: 104 and SEQ ID NO: 59
SEQ ID NO: 90 and SEQ ID NO: 167
SEQ ID NO: 105 and SEQ ID NO: 59
SEQ ID NO: 90 and SEQ ID NO: 164
SEQ ID NO: 106 and SEQ ID NO: 59
SEQ ID NO: 73 and SEQ ID NO: 174
SEQ ID NO: 107 and SEQ ID NO: 59
SEQ ID NO: 86 and SEQ ID NO: 159
SEQ ID NO: 108 and SEQ ID NO: 59
SEQ ID NO: 90 and SEQ ID NO: 169
SEQ ID NO: 109 and SEQ ID NO: 59
SEQ ID NO: 91 and SEQ ID NO: 165
SEQ ID NO: 110 and SEQ ID NO: 59
SEQ ID NO: 76 and SEQ ID NO: 175
SEQ ID NO: 111 and SEQ ID NO: 59
SEQ ID NO: 99 and SEQ ID NO: 189
SEQ ID NO: 112 and SEQ ID NO: 59
SEQ ID NO: 100 and SEQ ID NO: 168
SEQ ID NO: 113 and SEQ ID NO: 59
SEQ ID NO: 71 and SEQ ID NO: 170
SEQ ID NO: 114 and SEQ ID NO: 59
SEQ ID NO: 84 and SEQ ID NO: 188
SEQ ID NO: 115 and SEQ ID NO: 59
SEQ ID NO: 78 and SEQ ID NO: 179
SEQ ID NO: 116 and SEQ ID NO: 59
SEQ ID NO: 93 and SEQ ID NO: 176
SEQ ID NO: 117 and SEQ ID NO: 59
SEQ ID NO: 87 and SEQ ID NO: 154
SEQ ID NO: 118 and SEQ ID NO: 59
SEQ ID NO: 85 and SEQ ID NO: 162
SEQ ID NO: 119 and SEQ ID NO: 59
SEQ ID NO: 89 and SEQ ID NO: 170
SEQ ID NO: 120 and SEQ ID NO: 59
SEQ ID NO: 75 and SEQ ID NO: 181
SEQ ID NO: 121 and SEQ ID NO: 59
SEQ ID NO: 92 and SEQ ID NO: 184
SEQ ID NO: 122 and SEQ ID NO: 59
SEQ ID NO: 200 and SEQ ID NO: 201
SEQ ID NO: 123 and SEQ ID NO: 59
SEQ ID NO: 204 and SEQ ID NO: 205
SEQ ID NO: 124 and SEQ ID NO: 59
SEQ ID NO: 208 and SEQ ID NO: 209
SEQ ID NO: 125 and SEQ ID NO: 59
SEQ ID NO: 63 and SEQ ID NO: 150
SEQ ID NO: 126 and SEQ ID NO: 59
SEQ ID NO: 97 and SEQ ID NO: 187
SEQ ID NO: 127 and SEQ ID NO: 59
SEQ ID NO: 90 and SEQ ID NO: 156
SEQ ID NO: 128 and SEQ ID NO: 59
SEQ ID NO: 92 and SEQ ID NO: 153
SEQ ID NO: 129 and SEQ ID NO: 59
SEQ ID NO: 94 and SEQ ID NO: 166
SEQ ID NO: 130 and SEQ ID NO: 59
SEQ ID NO: 82 and SEQ ID NO: 159
SEQ ID NO: 131 and SEQ ID NO: 59
SEQ ID NO: 101 and SEQ ID NO: 158
SEQ ID NO: 132 and SEQ ID NO: 59
SEQ ID NO: 96 and SEQ ID NO: 157
SEQ ID NO: 133 and SEQ ID NO: 59
SEQ ID NO: 70 and SEQ ID NO: 161
SEQ ID NO: 134 and SEQ ID NO: 59
SEQ ID NO: 83 and SEQ ID NO: 158
SEQ ID NO: 135 and SEQ ID NO: 59
SEQ ID NO: 102 and SEQ ID NO: 185
SEQ ID NO: 136 and SEQ ID NO: 59
SEQ ID NO: 98 and SEQ ID NO: 160
SEQ ID NO: 137 and SEQ ID NO: 59
SEQ ID NO: 74 and SEQ ID NO: 186
SEQ ID NO: 138 and SEQ ID NO: 59
SEQ ID NO: 95 and SEQ ID NO: 157
SEQ ID NO: 139 and SEQ ID NO: 59
SEQ ID NO: 72 and SEQ ID NO: 178
SEQ ID NO: 140 and SEQ ID NO: 59
SEQ ID NO: 96 and SEQ ID NO: 163
SEQ ID NO: 141 and SEQ ID NO: 59
SEQ ID NO: 77 and SEQ ID NO: 183
SEQ ID NO: 142 and SEQ ID NO: 59
SEQ ID NO: 90 and SEQ ID NO: 171
SEQ ID NO: 143 and SEQ ID NO: 59
SEQ ID NO: 79 and SEQ ID NO: 180
SEQ ID NO: 144 and SEQ ID NO: 59
SEQ ID NO: 381 and SEQ ID NO: 152
SEQ ID NO: 145 and SEQ ID NO: 59
SEQ ID NO: 81 and SEQ ID NO: 177
SEQ ID NO: 146 and SEQ ID NO: 59
SEQ ID NO: 80 and SEQ ID NO: 172
SEQ ID NO: 147 and SEQ ID NO: 59
SEQ ID NO: 196 and SEQ ID NO: 197
SEQ ID NO: 148 and SEQ ID NO: 59
66 . The binding protein according to any one of claims 52 , 53 , and 56 , wherein the binding protein is capable of modulating a biological function of IL-1.
67 . The binding protein according to any one of claims 52 , 53 , and 56 , wherein the binding protein is capable of neutralizing IL-1.
68 . The binding protein according to any one of claims 52 , 53 , and 56 , wherein the binding protein has an on rate constant (K on ) to IL-1β selected from the group consisting of: at least about 10 2 M −1 s −1 ; at least about 10 3 M −1 s −1 ; at least about 10 4 M −1 s −1 ; at least about 10 5 M −1 s −1 ; and at least about 10 6 M −1 s −1 ; as measured by surface plasmon resonance.
69 . The binding protein according to any one of claims 52 , 53 , and 56 , wherein the binding protein has an off rate constant (K off ) to IL-1β selected from the group consisting of: at most about 10 −3 s −1 ; at most about 10 −4 s −1 ; at most about 10 −5 s −1 ; and at most about 10 −6 s −1 , as measured by surface plasmon resonance.
70 . The binding protein according to any one of claims 52 , 53 , and 56 , wherein the binding protein has a dissociation constant (K D ) to IL-1β 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.
71 . An IL-1β binding protein construct comprising a binding protein as described in claim 52 , said IL-1β binding protein construct further comprising a linker or an immunoglobulin constant domain.
72 . The IL-1β binding protein construct according to claim 71 , wherein said IL-1β binding protein is selected from the group consisting of: an immunoglobulin molecule, a disulfide linked Fv, a monoclonal antibody, an scFv, a chimeric antibody, a CDR-grafted antibody, a diabody, a humanized antibody, a multispecific antibody, an Fab, a dual specific antibody, a Fab′, a bispecific antibody, and a F(ab′) 2 , a DVD-Ig™, and an Fv.
73 . The IL-1β binding protein construct according to claim 71 , wherein said binding protein construct 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 IgG1 constant domain, a human IgE constant domain, a human IgG2 constant domain, and a human IgG3 constant domain, and a human IgA constant domain.
74 . The IL-1β binding protein construct according to claim 71 , wherein said binding protein construct comprises 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.
75 . An IL-1β binding protein conjugate comprising an IL-1β binding protein construct as described in claim 71 , said IL-1β 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.
76 . The IL-1β binding protein conjugate according to claim 75 , 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.
77 . The IL-1β binding protein conjugate according to claim 76 , wherein said radiolabel is selected from the group consisting of: 3 H, 14 C, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, and 153 Sm.
78 . The IL-1β binding protein conjugate according to claim 75 , 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.
79 . The IL-1β binding protein construct according to claim 71 , wherein said binding protein possesses a human glycosylation pattern.
80 . The IL-1β binding protein according to claim 52 , wherein said binding protein is a crystallized binding protein.
81 . The IL-1β binding protein construct according to claim 71 , wherein said IL-1β binding protein construct is a crystallized IL-1β binding protein construct.
82 . The IL-1β binding protein conjugate according to claim 75 , wherein said IL-1β binding protein conjugate is a crystallized binding protein.
83 . The crystallized IL-1β binding protein according to claim 80 , wherein said crystallized IL-1β binding protein is a carrier-free pharmaceutical controlled release crystallized IL-1β binding protein.
84 . The crystallized IL-1β binding protein construct according to claim 81 , wherein said crystallized IL-1β binding protein construct is a carrier-free pharmaceutical controlled release crystallized IL-1β binding protein construct.
85 . The crystallized IL-1β binding protein conjugate according to claim 82 , wherein said crystallized IL-1β binding protein conjugate is a carrier-free pharmaceutical controlled release crystallized IL-1β binding protein conjugate.
86 . The crystallized IL-1β binding protein according to claim 80 , wherein said crystallize IL-1β binding protein has a greater half life in vivo than the soluble counterpart.
87 . The IL-1β binding protein construct according to claim 81 , wherein said crystallized IL-1β binding protein construct has a greater half life in vivo than the soluble counterpart.
88 . The crystallized IL-1β binding protein conjugate according to claim 82 , wherein said crystallized IL-1β binding protein conjugate has a greater half life in vivo than the soluble counterpart.
89 . The crystallized IL-1β binding protein according to claim 80 , wherein said crystallized IL-1β binding protein retains biological activity.
90 . The crystallized IL-1β binding protein construct according to claim 81 , wherein said crystallized IL-1β binding protein construct retains biological activity.
91 . The crystallized IL-1β binding protein construct according to claim 82 , wherein said crystallized IL-1β binding protein conjugate retains biological activity.
92 . A composition for the release of a crystallized IL-1β binding protein according to claim 80 , a crystallized IL-1β binding protein construct according to claim 81 , or a crystallized IL-1β binding protein conjugate according to claim 82 , said composition comprising:
(a) a formulation, wherein said formulation comprises a crystallized IL-1β binding protein according to claim 80 , a crystallized IL-1β binding protein construct according to claim 81 , or a crystallized IL-1β binding protein conjugate according to claim 82 , and an ingredient; and
(b) at least one polymeric carrier.
93 . The composition according to claim 92 , 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.
94 . The composition according to claim 92 , wherein said ingredient is selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol and polyethylene glycol.
95 . A pharmaceutical composition comprising a binding protein as described in claim 52 , and a pharmaceutically acceptable carrier.
96 . The pharmaceutical composition according to claim 95 further comprising at least one additional agent.
97 . The pharmaceutical composition according to claim 96 , wherein said additional agent is selected from the group consisting of: a therapeutic agent; an imaging agent; a cytotoxic agent; an angiogenesis inhibitor; a kinase inhibitor; a co-stimulation molecule blocker; an adhesion molecule blockers; an anti-cytokine antibody or functional fragment thereof; methotrexate; cyclosporin; rapamycin; FK506; a 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 epinephrine or analog thereof; a cytokine; and a cytokine antagonist.
98 . A pharmaceutical composition comprising an IL-1β binding protein conjugate as described in claim 75 and a pharmaceutically acceptable carrier.
99 . The pharmaceutical composition according to claim 98 , wherein the IL-1β binding protein conjugate comprises 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.
100 . The pharmaceutical composition according to claim 99 , wherein said imaging agent is a radiolabel selected from the group consisting of: 3 H, 14 C, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, and 153 Sm.
101 . The pharmaceutical composition according to claim 98 , wherein said IL-1β binding protein conjugate comprises a therapeutic or cytotoxic agent selected from the group consisting of: an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, a toxin, and an apoptotic agent.
102 . An isolated nucleic acid encoding an amino acid sequence of an IL-1β binding protein as described in claim 52 .
103 . A vector comprising an isolated nucleic acid according to claim 102 .
104 . The vector according to claim 103 , wherein said vector is selected from the group consisting of pcDNA, pTT, pTT3, pEFBOS, pBV, pJV, and pBJ.
105 . A host cell comprising a vector according to claim 103 .
106 . The host cell according to claim 105 , wherein said host cell is a prokaryotic cell.
107 . The host cell according to claim 106 , wherein said prokaryotic host cell is Escherichia coli.
108 . The host cell according to claim 105 , wherein said host cell is a eukaryotic cell.
109 . The host cell according to claim 108 , wherein said eukaryotic cell is selected from the group consisting of: a protist cell, an animal cell, a plant cell, and a fungal cell.
110 . The host cell according to claim 109 , wherein said fungal cell is a yeast cell.
111 . The host cell according to claim 110 , wherein said yeast cell is Saccharomyces cerevisiae.
112 . The host cell according to claim 109 , wherein said animal cell is selected from the group consisting of: a mammalian cell, an avian cell, and an insect cell.
113 . The host cell according to claim 112 , wherein said mammalian cell is a CHO cell or a COS cell.
114 . The host cell according to claim 112 , wherein said insect host cell is an insect Sf9 cell.
115 . A method of producing an IL-1β binding protein, comprising culturing a host cell described in claim 105 in culture medium under conditions sufficient to produce the IL-1β binding protein.
116 . An IL-1β binding protein produced according to the method of claim 115 .
117 . A method for reducing human IL-1 activity comprising contacting a human IL-1 protein with a binding protein described in claim 52 , such that human IL-1 protein activity is reduced.
118 . A method for reducing human IL-1 activity in a human subject suffering from a disorder in which IL-1 activity is detrimental, comprising administering to the human subject a binding protein as described in claim 52 or a crystal thereof, such that human IL-1 activity in the human subject is reduced.
119 . A method for treating a subject for a disorder in which IL-1 activity is detrimental comprising administering to the subject a binding protein as described in claim 52 or a crystal thereof, such that treatment is achieved.
120 . The method of claim 119 , wherein said disorder is selected from the group consisting of: diabetes; uveitis; neuropathic pain; osteoarthritic pain; inflammatory pain; rheumatoid arthritis; osteoarthritis; juvenile chronic arthritis; septic arthritis; Lyme arthritis; psoriatic arthritis; reactive arthritis; spondyloarthropathy; systemic lupus erythematosus (SLE); Crohn's disease; ulcerative colitis; inflammatory bowel disease; autoimmune diabetes; insulin dependent diabetes mellitus; thyroiditis; asthma; allergic diseases; psoriasis; dermatitis; scleroderma; graft versus host disease; organ transplant rejection; acute immune disease associated with organ transplantation; chronic immune disease associated with organ transplantation; sarcoidosis; atherosclerosis; disseminated intravascular coagulation (DIC); 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; autoimmune uveitis; septic shock; toxic shock syndrome; sepsis syndrome; cachexia; infectious diseases; parasitic diseases; 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; polyglandular deficiency type II (Schmidt's syndrome); acute respiratory distress syndrome (ARDS); 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 (GCA); primary sclerosing hepatitis; cryptogenic autoimmune hepatitis; acquired immunodeficiency syndrome (AIDS); 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; post-inflammatory 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; Sjögren'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; 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; idiopathic male infertility; nitric oxide-associated male infertility; sperm autoimmunity; multiple sclerosis (all subtypes, including primary progressive, secondary progressive, relapsing remitting); 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; Sjörgren's syndrome; Takayasu's disease/arteritis; autoimmune thrombocytopaenia (AITP); 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 disease; alcoholic cirrhosis; alcohol-induced liver injury; cholestasis; idiosyncratic liver disease; drug-induced hepatitis; non-alcoholic steatohepatitis; allergy; group B Streptococci (GBS) infection; mental disorders (e.g., depression and schizophrenia); Th2 Type and Th1 Type mediated diseases; acute and chronic pain (different forms of pain); cancer (such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate, and rectal cancer); hematopoietic malignancies; leukemia; lymphoma; abetalipoproteinemia; acrocyanosis; acute and chronic parasitic or infectious processes; acute leukemia; acute lymphoblastic leukemia (ALL); T-cell ALL; FAB ALL; acute myeloid leukemia (AML); acute or chronic bacterial infection; acute pancreatitis; acute renal failure; adenocarcinomas; atrial 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 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 hemophagocytic 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; hemochromatosis; 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 (IPF); 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 syndrome migraine headache; idiopathic migraine headache; mitochondrial multisystem disorder; mixed connective tissue disease; monoclonal gammopathy; multiple myeloma; multiple systems degenerations (Menzel; Dejerine-Thomas; Shy-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-Hodgkin's lymphoma; occlusion of the abdominal aorta and its branches; occlusive arterial disorders; OKT3® therapy; orchitis/epididymitis; 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; Raynaud's disease; Refsum's disease; regular narrow QRS tachycardia; renovascular hypertension; reperfusion injury; restrictive cardiomyopathy; sarcomas; 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; 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 hemophagocytic 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; dacryocystitis; dermatomyositis; diabetic retinopathy; disk herniation; disk prolapse; drug induced immune hemolytic anemia; endocarditis; endometriosis; endophthalmitis; episcleritis; erythema multiforme; erythema multiforme major; gestational pemphigoid; Guillain-Barré 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; 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; 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; secondary Parkinsonism; prostatitis; pure red cell aplasia; primary adrenal insufficiency; recurrent neuromyelitis optica; restenosis; rheumatic heart disease; SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis); 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 (TNFR)-associated periodic syndrome); type B insulin resistance with acanthosis nigricans ; type 1 allergic reaction; type II diabetes; urticaria; usual interstitial pneumonia (UIP); vernal conjunctivitis; viral retinitis; Vogt-Koyanagi-Harada syndrome (VKH syndrome); wet macular degeneration; wound healing; Yersinia and Salmonella associated arthropathy.
121 . The method according to claim 119 , wherein said administering to the subject is by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intra-articular, 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.
122 . A method of treating a patient suffering from a disorder in which IL-1 is detrimental comprising the step of administering a binding protein as described in claim 52 or a crystal thereof, before, concurrently with, 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-1β; an antibody, or fragment thereof, capable of binding human IL-1α; methotrexate; a corticosteroid; a beta-agonist; an antagonist of a leukotriene; an antagonist of ar leukotriene receptor; ADVAIR; an IgE inhibitor; an anti-IgE antibody; XOLAIR; a phosphodiesterase inhibitor; a PDE4 inhibitor; a xanthine; an anticholinergic drug; a mast cell-stabilizing agent; Cromolyn; an IL-4 inhibitor; an IL-5 inhibitor; an eotaxin/CCR3 inhibitor; an antagonist of histamine; an antagonist of a histamine receptor, an antagonist of prostaglandin D; an inhibitor of receptor DP1; an inhibitor of CRTH2; a TNF antagonist; a soluble fragment of a TNF receptor; ENBREL; a TNF enzyme antagonist; a TNF converting enzyme (TACE) inhibitor; a muscarinic receptor antagonist; a TGF-beta antagonist; interferon gamma; perfenidone; a chemotherapeutic agent, leflunomide; sirolimus (rapamycin) or an analog thereof, CCI-779; a COX2 or cPLA2 inhibitor; a non-steroidal anti-inflammatory drug (NSAID); an immunomodulator; a p38 inhibitor; a TPL-2 inhibitor; an MK-2 inhibitor; an NFκB inhibitor; budenoside; epidermal growth factor; cyclosporine; sulfasalazine; an aminosalicylate; 6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor; mesalamine; olsalazine; balsalazide; an antioxidant; a thromboxane inhibitor; an IL-1 receptor antagonist; a growth factor; an elastase inhibitor; a pyridinyl-imidazole compound; an antibody or agonists of TNF, LT, 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; an antibody to CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90; FK506; mycophenolate mofetil; ibuprofen; prednisolone; an adensosine agonist; an antithrombotic agent; a complement inhibitor; an adrenergic agent; a kinase inhibitor; an IL-1β converting enzyme inhibitors; a T-cell signaling inhibitor; a metalloproteinase inhibitor; an angiotensin converting enzyme inhibitor; soluble cytokine receptor; soluble p55 TNF receptor; soluble p75 TNF receptor; soluble IL-1RI; soluble IL-1RII; soluble IL-6R; an anti-inflammatory cytokine; IL-4; IL-10; IL-11; and TGF-β.Cited by (0)
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