Anti-il-6 antibodies,compositions, methods and uses

Abstract

The present invention relates to at least one novel chimeric, humanized or CDR-grafted anti-IL-6 antibodies derived from the murine CLB-8 antibody, including isolated nucleic acids that encode at least one such anti-IL-6 antibody, vectors, host cells, transgenic animals or plants, and methods of making and using thereof, including therapeutic compositions, methods and devices.

1 . An isolated antibody or antibody fragment that binds to human IL-6, comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO:7, a light chain variable region having the amino acid sequence of SEQ ID NO:8, and a constant region derived from one or more human antibodies. 
     
     
         2 . An isolated antibody or antibody fragment that binds to human IL-6, comprising the heavy chain and light chain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOS:1-6, and a constant region derived from one or more human antibodies. 
     
     
         3 . An isolated antibody or antibody fragment that binds to human IL-6 comprising a heavy chain variable domain and a light chain variable domain containing complementarity determining regions (CDRs), and a constant region derived from one or more human antibodies, wherein the the heavy chain variable domain comprises the CDR3 of SEQ ID No. 3. 
     
     
         4 . The antibody or fragment according to  claim 1  or  2 , wherein said antibody or fragment competitively inhibits in vivo the binding to human IL-6 of the anti IL-6 murine antibody CLB-8 or an antibody having substantially the same binding characteristics of the CLB-8 antibody. 
     
     
         5 . An IL-6 antibody or specified portion or variant according to  claim 1 , wherein said antibody or specified portion or variant binds IL-6 with an affinity (Kd) of at least 10 −9 M. 
     
     
         6 . An IL-6 antibody or specified portion or variant according to  claim 1 , wherein said antibody or specified portion or variant binds IL-6 with an affinity (Kd) of at least 10 −11 M. 
     
     
         7 . An IL-6 antibody or specified portion or variant, according to  claim 1 , wherein said antibody or specified portion or variant binds with an affinity (Kd) of at least 10 −12 M. 
     
     
         8 . An IL-6 antibody or specified portion or variant according to  claim 1  or  2 , wherein said antibody or specified portion or variant substantially neutralizes at least one activity of at least one IL-6. 
     
     
         9 . An IL-6 antibody or specified portion or variant according to  claim 8 , wherein said activity is at least one selected from the group consisting of inhibition of IgM mu secretion from SKW6.4 cells, inhibition of IL-6 mediated MCP-1 production, inhibition of IL-6 signaling in THP-1 human monocytic leukemia cells, inhibition of IL-6 induced serum amyloid A production from HepG2 cells, and inhibition of rhIL-6 induced cell proliferation. 
     
     
         10 . An IL-6 antibody composition or specified portion or variant composition, comprising an isolated IL-6 antibody or specified portion or variant according to  claim 1  or  2 , and a carrier or diluent. 
     
     
         11 . A composition according to  claim 10 , further comprising at least one compound or protein selected from at least one of a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflamatory drug (SNAID), an analgesic, an anesthetic, a sedative, a local anethetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, a diabetes related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropieitin, a filgrastim, a sargramostim, an immunication, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog, dornase alpha, a cytokine, a cytokine antagonist. 
     
     
         12 . A method for treating an immune disorder or disease in a cell, tissue, organ or animal, comprising; contacting or administering at least one selected immune modulating effective amount of at least one IL-6 antibody or specified portion or variant according to  claim 1  or  2  with, or to, said cell, tissue, organ or animal 
     
     
         13 . A method according to  claim 12 , wherein said immune condition is at least one selected from rheumatoid arthritis/seronegative arthropathies, osteoarthritis, inflammatory bowel disease, systematic lupus erythematosis, iridocyclitis/uvetis/optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/wegener's granulomatosis, sarcoidosis, orchitis/vasectomy reversal procedures, allergic/atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivities, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, trauma/hemorrhage, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, systemic lupus erythematosus and rheumatoid arthritis, alcohol induced hepatitis, chronic inflammatory pathologies, sarcoidosis, Crohn's pathology, sickle cell anemia, diabetes, nephrosis, atopic diseases, hypersensitity reactions allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, asthmas, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic disease, thrombocytopenia, graft rejection of any organ or tissue, kidney transplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft rejection, cartilage transplant rejection, bone graft rejection, small bowel transplant rejection, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves disease, Raynoud's disease, type B insulin-resistant diabetes, asthma, myasthenia gravis, antibody-medicated cytotoxicity, type III hypersensitivity reactions, systemic lupus erythematosus, pemphigue, scleroderma, mixed connective tissue disease, idiopathic Addison's disease, diabetes mellitus, chronic active hepatitis, primary billiary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metabolic/idiopathic, Wilson's disease, hemachromatosis, alpha-1-antitrypsin deficiency, diabetes, hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, familial hematophagocytic lymphohistiocytosis, dermatologic, psoriasis, alopecia. Nephrotic syndrome, nephritis, hemodialysis, uremia, toxicity, okt3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy (e.g., including but not limite to asthenia, anemia, cachexia, and the like), chronic salicylate intoxication. 
     
     
         14 . A method according to  claim 13 , wherein said effective amount is 0.001-50 mg/kilogram of said cells, tissue, organ or animal. 
     
     
         15 . A method according to  claim 14 , wherein said effective amount is 0.0001-50 mg/kilogram of said cells, tissue, organ or animal. 
     
     
         16 . A method for modulating a cancerous disorder or condition in a cell, tissue, organ or animal, comprising contacting or administering a pharmaceutically effective amount of at least one IL-6 antibody or specified portion or variant according to  claim 1  or  2  with, or to, said cell, tissue, organ or animal. 
     
     
         17 . A method according to  claim 16 , wherein said cancerous disorder or condition is at least one selected from leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), a lymphoma, Hodgkin's disease, a malignant lymphoma, non-hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic carcinoma, renal cell carcinoma, prostatic cell carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome/hypercalcemia of malignancy, solid tumors, adenocarcinomas, sarcomas, and malignant melanoma. 
     
     
         18 . A method according to any one of  claims 12 - 17  wherein said effective amount is 0.01-100 mg/kilogram of said cells, tissue, organ or animal. 
     
     
         19 . A method according to any one of  claims 12 - 17 , wherein said contacting or said administrating is by at least one mode selected from intravenous, intramuscular, colus, subcutaneous, respiratory, inhalation, vaginal, rectal, buccal, sublingual, intranasal, or transdermal. 
     
     
         20 . A method according to any one of  claims 12 - 17 , further comprising administering, prior, concurrently or after said (1) contacting or administering, at least one composition comprising a therapeutically effective amount of at least one compound or protein selected from at least one of 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 anethetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, a diabetes related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropieitin, a filgrastim, a sargramostim, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog, dornase alpha, a cytokine, a cytokine antagonist. 
     
     
         21 . A medical device, comprising at least one IL-6 antibody or specified portion or variant according to  claim 1  or  2 , wherein said device is suitable to contacting or administering said at least one IL-6 antibody or specified portion or variant by at least one mode selected from intravenous, intracular, bolus, subcutaneous, respiratory, inhalation, vaginal, rectal, buccal, sublingual, intranasal, or transdermal. 
     
     
         22 . An isolated fully human antibody or specified portion or variant thereof, wherein said antibody or specified portion or variant binds the same epitope or antigenic region as an IL-6 antibody or fragment according to  claim 1  or  2 . 
     
     
         23 . A formulation comprising at least one IL-6 antibody or fragment according to  claim 1  or  2 , and at least one selected from sterile water, sterile buffered water, or at least one preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparaben, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, ormixtures thereof, in an aqueous diluent. 
     
     
         24 . A formulation of  claim 23 , wherein the concentration of IL-6 antibody or specified portion or variant is about 0.1 mg/ml to about 100 mg/ml. 
     
     
         25 . A formulation of  claim 23 , further comprising an isotonicity agent. 
     
     
         26 . A formulation of  claim 23 , further comprising a physiologically acceptable buffer. 
     
     
         27 . A formulation comprising at least one IL-6 antibody or fragment according to  claim 1  or  2  in lyophilized form in a first container, and an optional second container comprising sterile water, sterile buffered water, or at least one preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparaben, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous diluent. 
     
     
         28 . A formulation of  claim 27 , wherein the concentration of IL-6 antibody or specified portion or variant is reconsituted to a concentration of about 0.1 mg/ml to about 500 mg/ml. 
     
     
         29 . A formulation of  claim 27 , further comprising an isotonicity agent. 
     
     
         30 . A formulation of  claim 27 , further comprising a physiologically acceptable buffer. 
     
     
         31 . A method of treating at least one IL-6 mediated condition, comprising administering to a patient in need thereof a formulation according to  claim 27 . 
     
     
         32 . An article of manufacture for human pharmaceutical use, comprising packaging material and a container comprising a solution or a lyophilized form of at least one IL-6 antibody or specified portion or variant according to  claim 1  or  2 . 
     
     
         33 . The article of manufacture of  claim 32 , wherein said container is a glass or plastic container having a stopper for multi-use administration. 
     
     
         34 . A method for producing an IL-6 antibody or fragment according to  claim 1  or  2 , comprising expressing said antibody or fragment from a host cell or transgenic animal or transgenic plant or plant cell transformed with a nucleotide sequence encoding said antibody or fragment and recovering such antibody or fragment therefrom. 
     
     
         35 . A method according to  claim 34 , wherein said host cell is a mammalian cell, a plant cell or a yeast cell. 
     
     
         36 . A method according to  claim 34 , wherein said transgenic animal is a mammal 
     
     
         37 . A method according to  claim 34 , wherein said transgenic mammal is selected from a goat, a cow, a sheep, a horse, and a non-human primate. 
     
     
         38 . A transgenic animal or plant capable of expressing at least one antibody according to  claim 1  or  2 . 
     
     
         39 . At least one IL-6 antibody or specified portion or variant produced by a method according to  claim 34 . 
     
     
         40 . An isolated IL-6 antibody or fragment thereof, comprising a murine variable and human constant region, wherein said antibody or specified portion or variant specifically binds at least one epitope comprising amino acids Gln29-Lev34 of human IL-6. 
     
     
         41 . An IL-6 antibody or fragment thereof according to  claim 40 , wherein said antibody or specified portion or variant binds IL-6 with an affinity of at least 10 −9  M.