Antibodies that bind il-18 and methods of inhibiting il-18 activity

Abstract

Antibodies that bind human interleukin-18 (hIL-18) are provided, in particular antibodies that bind epitope(s) of human IL-18. The antibodies can be, for example, entirely human antibodies, recombinant antibodies, or monoclonal antibodies. Preferred antibodies have high affinity for hIL-18 and neutralize hIL-18 activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. Method of making and method of using the antibodies of the invention are also provided. The antibodies, or antibody portions, of the invention are useful for detecting hIL-18 and for inhibiting hIL-18 activity, e.g., in a human subject suffering from a disorder in which hIL-18 activity is detrimental.

1 - 60 . (canceled) 
     
     
         61 . A human monoclonal antibody, or antigen-binding portion thereof, capable of binding to human IL-18. 
     
     
         62 . The antibody of  claim 61 , wherein the antibody, or antigen-binding portion thereof, dissociates from human IL-18 with a k off  rate constant of 0.1 s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −6 M or less. 
     
     
         63 . The antibody of  claim 61 , wherein the antibody, or antigen-binding portion thereof, dissociates from human IL-18 with a k off  rate constant of 1×10 −2  s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −7 M or less. 
     
     
         64 . The antibody of  claim 61 , wherein the antibody, or antigen-binding portion thereof, dissociates from human IL-18 with a k off  rate constant of 1×10 −3  s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −8 M or less. 
     
     
         65 . The antibody of  claim 61 , wherein the antibody, or antigen-binding portion thereof, dissociates from human IL-18 with a k off  rate constant of 1×10 −4  s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −9 M or less. 
     
     
         66 . The antibody of  claim 61 , wherein the antibody, or antigen-binding portion thereof, dissociates from human IL-18 with a k off  rate constant of 1×10 −5  s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −10 M or less. 
     
     
         67 . The antibody of  claim 61 , wherein the antibody, or antigen-binding portion thereof, dissociates from human IL-18 with a k off  rate constant of 1×10 −6  s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −11 M or less. 
     
     
         68 . The antibody, or antigen-binding portion thereof, of  claim 61 , that binds an epitope of human IL-18, or portion thereof, comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3 and 31-60 and a combination thereof. 
     
     
         69 . The antibody, or antigen-binding portion thereof, of  claim 61 , wherein the antibody is a neutralizing antibody, a human antibody, a recombinant antibody, or a monoclonal antibody. 
     
     
         70 . An isolated antibody, or antigen-binding portion thereof, that binds to an epitope of human IL-18, wherein the antibody, or antigen-binding portion thereof, dissociates from human IL-18 with a k off  rate constant of 0.1 s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −6 M or less. 
     
     
         71 . The isolated antibody of  claim 70 , or an antigen-binding portion thereof, which dissociates from human IL-18 with a k off  rate constant of 1×10 −2  s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −7 M or less. 
     
     
         72 . The isolated antibody of  claim 70 , or an antigen-binding portion thereof, which dissociates from human IL-18 with a k off  rate constant of 1×10 −3  s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −8 M or less. 
     
     
         73 . The isolated antibody of  claim 70 , or an antigen-binding portion thereof, which dissociates from human IL-18 with a k off  rate constant of 1×10 −4  s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −9  M or less. 
     
     
         74 . The isolated antibody of  claim 70 , or an antigen-binding portion thereof, which dissociates from human IL-18 with a k off  rate constant of 1×10 −5  s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −10 M or less. 
     
     
         75 . The isolated antibody of  claim 70 , or an antigen-binding portion thereof, which dissociates from human IL-18 with a k off  rate constant of 1×10 −6  s −1  or less, as determined by surface plasmon resonance, or which inhibits human IL-18 activity with an IC 50  of 1×10 −11  M or less. 
     
     
         76 . An isolated human antibody, or an antigen-binding portion thereof, comprising at least one variable region CDR domain capable of binding an epitope of human IL-18. 
     
     
         77 . The isolated antibody, or an antigen-binding portion thereof, of  claim 76 , wherein said antibody, or an antigen-binding portion thereof, contains at least one amino acid substitution or insertion that improves IL-18 binding as compared to the unmodified antibody or antigen-binding portion thereof. 
     
     
         78 . The isolated antibody, or an antigen-binding portion thereof, of  claim 76 , wherein said antibody, or an antigen-binding portion thereof, contains at least one amino acid substitution or insertion that improves neutralization of IL-18 as compared to the unmodified antibody or antigen-binding portion thereof. 
     
     
         79 . An isolated nucleic acid encoding an antibody CDR amino acid sequence of  claim 61 . 
     
     
         80 . The isolated nucleic acid of  claim 79 , which is in a recombinant expression vector. 
     
     
         81 . A host cell into which the recombinant expression vector of  claim 80  has been introduced. 
     
     
         82 . A method of synthesizing an antibody that binds human IL-18, comprising culturing the host cell of  claim 81  in a culture medium until an antibody that binds human IL-18 is synthesized by the cell. 
     
     
         83 . The method of  claim 82 , wherein said antibody is human. 
     
     
         84 . A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of  claim 61 , and a pharmaceutically acceptable carrier. 
     
     
         85 . The pharmaceutical composition of  claim 84  which further comprises at least one additional therapeutic agent for treating a disorder in which IL-18 activity is detrimental. 
     
     
         86 . The pharmaceutical composition of  claim 85 , wherein said additional agent is selected from the group consisting of an antibody, or antigen binding portion thereof, capable of binding human IL-12, methotrexate, an antibody, or antigen binding portion thereof, capable of binding TNF, corticosteroids, cyclosporin, rapamycin, FK506, and non-steroidal anti-inflammatory agents. 
     
     
         87 . A method of making the antibody, or antigen binding portion thereof, of  claim 61 , comprising:
 exposing an antibody repertoire to an antigen comprising an epitope of human IL-18 or portion thereof; and   selecting from the antibody repertoire an antibody that binds the epitope of human IL-18, or portion thereof.   
     
     
         88 . The method of  claim 87 , wherein the antibody repertoire is an in vivo repertoire in an animal and the method comprises immunizing the animal with the antigen comprising an epitope of human IL-18 or portion thereof. 
     
     
         89 . The method of  claim 87 , wherein said epitope comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3 and 31-60 and a combination thereof. 
     
     
         90 . The method of  claim 87 , wherein said in vivo repertoire is a fully human immunoglobulin repertoire integrated into the genome of the animal. 
     
     
         91 . The method of  claim 87 , wherein the antibody repertoire is a recombinant antibody library and the method comprises screening the library with an antigen comprising the epitope of human IL-18 or portion thereof. 
     
     
         92 . The method of  claim 87 , wherein the library is a human antibody library. 
     
     
         93 . A method for inhibiting human IL-18 activity comprising contacting human IL-18 with the antibody, or antigen-binding portion thereof, of  claim 61  such that human IL-18 activity is inhibited. 
     
     
         94 . A method for inhibiting human IL-18 activity in a human subject suffering from a disorder in which IL-18 activity is detrimental, comprising administering to the human subject the antibody, or antigen-binding portion thereof, of  claim 61  such that human IL-18 activity in the human subject is inhibited. 
     
     
         95 . A method for treating a human subject suffering from a disorder in which IL-18 activity is detrimental by administering an antibody of  claim 61  such that treatment is achieved. 
     
     
         96 . The method of  claim 95 , wherein said disorder is selected from the group comprising rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthopathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, spondyloarthopathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis 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, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver diseases, allergy and asthma, mental disorders (e.g., depression and schizophrenia) and Th2 Type and Th1 Type mediated diseases. 
     
     
         97 . A method of treating a patient suffering from a disorder in which IL-18 is detrimental comprising the step of administering the antibody, or antigen binding portion thereof, of  claim 61 , before, concurrent, or after the administration of a second agent, wherein the second agent is selected from the group consisting of an anti-IL-12 antibody or antigen binding fragment thereof, methotrexate, anti-TNF antibody or antigen binding fragment thereof, corticosteroids, cyclosporin, rapamycin, FK506, and non-steroidal anti-inflammatory agents. 
     
     
         98 . The method of  claim 95 , wherein the disorder is selected from the group consisting of asthma, SLE, osteoarthritis, psoriatic arthritis and psoriasis. 
     
     
         99 . The antibody, or antigen binding portion thereof, of  claim 76 , wherein the epitope is selected from the group consisting of SEQ ID NOs: 1-3 and 31-60 and a combination thereof. 
     
     
         100 . The antibody, or antigen binding portion thereof, of  claim 76 , wherein the epitope is selected from the group consisting of SEQ ID NOs: 3, 33, 51-59 and a combination thereof. 
     
     
         101 . The antibody, or antigen binding portion thereof, of  claim 76 , wherein the epitope comprises SEQ ID NOs:51 and 58 or SEQ ID NOs:51 and 59.