Human antibodies that bind human il-12 and methods for producing

Abstract

Human antibodies, preferably recombinant human antibodies, that specifically bind to human interleukin-12 (hIL-12) are disclosed. Preferred antibodies have high affinity for hIL-12 and neutralize hIL-12 activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. The antibodies, or antibody portions, of the invention are useful for detecting hIL-12 and for inhibiting hIL-12 activity, e.g., in a human subject suffering from a disorder in which hIL-12 activity is detrimental. Nucleic acids, vectors and host cells for expressing the recombinant human antibodies of the invention, and methods of synthesizing the recombinant human antibodies, are also encompassed by the invention.

1 . An isolated antibody, or antigen binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and is capable of altering the conformational structure of said p40 subunit of IL-12. 
     
     
         2 . The isolated antibody of  claim 1 , or antigen binding portion thereof, which dissociates from the p40 subunit of human IL-12 with a K d  of 1×10 −10 M or less or a k off  rate constant of 1×10 −3  s −1  or less, as determined by surface plasmon resonance. 
     
     
         3 . The isolated antibody of  claim 1 , or antigen binding portion thereof, which is a neutralizing antibody 
     
     
         4 . The isolated antibody of  claim 3 , or antigen binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC 50  of 1×10 −9 M or less, or which inhibits human IFNγ production with an IC 50  of 1×10 −10  M or less. 
     
     
         5 . The isolated antibody of  claim 1 , or antigen binding portion thereof, which is a human antibody. 
     
     
         6 . A pharmaceutical composition comprising the antibody or an antigen binding portion thereof of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         7 . A method for detecting the p40 subunit of an interleukin comprising contacting the p40 subunit of IL-12 with the antibody, or antigen-binding portion thereof, of  claim 1  such that said p40 subunit is detected. 
     
     
         8 . A method for detecting the p40 subunit of an interleukin comprising contacting the p40 subunit of the interleukin with the antibody, or antigen-binding portion thereof, of  claim 1  such that the p40 subunit of the interleukin is detected 
     
     
         9 . The method of  claim 7 , wherein the p40 subunit of the interleukin is detected in vitro. 
     
     
         10 . The method of  claim 7 , wherein the p40 subunit of the interleukin is detected in a biological sample for diagnostic purposes. 
     
     
         11 . A method for inhibiting an activity of an interleukin comprising a p40 subunit, comprising contacting the interleukin with the antibody, or antigen-binding portion thereof, of  claim 1  such that the activity is inhibited. 
     
     
         12 . A method for inhibiting an activity of an interleukin comprising a p40 subunit in a human subject suffering from a disorder in which the activity is detrimental, comprising administering to the human subject the antibody, or antigen-binding portion thereof, of  claim 1  such that the activity in the human subject is inhibited. 
     
     
         13 . The method of  claim 11 , wherein said interleukin is IL-12. 
     
     
         14 . The method of  claim 11 , wherein said interleukin comprises a p40 subunit and a p19 subunit. 
     
     
         15 . The method of  claim 11 , wherein said interleukin is IL-23. 
     
     
         16 . The method of  claim 12 , wherein the disorder is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyoarthropathy, ankylosing spondylitis, systemic lupus erythematosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, thyroiditis, 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, polyarteritis nodosa, Wegener's granulomatosis, Henoch-Schonlein purpura, microscopic vasculitis of the kidneys, chronic active hepatitis, Sjogren's syndrome, uveitis, sepsis, septic shock, sepsis syndrome, adult respiratory distress syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, myasthenia gravis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, fibrotic lung diseases, hemolytic anemia, malignancies, heart failure and myocardial infarction. 
     
     
         17 . The method of  claim 12 , wherein the disorder is psoriasis. 
     
     
         18 . The method of  claim 12 , wherein the disorder is rheumatoid arthritis. 
     
     
         19 . A method for altering the conformational structure of the p40 subunit of IL-12, the method comprising contacting said subunit with an antibody, or antigen binding portion thereof, that is capable of binding to said subunit and is capable of altering the conformational structure of said subunit in an amount effective to alter the conformational structure of said subunit, thereby altering the conformational structure of said subunit. 
     
     
         20 . A method for inhibiting the activity of an interleukin comprising a p40 subunit, the method comprising contacting the interleukin with an antibody, or antigen binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and is capable of altering the conformational structure of the interleukin in an amount effective to alter the conformational structure of the interleukin, thereby inhibiting the activity of the interleukin.