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 human antibody, or antigen-binding portion thereof, which is capable of binding to an epitope of the p40 subunit of IL-12. 
     
     
         2 . The antibody of  claim 1 , or antigen-binding portion thereof, which is capable of binding to the epitope of the p40 subunit when the p40 subunit is bound to the p35 subunit of IL-12. 
     
     
         3 . The antibody of  claim 1 , or antigen-binding portion thereof, which is capable of binding to the epitope of the p40 subunit when the p40 subunit is bound to a p19 subunit. 
     
     
         4 . The antibody of  claim 1 , or antigen-binding portion thereof, which is capable of binding to the epitope of the p40 subunit when the p40 subunit is bound to the p35 subunit of IL-12 and when the p40 subunit is bound to a p19 subunit. 
     
     
         5 . The antibody of  claim 1 , wherein the antibody is further capable of binding to a first heterodimer and is also capable of binding to a second heterodimer, wherein the first heterodimer comprises the p40 subunit of I1-12 and the p35 subunit of Il-12, and wherein the second heterodimer comprises the p40 subunit of IL-12 and a p19 subunit. 
     
     
         6 . The antibody of  claim 5 , wherein the antibody neutralizes the biological activity of the first heterodimer. 
     
     
         7 . The antibody of  claim 5 , wherein the antibody neutralizes the biological activity of the second heterodimer. 
     
     
         8 . The antibody of  claim 5 , wherein the antibody neutralizes the biological activity of the first heterodimer and the second heterodimer. 
     
     
         9 . The isolated antibody of  claim 6  or  8 , 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. 
     
     
         10 . The isolated antibody of any one of  claims 1 - 4 , or antigen binding portion thereof, which dissociates from the p40 subunit of 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. 
     
     
         11 . An isolated human antibody, or antigen-binding portion thereof, which is capable of binding to an interleukin comprising a p40 subunit. 
     
     
         12 . The antibody of  claim 11 , wherein the interleukin comprises a p40 subunit and a p35 subunit. 
     
     
         13 . The antibody of  claim 12 , wherein the interleukin is IL-12. 
     
     
         14 . The antibody of  claim 11 , wherein the interleukin comprises a p40 subunit and a p19 subunit. 
     
     
         15 . The isolated antibody of any one of  claims 11 - 14 , or antigen binding portion thereof, wherein the antibody binds to an epitope of the p40 subunit. 
     
     
         16 . The isolated antibody of  claim 11 , or antigen binding portion thereof, which dissociates from the p40 subunit of the interleukin 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. 
     
     
         17 . The isolated antibody of  claim 11 , or antigen binding portion thereof, wherein the antibody neutralizes the biological activity of the interleukin. 
     
     
         18 . The isolated antibody of  claim 17 , 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. 
     
     
         19 . A pharmaceutical composition comprising the antibody or an antigen binding portion thereof, of any one of  claims 1 - 8 ,  11 - 14  and  16 - 18  and a pharmaceutically acceptable carrier. 
     
     
         20 . A pharmaceutical composition comprising the antibody or an antigen binding portion thereof, of  claim 9  and a pharmaceutically acceptable carrier. 
     
     
         21 . A pharmaceutical composition comprising the antibody or an antigen binding portion thereof, of  claim 10  and a pharmaceutically acceptable carrier. 
     
     
         22 . A pharmaceutical composition comprising the antibody or an antigen binding portion thereof, of  claim 15  and a pharmaceutically acceptable carrier.