Engineered Anti-IL-23 Antibodies

Abstract

Engineered antibodies to human IL-23p19 are provided, as well as uses thereof, e.g. in treatment of inflammatory, autoimmune, and proliferative disorders.

1 . A binding compound that binds to human IL-23, comprising:
 at least one antibody light chain variable region, or binding fragment thereof, comprising at least one CDR sequences selected from the group consisting of SEQ ID NOs: 81-89; and   at least one antibody heavy chain variable region, or binding fragment thereof, comprising at least one CDR sequences selected from the group consisting of SEQ ID NOs: 78-80.   
     
     
         2 . The binding compound of  claim 1 , wherein:
 the antibody light chain variable region, or binding fragment thereof, comprises at least two CDR sequences selected from the group consisting of SEQ ID NOs: 81-89; and   the antibody heavy chain variable region, or binding fragment thereof, comprises at least two CDR sequences selected from the group consisting of SEQ ID NOs: 78-80.   
     
     
         3 . The binding compound of  claim 1 , wherein:
 the antibody light chain variable region, or binding fragment thereof, has at least three CDR sequences selected from the group consisting of SEQ ID NOs: 81-89; and   the antibody heavy chain variable region, or binding fragment thereof, has at least three CDR sequences selected from the group consisting of SEQ ID NOs: 78-80.   
     
     
         4 . The binding compound of  claim 3 , comprising:
 at least one CDRL1 from the group consisting of SEQ ID NOs: 81-83;   at least one CDRL2 from the group consisting of SEQ ID NOs: 84-86; and   at least one CDRL3 from the group consisting of SEQ ID NOs: 87-89;   
     
     
         5 . The binding compound of  claim 4 , comprising:
 at least one CDRL1 from the group consisting of SEQ ID NOs: 69-71;   at least one CDRL2 from the group consisting of SEQ ID NOs: 72-74; and   at least one CDRL3 from the group consisting of SEQ ID NOs: 75-77;   
     
     
         6 . A binding compound that binds to human IL-23, comprising:
 an antibody light chain variable region, or binding fragment thereof, comprising:
 at least one CDRL1 from the group consisting of SEQ ID NOs: 69-71 or a variant thereof; 
 at least one CDRL2 from the group consisting of SEQ ID NOs: 72-74 or a variant thereof; 
 at least one CDRL3 from the group consisting of SEQ ID NOs: 75-77 or a variant thereof; and 
   an antibody heavy chain variable region, or fragment thereof, comprising the CDR sequences of SEQ ID NOs: 66-68 or a variant thereof;   wherein the variant comprises up to five conservatively modified amino acid substitutions.   
     
     
         7 . The binding compound of  claim 6  wherein:
 CDRL1 comprises the sequence of SEQ ID NO: 69 or a variant thereof; 
 CDRL2 comprises the sequence of SEQ ID NO: 72 or a variant thereof; and 
 CDRL1 comprises the sequence of SEQ ID NO: 75 or a variant thereof. 
 
     
     
         8 . A binding compound that binds to human IL-23, comprising:
 an antibody light chain variable region, or binding fragment thereof, comprising the sequence of residues 20-129 of SEQ ID NO: 2 or 4, or a variant thereof; and   an antibody heavy chain variable region, or binding fragment thereof, comprising the sequence of residues 20-134 of SEQ ID NO: 1 or 3, or a variant thereof;   wherein the variant comprises up to 20 conservatively modified amino acid substitutions.   
     
     
         9 . The binding compound of  claim 8 , wherein the binding compound is an antibody or binding fragment thereof comprising:
 a light chain variable region comprising residues 20-129 of SEQ ID NO: 2 or 4; and   a heavy chain variable region comprising residues 20-134 SEQ ID NO: 1 or 3.   
     
     
         10 . The binding compound of  claim 9 , comprising:
 a light chain consisting essentially of the mature form (residues 20-233) of SEQ ID NO: 2; and   a heavy chain consisting essentially of the mature form (residues 20-464) of SEQ ID NO: 1.   
     
     
         11 . A binding compound that binds to human IL-23 at an epitope comprising residues 82-95 or residues 133-140 of SEQ ID NO: 29. 
     
     
         12 . The binding compound of  claim 11 , wherein the binding compound binds to an epitope comprising of residues 82-95 and residues 133-140 of SEQ ID NO: 29. 
     
     
         13 . The binding compound of  claim 12 , wherein the binding compound binds to an epitope comprising residues E82, G86, S87, D88, T91, G92, E93, P94, S95, H106, P133, S134, Q135, P136, W137, R139 and L140 of SEQ ID NO: 29. 
     
     
         14 . A binding compound that binds to human IL-23, comprising:
 a light chain variable region having at least 90% homology to residues 20-129 of SEQ ID NO: 2 or 4; and   a heavy chain variable region having at least 90% homology to residues 20-134 of SEQ ID NO: 1 or 3.   
     
     
         15 . An antibody that is able to block binding of the binding compound of  claim 4  to human IL-23 in a cross-blocking assay. 
     
     
         16 . The binding compound of  claim 4  wherein the binding compound blocks IL-23 mediated activity. 
     
     
         17 . An isolated nucleic acid encoding at least one of the light chain variable region or heavy chain variable region of the binding compound of  claim 4 . 
     
     
         18 . An expression vector comprising the nucleic acid of  claim 17  operably linked to control sequences that are recognized by a host cell when the host cell is transfected with the vector. 
     
     
         19 . A host cell comprising the expression vector of  claim 18 . 
     
     
         20 . A method of producing a polypeptide comprising:
 culturing the host cell of  claim 19  in culture medium under conditions wherein the nucleic acid sequence is expressed, thereby producing polypeptides comprising the light and heavy chain variable regions; and   recovering the polypeptides from the host cell or culture medium.   
     
     
         21 . The binding compound of  claim 4 , further comprising a heavy chain constant region comprising a γ1 human heavy chain constant region or a variant thereof, wherein the variant comprises up to 20 conservatively modified amino acid substitutions. 
     
     
         22 . The binding compound of  claim 4 , further comprising a heavy chain constant region comprising a γ4 human heavy chain constant region or a variant thereof, wherein the variant comprises up to 20 conservatively modified amino acid substitutions. 
     
     
         23 . The binding compound of  claim 4 , wherein the binding compound is an antibody fragment selected from the group consisting of Fab, Fab′, Fab′-SH, Fv, scFv, F(ab′) 2 , and a diabody. 
     
     
         24 . A method of suppressing an immune response in a human subject comprising administering to a subject in need thereof an antibody specific for IL-23, or a binding fragment thereof, in an amount effective to block the biological activity of IL-23, wherein the antibody is the antibody of  claim 4 . 
     
     
         25 . The method of  claim 24 , wherein the immune response is an inflammatory response. 
     
     
         26 . The method of  claim 25 , wherein the subject has a disorder selected from the group consisting of arthritis, psoriasis and inflammatory bowel disease. 
     
     
         27 . The method of  claim 24 , wherein the immune response is an autoimmune response. 
     
     
         28 . The method of  claim 27 , wherein the subject has a disorder selected from the group consisting of multiple sclerosis, systemic lupus erythematosus and diabetes. 
     
     
         29 . The method of  claim 24 , wherein the subject has cancer. 
     
     
         30 . The method of  claim 24 , further comprising administering an immunosuppressive or anti-inflammatory agent. 
     
     
         31 . A composition comprising the binding compound of  claim 4  in combination with a pharmaceutically acceptable carrier or diluent. 
     
     
         32 . The composition of  claim 31 , further comprising an immunosuppressive or anti-inflammatory agent.