US2014086922A1PendingUtilityA1

Anti-il-12/il-23 antibodies

52
Assignee: CEPHALON AUSTRALIA PTY LTDPriority: Aug 14, 2008Filed: Sep 18, 2013Published: Mar 27, 2014
Est. expiryAug 14, 2028(~2.1 yrs left)· nominal 20-yr term from priority
Inventors:Adam ClarkeAnthony G. DoylePhilip Anthony JenningsLynn Dorothy PoultonBernadette WaiAndrew James PowGeorge Kopsidas
A61P 3/08A61P 9/10A61P 37/08A61P 37/02A61P 9/00A61P 37/06A61P 5/14A61P 41/00A61P 7/00A61P 3/00A61P 25/04A61P 31/04A61P 35/00A61P 27/00A61P 31/00A61P 25/28A61P 29/00A61P 25/00A61P 27/02A61P 11/00A61P 1/04A61P 1/02A61P 17/00A61P 19/04A61P 19/10A61P 17/06A61P 1/00A61P 13/12A61P 17/14A61P 19/08A61P 19/02A61P 1/16A61K 39/395C07K 14/5434C07K 2317/92C07K 2317/622C07K 2317/565C07K 2317/24A61K 2039/505C07K 16/244C07K 2317/34C07K 2317/76C07K 2317/56C07K 2317/567
52
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Claims

Abstract

Provided herein is an antibody comprising an antigen binding domain which binds to human IL-12 and human IL-23. The antibody binds human IL-12p40 existing as a monomer (human IL-12p40) and as a homodimer (human IL-12p80), and the antibody inhibits the binding of human IL-12 to human IL-12Rβ2 and human IL-23 to human IL-23R but does not inhibit the binding of human IL-12 or human IL-23 or human IL-12p40 or human IL-12p80 to human IL-12Rβ1.

Claims

exact text as granted — not AI-modified
What is claimed: 
     
         1 . An antibody comprising an antigen binding domain which binds to human IL-12 and human IL-23, wherein the antibody binds to a portion of human IL-12p40 having the sequence VQVQGKSKREKKDRVFTDKTSATVICRKNASISV (SEQ ID NO: 65). 
     
     
         2 . The antibody of  claim 1  in which the antibody specifically binds to human IL-12p40 (SEQ ID NO: 1) at Asp 265. 
     
     
         3 . The antibody of  claim 1  in which the level of binding of the antibody to human IL-23 (SEQ ID NO: 66) is greater than the level of binding of the antibody to mutant IL-23 D265A (SEQ ID NO: 75). 
     
     
         4 . The antibody of  claim 1  in which the antibody comprises three heavy chain CDR sequences selected from:
 HCDR1 DYYX 1 H, wherein; 
 X 1 =M or L; 
 HCDR2 WIDPENGDTEX 2 APKFQG, wherein;
 X 2 ═Y, H, or S; 
 
 HCDR3 X 3 KELRYFDV, wherein;
 X 3 ═C, A, N, D, E, Q, G, H, I, L, P or V. 
 
 
     
     
         5 . The antibody of  claim 1  in which the antibody comprises three light chain CDR sequences selected from:
 LCDR1 RAX 4 X 5 SISINLH, wherein;
 X 4 ═S or P; 
 X 5 =Q or R; 
 
 LCDR2 FAX 6 QSX 7 S, wherein;
 X 6 ═S or R; 
 X 7 ═I or T; 
 
 LCDR3 QQSNSX 8 PLT, wherein;
 X 8 ═W or F. 
 
 
     
     
         6 . The antibody of  claim 1  in which the antibody comprises three heavy chain CDR sequences selected from:
 HCDR1 DYYX 1 H, wherein;
 X 1 =M or L; 
 
 HCDR2 WIDPENGDTEX 2 APKFQG, wherein;
 X 2 ═Y, H, or S; 
 
 HCDR3 X 3 KELRYFDV, wherein;
 X 3 ═C, A, N, D, E, Q, G, H, I, L, P or V. 
 
 
       and three light chain CDR sequences selected from:
 LCDR1 RAX 4 X 5 SISINLH, wherein;
 X 4 ═S or P; 
 X 5 =Q or R; 
 
 LCDR2 FAX 6 QSX 7 S, wherein;
 X 6 ═S or R; 
 X 7 ═I or T; 
 
 LCDR3 QQSNSX 8 PLT, wherein;
 X 8 ═W or F. 
 
 
     
     
         7 . The antibody of  claim 6  in which the antibody further comprises a human heavy chain acceptor framework sequence of SEQ ID NO: 202, SEQ ID NO: 205, SEQ ID NO: 208, SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 209, SEQ ID NO: 204, or SEQ ID NO: 207. 
     
     
         8 . The antibody of  claim 6  in which the antibody further comprises a human light chain acceptor framework sequence of SEQ ID NO: 210, SEQ ID NO: 213, SEQ ID NO: 216, SEQ ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 212, or SEQ ID NO: 215. 
     
     
         9 . The antibody of  claim 6  in which the antibody further comprises an antibody human acceptor framework which comprises at least one Framework Region amino acid substitution at a key residue, said key residue selected from the group consisting of a residue adjacent to a CDR, a glycosylation site residue, a rare residue, a residue capable of interacting with the p40 subunit of human IL-12, a residue capable of interacting with a CDR, a canonical residue, a contact residue between heavy chain variable region and light chain variable region; a residue within a Vernier zone and a residue in a region that overlaps between a Chothia-defined VH domain CDR1 and a Kabat-defined first heavy chain framework. 
     
     
         10 . The antibody of  claim 6  in which the antibody further comprises an antibody human acceptor framework which comprises at least one Framework Region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to the sequence of said human acceptor framework and comprises at least 70 amino acid residues identical to said human acceptor framework. 
     
     
         11 . The antibody of  claim 1  in which the antibody comprises an immunoglobulin heavy chain variable region of SEQ ID NO: 6, SEQ ID NO: 62, SEQ ID NO: 114, SEQ ID NO: 142, SEQ ID NO: 28, SEQ ID NO: 87, SEQ ID NO: 115, SEQ ID NO: 143, SEQ ID NO: 29, SEQ ID NO: 88, SEQ ID NO: 116, SEQ ID NO: 144, SEQ ID NO: 30, SEQ ID NO: 90, SEQ ID NO: 117, SEQ ID NO: 145, SEQ ID NO: 31, SEQ ID NO: 91, SEQ ID NO: 118, SEQ ID NO: 146, SEQ ID NO: 33, SEQ ID NO: 92, SEQ ID NO: 119, SEQ ID NO: 147, SEQ ID NO: 34, SEQ ID NO: 93, SEQ ID NO: 120, SEQ ID NO: 148, SEQ ID NO: 35, SEQ ID NO: 94, SEQ ID NO: 122, SEQ ID NO: 149, SEQ ID NO: 36, SEQ ID NO: 95, SEQ ID NO: 124, SEQ ID NO: 150, SEQ ID NO: 38, SEQ ID NO: 96, SEQ ID NO: 125, SEQ ID NO: 151, SEQ ID NO: 39, SEQ ID NO: 97, SEQ ID NO: 126, SEQ ID NO: 152, SEQ ID NO: 40, SEQ ID NO: 99, SEQ ID NO: 127, SEQ ID NO: 153, SEQ ID NO: 41, SEQ ID NO: 100, SEQ ID NO: 128, SEQ ID NO: 154, SEQ ID NO: 101, SEQ ID NO: 129, SEQ ID NO: 155, SEQ ID NO: 43, SEQ ID NO: 102, SEQ ID NO: 130, SEQ ID NO: 156, SEQ ID NO: 44, SEQ ID NO: 103, SEQ ID NO: 131, SEQ ID NO: 157, SEQ ID NO: 45, SEQ ID NO: 104, SEQ ID NO: 132, SEQ ID NO: 158, SEQ ID NO: 53, SEQ ID NO: 105, SEQ ID NO: 133, SEQ ID NO: 159, SEQ ID NO: 54, SEQ ID NO: 106, SEQ ID NO: 134, SEQ ID NO: 160, SEQ ID NO: 55, SEQ ID NO: 107, SEQ ID NO: 135, SEQ ID NO: 161, SEQ ID NO: 56, SEQ ID NO: 108, SEQ ID NO: 136, SEQ ID NO: 162, SEQ ID NO: 57, SEQ ID NO: 109, SEQ ID NO: 137, SEQ ID NO: 163, SEQ ID NO: 58, SEQ ID NO: 110, SEQ ID NO: 138, SEQ ID NO: 164, SEQ ID NO: 59, SEQ ID NO: 111, SEQ ID NO: 139, SEQ ID NO: 165, SEQ ID NO: 60, SEQ ID NO: 112, SEQ ID NO: 140, SEQ ID NO: 166, SEQ ID NO: 61, SEQ ID NO: 113, SEQ ID NO: 141, SEQ ID NO: 167, or SEQ ID NO: 168. 
     
     
         12 . The antibody of  claim 1  in which the antibody comprises an immunoglobulin light chain variable region of SEQ ID NO: 7, SEQ ID NO: 169, SEQ ID NO: 181, SEQ ID NO: 193, SEQ ID NO: 32, SEQ ID NO: 170, SEQ ID NO: 182, SEQ ID NO: 194, SEQ ID NO: 37, SEQ ID NO: 171, SEQ ID NO: 183, SEQ ID NO: 195, SEQ ID NO: 42, SEQ ID NO: 172, SEQ ID NO: 184, SEQ ID NO: 196, SEQ ID NO: 46, SEQ ID NO: 173, SEQ ID NO: 185, SEQ ID NO: 197, SEQ ID NO: 47, SEQ ID NO: 174, SEQ ID NO: 186, SEQ ID NO: 198, SEQ ID NO: 48, SEQ ID NO: 175, SEQ ID NO: 187, SEQ ID NO: 199, SEQ ID NO: 49, SEQ ID NO: 176, SEQ ID NO: 188, SEQ ID NO: 200, SEQ ID NO: 50, SEQ ID NO: 177, SEQ ID NO: 189, SEQ ID NO: 201, SEQ ID NO: 51, SEQ ID NO: 178, SEQ ID NO: 190, SEQ ID NO: 52, SEQ ID NO: 179, or SEQ ID NO: 192. 
     
     
         13 . The antibody of  claim 1  in which the antibody comprises two immunoglobulin variable regions, wherein the said two immunoglobulin variable regions are: 
       
         
           
                 
                 
               
                     
                     
                 
                     
                   SEQ ID NO: 6 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 6 & SEQ ID NO: 169; 
                 
                     
                   SEQ ID NO: 28 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 29 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 30 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 31 & SEQ ID NO: 32; 
                 
                     
                   SEQ ID NO: 33 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 34 & SEQ ID NO: 51; 
                 
                     
                   SEQ ID NO: 34 & SEQ ID NO: 47; 
                 
                     
                   SEQ ID NO: 35 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 36 & SEQ ID NO: 37; 
                 
                     
                   SEQ ID NO: 38 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 38 & SEQ ID NO: 51; 
                 
                     
                   SEQ ID NO: 38 & SEQ ID NO: 32; 
                 
                     
                   SEQ ID NO: 38 & SEQ ID NO: 47; 
                 
                     
                   SEQ ID NO: 38 & SEQ ID NO: 52; 
                 
                     
                   SEQ ID NO: 39 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 40 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 41 & SEQ ID NO: 42; 
                 
                     
                   SEQ ID NO: 43 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 44 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 44 & SEQ ID NO: 51; 
                 
                     
                   SEQ ID NO: 44 & SEQ ID NO: 32; 
                 
                     
                   SEQ ID NO: 44 & SEQ ID NO: 47; 
                 
                     
                   SEQ ID NO: 44 & SEQ ID NO: 52; 
                 
                     
                   SEQ ID NO: 45 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 45 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 53 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 54 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 55 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 56 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 57 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 58 & SEQ ID NO: 42; 
                 
                     
                   SEQ ID NO: 59 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 60 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 61 & SEQ ID NO: 42; 
                 
                     
                   SEQ ID NO: 62 & SEQ ID NO: 42; 
                 
                     
                   SEQ ID NO: 87 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 88 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 90 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 91 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 92 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 93 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 94 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 95 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 96 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 97 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 99 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 100 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 101 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 102 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 103 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 104 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 105 & SEQ ID NO: 7; 
                 
                     
                   SEQ ID NO: 106 & SEQ ID NO: 171; 
                 
                     
                   SEQ ID NO: 106 & SEQ ID NO: 172; 
                 
                     
                   SEQ ID NO: 107 & SEQ ID NO: 171; 
                 
                     
                   SEQ ID NO: 107 & SEQ ID NO: 172; 
                 
                     
                   SEQ ID NO: 108 & SEQ ID NO: 171; 
                 
                     
                   SEQ ID NO: 108 & SEQ ID NO: 172; 
                 
                     
                   SEQ ID NO: 109 & SEQ ID NO: 170; 
                 
                     
                   SEQ ID NO: 110 & SEQ ID NO: 171; 
                 
                     
                   SEQ ID NO: 111 & SEQ ID NO: 172; 
                 
                     
                   SEQ ID NO: 112 & SEQ ID NO: 169; 
                 
                     
                   SEQ ID NO: 113 & SEQ ID NO: 173; 
                 
                     
                   SEQ ID NO: 113 & SEQ ID NO: 174; 
                 
                     
                   SEQ ID NO: 113 & SEQ ID NO: 175; 
                 
                     
                   SEQ ID NO: 113 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 113 & SEQ ID NO: 177; 
                 
                     
                   SEQ ID NO: 113 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 114 & SEQ ID NO: 173; 
                 
                     
                   SEQ ID NO: 114 & SEQ ID NO: 174; 
                 
                     
                   SEQ ID NO: 114 & SEQ ID NO: 175; 
                 
                     
                   SEQ ID NO: 114 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 114 & SEQ ID NO: 177; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 173; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 174; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 175; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 177; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 181; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 182; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 183; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 184; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 185; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 186; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 187; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 188; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 189; 
                 
                     
                   or 
                 
                     
                   SEQ ID NO: 168 & SEQ ID NO: 189. 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 190; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 192; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 193; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 194; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 195; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 196; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 197; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 198; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 199; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 200; 
                 
                     
                   SEQ ID NO: 115 & SEQ ID NO: 201; 
                 
                     
                   SEQ ID NO: 116 & SEQ ID NO: 173; 
                 
                     
                   SEQ ID NO: 116 & SEQ ID NO: 174; 
                 
                     
                   SEQ ID NO: 116 & SEQ ID NO: 175; 
                 
                     
                   SEQ ID NO: 116 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 116 & SEQ ID NO: 177; 
                 
                     
                   SEQ ID NO: 117 & SEQ ID NO: 173; 
                 
                     
                   SEQ ID NO: 117 & SEQ ID NO: 174; 
                 
                     
                   SEQ ID NO: 117 & SEQ ID NO: 175; 
                 
                     
                   SEQ ID NO: 117 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 117 & SEQ ID NO: 177; 
                 
                     
                   SEQ ID NO: 118 & SEQ ID NO: 178; 
                 
                     
                   SEQ ID NO: 118 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 178; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 51; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 46; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 47; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 48; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 49; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 50; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 51; 
                 
                     
                   SEQ ID NO: 119 & SEQ ID NO: 52; 
                 
                     
                   SEQ ID NO: 120 & SEQ ID NO: 178; 
                 
                     
                   SEQ ID NO: 120 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 122 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 124 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 125 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 126 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 127 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 128 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 129 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 130 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 131 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 132 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 133 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 134 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 135 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 136 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 137 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 138 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 139 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 140 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 141 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 142 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 143 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 144 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 145 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 146 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 147 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 148 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 149 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 150 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 151 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 152 & SEQ ID NO: 176; 
                 
                     
                   SEQ ID NO: 153 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 154 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 155 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 156 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 157 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 158 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 159 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 160 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 161 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 161 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 162 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 162 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 163 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 163 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 164 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 164 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 165 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 165 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 166 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 166 & SEQ ID NO: 179; 
                 
                     
                   SEQ ID NO: 167 & SEQ ID NO: 189; 
                 
                     
                   SEQ ID NO: 167 & SEQ ID NO: 179; 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         14 . The antibody of  claim 1  in which the antibody comprises a human or non-human primate heavy chain immunoglobulin constant region, wherein said heavy chain immunoglobulin constant region is a IgG1 heavy chain immunoglobulin constant region, IgG2 heavy chain immunoglobulin constant region, IgG3 heavy chain immunoglobulin constant region, IgG4 heavy chain immunoglobulin constant region, IgM heavy chain immunoglobulin constant region, IgE heavy chain immunoglobulin constant region, or IgA heavy chain immunoglobulin constant region. 
     
     
         15 . The antibody of  claim 1  in which the antibody comprises a human or non-human primate light chain immunoglobulin constant region, wherein said light chain immunoglobulin constant region is a kappa light chain immunoglobulin constant region or lambda light chain immunoglobulin constant region. 
     
     
         16 . The antibody of  claim 1  in which the antibody is modified by the covalent attachment of an organic moiety. 
     
     
         17 . The antibody of  claim 16  in which the organic moiety is a linear hydrophilic polymeric group, branched hydrophilic polymeric group, fatty acid group, or fatty acid ester group. 
     
     
         18 . The antibody of  claim 1  in which the antibody is modified to modulate antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, serum half-life, biodistribution, or binding to Fc receptors. 
     
     
         19 . The antibody of  claim 18  in which the modification is by protein engineering, glycoengineering or chemical methods. 
     
     
         20 . A method of treating a disease in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of an antibody of  claim 1 , wherein the disease is rheumatoid arthritis, reactive arthritis, psoriatic arthritis, a demyelinating disorder, psoriasis, multiple sclerosis, systemic lupus erythematosus, an autoimmune inflammatory bowel disease, a vasculitis, sarcoidosis, cirrhosis, hepatitis (including autoimmune hepatitis), primary biliary cirrhosis, uveitis, or atherosclerosis.

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