Tweak binding antibodies

Abstract

Anti-Tweak antibodies are described.

1 . An antibody or antigen binding fragment thereof comprising heavy chain complementarity determining regions (CDRs) 1-3 that have the amino acid sequences set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively and light chain CDRs 1-3 that have the amino acid sequences set forth in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively, wherein the CDRs are modified at zero to four amino acid residues per CDR. 
     
     
         2 . The antibody or antigen binding fragment of  claim 1  further comprising a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, or SEQ ID NO: 49. 
     
     
         3 . The antibody or antigen binding fragment of  claim 1  further comprising a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, or SEQ ID NO: 26. 
     
     
         4 . The antibody or antigen binding fragment of  claim 1 , wherein the heavy chain variable domain varies from the sequence set forth in SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, and SEQ ID NO: 49 by fewer than eight amino acid substitutions, insertions or deletions. 
     
     
         5 . The antibody or antigen binding fragment of  claim 1 , wherein the light chain variable domain varies from the sequence set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26 by fewer than eight amino acid substitutions, insertions or deletions. 
     
     
         6 . The antibody or antigen binding fragment of  claim 1 , wherein the heavy chain variable domain comprises an amino acid sequence selected from the group consisting of:
 a) an amino acid sequence that is at least 95% identical to the sequence set forth in SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, or SEQ ID NO: 49; and   b) an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, or SEQ ID NO: 49.   
     
     
         7 . The antibody or antigen binding fragment of  claim 1 , wherein the light chain variable domain comprises an amino acid sequence selected from the group consisting of:
 a) an amino acid sequence that is at least 95% identical to the sequence set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, or SEQ ID NO: 26; and   b) an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, or SEQ ID NO: 26.   
     
     
         8 . An antibody or antigen binding fragment thereof comprising a heavy chain variable domain as set forth in  claim 6  and a light chain variable domain as set forth in  claim 7 . 
     
     
         9 . The antibody or antigen binding fragment of  claim 1 , wherein the heavy chain variable domain comprises an amino acid sequence selected from the group consisting of
 a) an amino acid sequence set forth in SEQ ID NO: 50;   b) an amino acid sequence that is at least 95% identical to the sequence set forth in SEQ ID NO: 50; and   c) an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NO: 50.   
     
     
         10 . The antibody or antigen binding fragment of  claim 1 , wherein the light chain variable domain comprises an amino acid sequence selected from the group consisting of
 a) an amino acid sequence set forth in SEQ ID NO: 51;   b) an amino acid sequence that is at least 95% identical to the sequence set forth in SEQ ID NO: 51; and   c) an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NO: 51.   
     
     
         11 . The antibody or antigen binding fragment of  claim 1  further comprising a heavy and light chain variable domain comprising:
 1) a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of:
 a) an amino acid sequence set forth in SEQ ID NO: 50; 
 b) an amino acid sequence that is at least 95% identical to the sequence set forth in SEQ ID NO: 50; and 
 c) an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NO: 50; and 
 
 2) a light chain variable domain comprising an amino acid sequence selected from the group consisting of
 a) an amino acid sequence set forth in SEQ ID NO: 51; 
 b) an amino acid sequence that is at least 95% identical to the sequence set forth in SEQ ID NO: 51; and 
 c) an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NO: 51. 
 
 
     
     
         12 . The antibody or antigen binding fragment of  claim 1  further comprising a heavy chain comprising an amino acid sequence selected from the group consisting of
 a) an amino acid sequence set forth in SEQ ID NOs: 59, or 64; 
 b) an amino acid sequence that is at least 95% identical to the sequence set forth in SEQ ID NOs: 59, or 64; and 
 c) an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs: 59 or 64. 
 
     
     
         13 . The antibody or antigen binding fragment of  claim 1  further comprising a light chain comprising an amino acid sequence selected from the group consisting of:
 a) an amino acid sequence set forth in SEQ ID NOs: 61, 63, 66, or 68; 
 b) an amino acid sequence that is at least 95% identical to the sequence set forth in SEQ ID NOs: 61, 63, 66, or 68; and 
 c) an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs: 61, 63, 66, or 68. 
 
     
     
         14 . The antibody or antigen binding fragment of  claim 1  further comprising a heavy and light chain comprising an amino acid sequence selected from the group consisting of:
 1) a heavy chain comprising an amino acid sequence selected from the group consisting of:
 a) an amino acid sequence set forth in SEQ ID NOs: 59, or 64; 
 b) an amino acid sequence that is at least 95% identical to the sequence set forth in SEQ ID NOs: 59, or 64; and 
 c) an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs: 59 or 64; and 
 
 2) a light chain comprising an amino acid sequence selected from the group consisting of:
 a) an amino acid sequence set forth in SEQ ID NOs: 61, 63, 66, or 68; 
 b) an amino acid sequence that is at least 95% identical to the sequence set forth in SEQ ID NOs: 61, 63, 66, or 68; and 
 c) an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs: 61, 63, 66, or 68. 
 
 
     
     
         15 . The antibody or antigen binding fragment of  claim 1 , wherein the heavy chain variable domain sequence is at least 95% identical to the amino acid sequence of the corresponding variable domain of SEQ ID NO: 59, or SEQ ID NO: 64, and the light chain variable domain sequence is at least 95% identical to the amino acid sequence of the corresponding variable domain of SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 66; or SEQ ID NO: 68. 
     
     
         16 . The antibody or antigen binding fragment of  claim 1 , wherein the heavy chain variable domain sequence is identical to the amino acid sequence of the corresponding variable domain of SEQ ID NO: 59, or SEQ ID NO: 64, and wherein the light chain variable domain sequence is identical to the amino acid sequence of the corresponding variable domain of SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 66; or SEQ ID NO: 68. 
     
     
         17 . An antibody or antigen binding fragment thereof comprising a variable heavy domain comprising the amino acids set forth in SEQ ID NO: 59 and a variable light domain comprising the amino acids set forth in SEQ ID NO: 61. 
     
     
         18 . An antibody or antigen binding fragment thereof comprising a variable heavy domain comprising the amino acids set forth in SEQ ID NO: 59 and a variable light domain comprising the amino acids set forth in SEQ ID NO: 63. 
     
     
         19 . The antibody or antigen binding fragment of any one of  claims 1 - 18 , wherein the antibody or antigen binding fragment is linked to one or more other functional molecules. 
     
     
         20 . The antibody or antigen binding fragment of  claim 19 , wherein the one or more other functional molecules is selected from the group consisting of another antibody or antigen binding fragment thereof, toxins, radioisotopes, polymers, and cytotoxic or cytostatic agents. 
     
     
         21 . The antibody or antigen binding fragment of  claim 20 , wherein the antigen binding fragment is an scFv. 
     
     
         22 . The antibody or antigen binding fragment of  claim 1  further comprising a heavy chain framework region comprising FR1, FR2, and FR3, wherein FR1, FR2, and FR3 comprise an amino acid sequence that is at least 85% identical to the heavy chain framework selected from the group consisting of:
 a germline V segment sequence selected from the group consisting of: DP-25, DP-1, DP-12, DP-9, DP-7, DP-31, DP-32, DP-33, DP-58, and DP-54; 
 a V H  I subgroup germline sequence; 
 a V H  III subgroup germline sequence; and 
 a V gene which is compatible with the canonical structure class 1-3. 
 
     
     
         23 . The antibody or antigen binding fragment of  claim 22  wherein the framework sequence comprises one or more of the following residues according to Kabat numbering: Ala, Gly, Thr, or Val at position 26; Gly at position 26; Tyr, Phe, or Gly at position 27; Phe, Val, Ile, or Leu at position 29; Met, He, Leu, Val, Thr, Trp, or Ile at position 34; Arg, Thr, Ala, or Lys at position 94; Gly, Ser, Asn, or Asp at position 54; Arg at position 71. 
     
     
         24 . The antibody or antigen binding fragment of  claim 1  further comprising a light chain framework regions FR1, FR2, FR3, wherein FR1, FR2, and FR3 comprise an amino acid sequence that is at least 85% identical to the light chain framework selected from the group consisting of:
 a Vκ II subgroup germline sequence; 
 a germline V segment sequence selected from the group consisting of: A17, A1, A 18, A2, A19/A3, and A23; 
 a Vκ I subgroup germline sequence including DPK9; 
 a V gene which is compatible with the canonical structure class 4-1. 
 
     
     
         25 . The antibody or antigen binding fragment of  claim 24 , wherein the framework sequence comprises one or more of the following residues according to Kabat numbering: Val, Leu, or Ile at position 2; Ser or Pro at position 25; Ile or Leu at position 27b; Gly at position 29; Phe or Leu at position 33; Ile or Val at position 48; Phe at position 71. 
     
     
         26 . The antibody or antigen binding fragment of  claim 22 , wherein the framework regions of the heavy chain variable domain sequence are at least 95% identical, collectively, to the DP54 germ line sequence. 
     
     
         27 . The antibody or antigen binding fragment of  claim 24 , wherein the framework regions of the light chain variable domain sequence are at least 95% identical, collectively, to the sequence of a Vκ I subgroup germline sequence. 
     
     
         28 . The antibody or antigen binding fragment of  claim 22 , wherein the framework regions of the heavy chain variable domain sequence are at least 95% identical, collectively, to the sequence of a V H  I subgroup germline sequence. 
     
     
         29 . A pharmaceutical composition comprising the antibody or antigen binding fragment according to any one of  claim 1 - 18 , or  22 - 28  and a pharmaceutically acceptable carrier.