Antibodies against tl1a and uses thereof

Abstract

The disclosure provides TNF-like ligand 1a (TL1a)-binding proteins comprising an antigen binding domain of an antibody which binds specifically to TL1a and inhibits interaction of TL1a and Death Receptor 3 (DR3) and which does not inhibit the interaction of TL1a and Decoy Receptor 3 (DcR3). The disclosure also provides uses of the TL1a-binding proteins.

1 . (canceled) 
     
     
         2 . An antibody or antigen binding domain thereof which specifically binds to TNF-like ligand (TL1a), wherein the antibody or antigen binding domain binds to an epitope within TL1a comprising at least the amino acid residue arginine at position 32 of a human TL1a which comprises an amino acid sequence as set forth in SEQ ID NO: 202. 
     
     
         3 . The antibody or antigen binding domain thereof of  claim 2 , wherein the epitope further comprises amino acid residue arginine at position 85 of the human TL1a which comprises the amino acid sequence as set forth in SEQ ID NO: 202. 
     
     
         4 . The antibody or antigen binding domain thereof of  claim 2 , wherein the epitope further comprises amino acid residue glycine at position 53 of the human TL1a which comprises the amino acid sequence as set forth in SEQ ID NO: 202. 
     
     
         5 . The antibody or antigen binding domain thereof of  claim 2 , wherein the antibody or antigen binding domain thereof comprises (a) a variable heavy chain comprising an amino acid sequence that is at least 95%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 186 and (b) a variable light chain comprising an amino acid sequence that is at least 95%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 199. 
     
     
         6 . The antibody or antigen binding domain thereof of  claim 2 , wherein the antibody or antigen binding domain thereof binds to SEQ ID NO: 202 in which the arginine at position 32 has been substituted with an alanine at a level that is at least 75% lower than the level which the antibody or antigen binding domain thereof binds to human TL1a comprising the amino acid sequence of SEQ ID NO: 202, or wherein the antibody or antigen binding domain thereof binds to SEQ ID NO: 202 in which the arginine at position 32 has been substituted with an alanine at a level that is no greater than 25% of the level with which the protein binds to soluble human TL1a comprising a sequence set forth in SEQ ID NO: 202. 
     
     
         7 . The antibody or antigen binding domain thereof of  claim 2 , wherein the antibody or antigen binding domain thereof binds to SEQ ID NO: 202 in which the arginine at position 85 has been substituted with an alanine at a level that is at least 75% lower than the level which the antibody or antigen binding domain thereof binds to human TL1a comprising the amino acid sequence of SEQ ID NO: 202, or wherein the antibody or antigen binding domain thereof binds to SEQ ID NO: 202 in which the arginine at position 85 has been substituted with an alanine at a level that is no greater than 25% of the level with which the protein binds to soluble human TL1a comprising a sequence set forth in SEQ ID NO: 202. 
     
     
         8 . The antibody or antigen binding domain thereof of  claim 2 , wherein the antibody or antigen binding domain thereof binds to SEQ ID NO: 202 in which the arginine at position 32 has been substituted with alanine and the arginine at position 85 has been substituted with an alanine at a level that is at least 75% lower than the level which the antibody or antigen binding domain thereof binds to human TL1a comprising the amino acid sequence of SEQ ID NO: 202, or wherein the antibody or antigen binding domain thereof binds to SEQ ID NO: 202 in which the arginine at position 32 has been substituted with alanine and the arginine at position 85 has been substituted with an alanine at a level that is no greater than 25% of the level with which the protein binds to soluble human TL1a comprising a sequence set forth in SEQ ID NO: 202. 
     
     
         9 . The antibody or antigen binding domain of  claim 2 , wherein the antibody or antigen binding domain comprises an IgG1 heavy chain constant domain. 
     
     
         10 . The antibody or antigen binding domain of  claim 2 , wherein the antibody or antigen binding domain comprises a lambda light chain constant domain. 
     
     
         11 . The antibody or antigen binding domain of  claim 2 , wherein the antibody or antigen binding domain comprises a human IgG1 heavy chain constant domain and a human lambda light chain constant domain. 
     
     
         12 . A nucleic acid encoding a variable heavy chain and/or a variable light chain of the antibody or antigen binding domain of  claim 2 . 
     
     
         13 . A cell expressing the antibody or antigen binding domain of  claim 2 . 
     
     
         14 . A method of producing an antibody or antigen binding domain comprising culturing the cell of  claim 13  under conditions sufficient for the antibody or antigen binding domain to be produced. 
     
     
         15 . A method of detecting TL1a in a sample, the method comprising contact the sample with the antibody or antigen binding domain of  claim 2  such that the antibody or antigen binding domain forms a complex with the TL1a and detecting the complex. 
     
     
         16 . A method of diagnosing a condition in a subject, the method comprising contacting a sample obtained from the subject with the antibody or antigen binding domain of  claim 2  such than the antibody or antigen binding domain forms a complex with the TL1a and detecting the complex. 
     
     
         17 . A composition comprising the antibody or antigen binding domain of  claim 2  and a suitable carrier. 
     
     
         18 . A method of treating an autoimmune disease in a subject, comprising administering the antibody or antigen binding domain thereof of  claim 2  to the subject. 
     
     
         19 . An antibody or antigen binding domain thereof which specifically binds to the same epitope as recognized by an antibody comprising a variable heavy chain comprising an amino acid sequence of SEQ ID NO: 186 and a variable light chain comprising an amino acid sequence of SEQ ID NO: 199. 
     
     
         20 . An antibody or antigen binding domain thereof which specifically binds to the same epitope as recognized by an antibody comprising a variable heavy chain comprising an amino acid sequence of SEQ ID NO: 181, and a variable light chain comprising an amino acid sequence of SEQ ID NO: 194. 
     
     
         21 . An antibody or antigen binding domain thereof which specifically binds to the same epitope as recognized by an antibody comprising a variable heavy chain comprising an amino acid sequence of SEQ ID NO: 42 and a variable light chain comprising an amino acid sequence of SEQ ID NO: 46.