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.

We claim: 
     
         1 . An isolated or recombinant TNF-like ligand 1a (TL1a)-binding protein, comprising an antigen binding domain of an antibody that specifically binds to TL1a and inhibits interaction of TL1a and Death Receptor 3 (DR3) and does not inhibit the interaction of TL1a with Decoy Receptor 3 (DcR3). 
     
     
         2 . The TL1a-binding protein of  claim 1 , wherein:
 (i) the TL1a-binding protein reduces the level of apoptosis of TF-1 cells cultured in the presence of human TL1a and cycloheximide with an effective concentration (EC 50 ) of from about 1.5 nM to about 10 fM;   (ii) the antigen binding domain binds specifically to TL1a and inhibits the interaction of biotinylated TL1a and a polypeptide comprising DR3 fused to a Fc region of an antibody (“DR3/Fc”) with an EC 50  of from about 2.5 nM to about 10 fM, or about 1.0 nM to about 10 fM, or about 0.5 nM to about 10 fM, or about 0.1 nM to about 10 fM in a competition ELISA; or   (iii) the TL1a-binding protein binds to TL1a on the surface of a cell with an EC 50  of from about 10 nM to about 10 fM or 5.0 nM to about 10 fM or 1.0 nM to about 10 fM or 0.5 nM to about 10 fM or 0.1 nM to about 10 fM, as determined using flow cytometry.   
     
     
         3 . The TL1a-binding protein of  claim 1 , wherein the TL1a-binding protein binds a mutant form of soluble human TL1a comprising the amino acid sequence of SEQ ID NO: 202 in which the arginine at position 32 has been substituted with alanine and/or the arginine at position 85 has been substituted with alanine at a level that is at least 75% lower than the level with which the protein binds to soluble human TL1a comprising the sequence of SEQ ID NO: 202, wherein the mutant form of TL1a is immobilized on a solid or semi-solid substrate at a concentration of about 1 μg/mL, and wherein the TL1a binding protein at a concentration of 10 μg/mL is then contacted to the immobilized mutant TL1a. 
     
     
         4 . The TL1a binding protein of  claim 1 , wherein the TL1a binding protein binds at least the amino acid residues arginine at position 32 and arginine at position 85 of a human TL1a comprising the amino acid sequence of SEQ ID NO: 202. 
     
     
         5 . The TL1a-binding protein of  claim 1 , wherein the antigen binding domain comprises at least a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL form an Fv. 
     
     
         6 . The TL1a-binding protein of  claim 1 , wherein the antigen binding domain comprises
 (a) a heavy chain variable region (VH) comprising:
 (i) a FR1 comprising the amino acid sequence of SEQ ID NO: 144; 
 (ii) a CDR1 comprising the amino acid sequence of SEQ ID NO: 43; 
 (iii) a FR2 comprising the amino acid sequence of SEQ ID NO: 145; 
 (iv) a CDR2 comprising the amino acid sequence of SEQ ID NO: 142; 
 (v) a FR3 comprising the amino acid sequence of SEQ ID NO: 146; 
 (vi) a CDR3 comprising the amino acid sequence of SEQ ID NO: 143; and 
 (vii) a FR4 comprising the amino acid sequence of SEQ ID NO: 147; and 
   (b) a light chain variable region comprising:
 (i) a FR1 comprising the amino acid sequence of SEQ ID NO: 148; 
 (ii) a CDR1 comprising the amino acid sequence of SEQ ID NO: 139; 
 (iii) a FR2 comprising the amino acid sequence of SEQ ID NO: 149; 
 (iv) a CDR2 comprising the amino acid sequence of SEQ ID NO: 140; 
 (v) a FR3 comprising the amino acid sequence of SEQ ID NO: 150; 
 (vi) a CDR3 comprising the amino acid sequence of SEQ ID NO: 141; and 
 (vii) a FR4 comprising the amino acid sequence of SEQ ID NO: 151. 
   
     
     
         7 . The TL1a-binding protein of  claim 5 , wherein the VH and the VL are in a single polypeptide chain, and the TL1a-binding protein is:
 (i) a single chain Fv fragment (scFv);   (ii) a dimeric scFv (di-scFv);   (iii) a scFv or di-scFv linked to a Fc or a heavy chain constant domain (CH) 2 and/or CH3; or   (iv) a scFv or di-scFv linked to a protein that binds to an immune effector cell; or   wherein the VL and VH are in separate polypeptide chains and the TL1a-binding protein is:   (i) a diabody;   (ii) a triabody;   (iii) a tetrabody;   (iv) a Fab;   (v) a F(ab′)2;   (vi) a Fv;   (vii) a diabody, triabody, tetrabody, Fab, F(ab′)2, or Fv linked to a Fc or a heavy chain constant domain (CH) 2 and/or CH3;   (viii) a diabody, triabody, tetrabody, Fab, F(ab′)2, or Fv linked to a protein that binds to an immune effector cell; or   (ix) an antibody.   
     
     
         8 . The TL1a-binding protein of  claim 1 , wherein the antigen binding domain is comprised in a chimeric, de-immunized, humanized, synhumanized, human, or primatized antibody. 
     
     
         9 . A nucleic acid encoding the TL1a-binding protein of  claim 1 . 
     
     
         10 . A cell expressing the TL1a-binding protein of  claim 1 . 
     
     
         11 . A composition, comprising the TL1a-binding protein of  claim 1  and a suitable carrier. 
     
     
         12 . A method, comprising administering the TL1a-binding protein of  claim 1  to a cell, tissue, organ or subject, thereby treating a TL1a-mediated condition in the cell, tissue, organ or subject. 
     
     
         13 . A method for detecting TL1a in a sample, comprising contacting a sample with the TL1a-binding protein of  claim 1 , thereby forming a complex of the TL1a-binding protein and TL1a if Tl1a is in the sample, and detecting the complex. 
     
     
         14 . A method for detecting TL1a in a subject, comprising administering the TL1a-binding protein of  claim 1  conjugated to a detectable label to the subject, and detecting a complex of the TL1a-binding protein in the subject. 
     
     
         15 . The method of  claim 12 , wherein the TL1a-mediated condition is an autoimmune disease. 
     
     
         16 . The method of  claim 12 , wherein the TL1a-mediated condition is ulcerative colitis, Crohn's disease, irritable bowel syndrome, rheumatoid arthritis, polyarthritis, multiple sclerosis, uveitis, asthma or chronic obstructive pulmonary disease.