Antibodies that bind to tl1a and their uses

Abstract

The present invention relates to antibodies or fragments thereof that bind to TL1A. More specifically, the present invention relates to an antibody or fragment thereof that binds to TL1A comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 51, and/or a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and/or a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 53; and/or comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 54, and/or a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 55 and/or a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 56.

1 . An antibody or fragment thereof that binds to TL1A comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 51, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 53; and/or comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 54, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 55, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 56. 
     
     
         2 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof is a murine antibody, chimeric antibody or a humanized antibody. 
     
     
         3 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof is a humanized antibody. 
     
     
         4 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a heavy chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 1. 
     
     
         5 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a non-CDR region of a heavy chain variable region sequence which is at least 80% identical to the non-CDR region of the heavy chain variable region sequence of SEQ ID NO: 1. 
     
     
         6 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a heavy chain variable region sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 26, 27, 28 and 29. 
     
     
         7 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a non-CDR region of a heavy chain variable region sequence which is at least 80% identical to the non-CDR region of the heavy chain variable region sequence selected from the group consisting of SEQ ID NOS: 26, 27, 28 and 29. 
     
     
         8 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a heavy chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 29. 
     
     
         9 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a non-CDR region of a heavy chain variable region sequence which is at least 80% identical to the non-CDR region of the heavy chain variable region sequence of SEQ ID NO: 29. 
     
     
         10 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a heavy chain sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 21, 22, 23 and 24. 
     
     
         11 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a heavy chain sequence comprising a non-CDR region which is at least 80% identical to the non-CDR region of the heavy chain variable region sequence of a heavy chain sequence selected from the group consisting of SEQ ID NOS: 21, 22, 23 and 24. 
     
     
         12 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a heavy chain variable framework region that is the product of or derived from a human gene selected from the group consisting of IGHV1-2*02 (SEQ ID NO: 3), IGHV1-2*04 (SEQ ID NO: 4), IGHV1-2*05 (SEQ ID NO: 5), IGHV1-2*01 (SEQ ID NO: 6), and IGHV1-46*01 (SEQ ID NO: 7). 
     
     
         13 . The antibody or fragment thereof of  claim 3 , wherein the antibody or fragment thereof comprises a heavy chain variable framework region that is the product of or derived from human gene IGHV1-2*01 (SEQ ID NO: 3) and wherein the heavy chain variable framework region comprises at least one amino acid modification from the corresponding heavy chain variable framework region of a corresponding murine antibody. 
     
     
         14 . The antibody or fragment thereof of  claim 3 , wherein the antibody or fragment thereof comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 16 and wherein the heavy chain variable framework region comprises at least one amino acid modification from the corresponding heavy chain variable framework region of a corresponding murine antibody. 
     
     
         15 . The antibody or fragment thereof of  claim 13  or  14 , wherein the amino acid modification comprises an amino acid substitution at amino acid position selected from the group consisting of 37, 48, 50, 67, 69, 71 and 75, wherein the amino acid position of each group member is indicated according to the Kabat numbering. 
     
     
         16 . The antibody or fragment thereof of  claim 13  or  14 , wherein the amino acid modification comprises an amino acid substitution selected from the group consisting of 37A, 48I, 50E, 67A, 69L, 71V and 75S, wherein the amino acid position of each group member is indicated according to the Kabat numbering. 
     
     
         17 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 2. 
     
     
         18 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a non-CDR region of a light chain variable region sequence which is at least 80% identical to the non-CDR region of the light chain variable region sequence of SEQ ID NO: 8. 
     
     
         19 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a light chain variable region sequence comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 14 and 30. 
     
     
         20 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a non-CDR region of a light chain variable region sequence which is at least 80% identical to the non-CDR region of the light chain variable region sequence selected from the group consisting of SEQ ID NO: 14 and 30. 
     
     
         21 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a light chain sequence comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 17 and 25. 
     
     
         22 . The antibody or fragment thereof of  claim 1 , wherein the light chain sequence comprises a non-CDR region which is at least 80% identical to the non-CDR region of the light chain variable region sequence of the light chain sequence selected from the group consisting of SEQ ID NO: 17 and 25. 
     
     
         23 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises a light chain variable framework region that is the product of or derived from a human gene selected from the group consisting of IGKV1-33*01 (SEQ ID NO: 8), IGKV1D-33*01 (SEQ ID NO: 9), IGKV1D-12*02 (SEQ ID NO: 10), IGKV1D-12*01 (SEQ ID NO: 11) and IGKV1-12*02 (SEQ ID NO: 12). 
     
     
         24 . The antibody or fragment thereof of  claim 3 , wherein the antibody or fragment thereof comprises a light chain variable framework region that is the product of or derived from human gene IGKV1-33*01 (SEQ ID NO: 8) and wherein the light chain variable framework region comprises at least one amino acid modification from the corresponding framework region of the light chain variable region of a corresponding murine antibody. 
     
     
         25 . The antibody or fragment thereof of  claim 3 , wherein the antibody or fragment thereof comprises a light chain sequence comprising the amino acid sequence of SEQ ID NO: 17 and wherein the light chain variable framework region comprises at least one amino acid modification from the corresponding light chain variable framework region of the corresponding murine antibody. 
     
     
         26 . The antibody or fragment thereof of  claim 24  or  25 , wherein the amino acid modification comprises an amino acid substitution at amino acid position selected from the group consisting of 5 and 34, wherein the amino acid position of each group member is indicated according to the Kabat numbering. 
     
     
         27 . The antibody or fragment thereof of  claim 24  or  25 , wherein the amino acid modification comprises an amino acid substitution selected from the group consisting of 5N and 34S, wherein the amino acid position of each group member is indicated according to the Kabat numbering. 
     
     
         28 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises:
 (a) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 22 or SEQ ID NO: 24; and   (b) a light chain sequence comprising the amino acid sequence of SEQ ID NO: 17.   
     
     
         29 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof comprises:
 (a) a heavy chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 27 or SEQ ID NO: 29; and   (b) a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 14.   
     
     
         30 . The antibody or fragment thereof of  claim 1 , wherein at least one of the heavy chain CDRs and/or at least one of the light chain CDRs comprises at least one amino acid modification. 
     
     
         31 . The antibody or fragment thereof of  claim 1 , further comprising heavy and/or light constant regions. 
     
     
         32 . The antibody or fragment thereof of  claim 31 , wherein the human heavy constant region is selected from the group of human immunoglobulins consisting of IGHG1, non fucosylated IGHG1 and IGHG4. 
     
     
         33 . The antibody or fragment thereof of  claim 1 , wherein the antibody has a non fucosylated IGHG1 Fc region. 
     
     
         34 . The antibody or fragment thereof of  claim 1 , wherein the antibody comprises an isotypic variant comprising the CH1 from human IgG4 (IGHG4), the hinge from human IgG4 (IGHG4), having S228P substitution and the CH2 and CH3 from human IgG4 (IGHG4). 
     
     
         35 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof binds to human TL1A. 
     
     
         36 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof binds to human TL1A and is cross reactive with murine, rat and cynomologus TL1A. 
     
     
         37 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof binds to hTL1A and inhibits the interaction of hTL1A with both DR3 and DcR3. 
     
     
         38 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof is an antagonist antibody. 
     
     
         39 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof is a neutralizing antibody. 
     
     
         40 . The antibody or fragment thereof of  claim 1 , wherein the antibody is a monovalent antibody. 
     
     
         41 . The antibody or fragment thereof of  claim 1 , wherein the antibody is a full length antibody. 
     
     
         42 . The antibody or fragment thereof of  claim 1 , wherein the antibody is an antibody fragment selected from the group consisting of Fab, Fab′, Fab′-SH, Fd, Fv, dAb, F(ab′)2, scFv, bispecific single chain Fv dimers, diabodies, triabodies and scFv genetically fused to the same or a different antibody. 
     
     
         43 . The antibody or fragment thereof of  claim 1 , wherein the antibody comprises a variant Fc region which comprises at least one amino acid modification relative to the Fc region of the parent antibody, wherein the antibody comprising the variant Fc region exhibits altered effector function compared to the parent antibody. 
     
     
         44 . The antibody or fragment thereof of  claim 1 , wherein the antibody or fragment thereof binds to human TL1A with an affinity (K D ) of 700 pM or less. 
     
     
         45 . The antibody or fragment thereof of  claim 1  or  3 , wherein the antibody or fragment thereof retains at least 85% of the TL1A binding affinity (K D ) of the corresponding chimeric antibody. 
     
     
         46 . The antibody or fragment thereof of  claim 3 , wherein the antibody or fragment thereof has equivalent or higher TL1A binding affinity (K D ) when compared to the corresponding chimeric antibody. 
     
     
         47 . The antibody or fragment thereof of  claim 3 , wherein the antibody or fragment thereof binds human TL1A with three-fold higher affinity than the corresponding chimeric antibody 
     
     
         48 . The antibody or fragment thereof of  claim 1 , wherein the antibody has a Fab fragment thermostability temperature greater than 80° C. 
     
     
         49 . An antibody or fragment thereof that binds to human TL1A and which binds to the same epitope as the antibody of  claim 1 . 
     
     
         50 . An epitope on soluble human TL1A which is bound by the antibody of  claim 1 . 
     
     
         51 . An isolated nucleic acid encoding the antibody or fragment thereof of  claim 1 . 
     
     
         52 . The isolated nucleic acid of  claim 51  comprising DNA encoding the heavy chain variable region comprising the nucleic acid sequence of SEQ ID NO: 33 or 35; and/or DNA encoding the light chain variable region comprising the nucleic acid sequence of SEQ ID NO: 36. 
     
     
         53 . A vector comprising the isolated nucleic acid of  claim 52 . 
     
     
         54 . A host cell comprising the isolated nucleic acid of  claim 51  or the vector of  claim 53 . 
     
     
         55 . A method of producing an antibody or fragment thereof that binds to human TL1A comprising culturing the host cell of  claim 54  so that the nucleic acid is expressed and the antibody produced. 
     
     
         56 . An antibody or fragment thereof that binds to human. TL1A encoded by the isolated nucleic acid of  claim 51 . 
     
     
         57 . A composition comprising the antibody or fragment thereof of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         58 . An immunoconjugate comprising the antibody or fragment thereof of  claim 1  linked to a therapeutic agent. 
     
     
         59 . A composition comprising the immunoconjugate of  claim 58  and a pharmaceutically acceptable carrier. 
     
     
         60 . The composition of  claim 57  further comprising a second pharmaceutically active agent. 
     
     
         61 . A method for treating a TL1A mediated disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the antibody or fragment thereof of  claim 1 . 
     
     
         62 . The method of  claim 61 , wherein the TL1A mediated disorder is selected from the group consisting of inflammatory bowel disease (IBD) including ulcerative colitis and Crohn's disease, rheumatoid arthritis, MS, type 1 and type 2 diabetes, psoriasis, psoriatic arthritis, ankylosing spondylitis, atopic dermatitis; allergic reactions or conditions, including for example, asthma and allergic lung inflammation; cancers, atherosclerosis, infections, neurodegenerative diseases, graft rejection, graft versus host diseases (GVHD) and cardiovascular disorders/diseases. transplant rejection, central nervous system injury, psoriasis, leukaemia or lymphoma (e.g., chronic lymphocytic leukaemia (CLL)), atherosclerosis, and lung and colon carcinomas, chronic obstructive pulmonary disease (COPD), optic neuritis, age related macular degeneration, systemic lupus erythematosus (SLE), sjogen's syndrome, scleroderma, systemic sclerosis, chronic Kidney disease, liver fibrosis, tuberculosis, idiopathic pulmonary fibrosis, tuberculosis induced lung fibrosis, retroperitoneal Fibrosis, pulmonary fibrosis, cystic fibrosis, endomyocardial fibrosis, atrial fibrosis, mediastinal fibrosis, myelofibrosis (bone marrow), retroperitoneal fibrosis, progressive massive fibrosis, npephrogenic systemic fibrosis, and arthrofibrosis. 
     
     
         63 . The method of  claim 61 , wherein the antibody has a non fucosylated IGHG1 Fc region and exhibits enhanced cytotoxicity as compared to the antibody having human heavy chain constant region IGHG1. 
     
     
         64 . The antibody or fragment thereof of  claim 1 , for use as a medicament. 
     
     
         65 . The antibody or fragment thereof of  claim 1 , for use in a method for treating a TL1A mediated disorder. 
     
     
         66 . An article of manufacture comprising the antibody or fragment thereof of  claim 1 , for the treatment of a TL1A mediated disorder. 
     
     
         67 . A kit comprising the antibody or fragment thereof of  claim 1 , for the treatment of a TL1A mediated disorder.