Optimized anti-tl1a antibodies

Abstract

Described herein are humanized anti-TL1A antibodies and pharmaceutical compositions for the treatment of inflammatory bowel disease (IBD), such as Crohns Disease (CD) and ulcerative colitis (UC).

What is claimed is: 
     
         1 . An antibody or antigen-binding fragment that specifically binds TL1A, comprising:
 a heavy chain variable region comprising:
 (a) an HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 553; 
 (b) an HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 554 to 564 or 574 to 577; and 
 (c) an HCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 565 to 568 or 578 to 581; and 
   a light chain variable region comprising:
 (d) an LCDR1 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 569 or 570; 
 (e) an LCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 488; and 
 (f) an LCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 571 to 573 or 582 to 585. 
   
     
     
         2 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 1 , wherein:
 (a) the HCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 553;   (b) the HCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 559;   (c) the HCDR3 comprises the amino acid sequence set forth by SEQ ID NO: 567;   (d) the LCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 569;   (e) the LCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 488; and   (f) the LCDR3 comprises the amino acid sequence set forth by SEQ ID NO: 573.   
     
     
         3 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 1 , wherein:
 (a) the HCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 553;   (b) the HCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 563;   (c) the HCDR3 comprises the amino acid sequence set forth by SEQ ID NO: 568;   (d) the LCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 569;   (e) the LCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 488; and   (f) the LCDR3 comprises the amino acid sequence set forth by SEQ ID NO: 572.   
     
     
         4 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 1 , wherein:
 (a) the HCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 553;   (b) the HCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 555;   (c) the HCDR3 comprises the amino acid sequence set forth by SEQ ID NO: 566;   (d) the LCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 569;   (e) the LCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 488; and   (f) the LCDR3 comprises the amino acid sequence set forth by SEQ ID NO: 572.   
     
     
         5 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 1 , wherein:
 (a) the HCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 553;   (b) the HCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 558;   (c) the HCDR3 comprises the amino acid sequence set forth by SEQ ID NO: 566;   (d) the LCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 569;   (e) the LCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 488; and   (f) the LCDR3 comprises the amino acid sequence set forth by SEQ ID NO: 572.   
     
     
         6 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 1 , wherein:
 (a) the HCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 553;   (b) the HCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 564;   (c) the HCDR3 comprises the amino acid sequence set forth by SEQ ID NO: 568;   (d) the LCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 569;   (e) the LCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 488; and   (f) the LCDR3 comprises the amino acid sequence set forth by SEQ ID NO: 572.   
     
     
         7 . An antibody or antigen-binding fragment that specifically binds TL1A, comprising: a heavy chain variable region comprising:
 (a) an HCDR1, an HCDR2, and an HCDR3 selected from any one of SEQ ID NOs: 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, or 541; and   a light chain variable region comprising   (b) an LCDR1, an LCDR2, and an LCDR3 selected from any one of SEQ ID NOs: 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, or 540;
 wherein the CDRs are defined by the Kabat, Chothia, or IMGT method or a combination thereof. 
   
     
     
         8 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  7 , comprising:
 (a) a human heavy chain framework region 1 that is at least 95% identical to that set forth is SEQ ID NO: 545; 
 (b) a human heavy chain framework region 2 that is at least 95% identical to that set forth is SEQ ID NO: 546; 
 (c) a human heavy chain framework region 3 that is at least 95% identical to that set forth is SEQ ID NO: 547 or 586 to 588; 
 (d) a human heavy chain framework region 4 that is at least 95% identical to that set forth is SEQ ID NO: 548; 
 (e) a human light chain framework region 1 that is at least 95% identical to that set forth is SEQ ID NO: 549; 
 (f) a human light chain framework region 2 that is at least 95% identical to that set forth is SEQ ID NO: 550; 
 (g) a human light chain framework region 3 that is at least 95% identical to that set forth is SEQ ID NO: 551; and 
 (h) a human light chain framework region 4 that is at least 95% identical to that set forth is SEQ ID NO: 552. 
 
     
     
         9 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  8 , comprising a heavy chain variable region comprising an amino acid sequence at least about 90% identical to any one of SEQ ID NOs: 503, 511, 493, 501, or 515; and a light chain variable region comprising an amino acid sequence at least about 90% identical to any one of SEQ ID NOs: 502, 510, 492, 500, or 514. 
     
     
         10 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  8 , comprising a heavy chain variable region comprising an amino acid sequence set forth in any one of SEQ ID NOs: 503, 511, 493, 501, or 515; and a light chain variable region comprising an amino acid sequence set forth in any one of SEQ ID NOs: 502, 510, 492, 500, or 514. 
     
     
         11 . An antibody or antigen-binding fragment that specifically binds TL1A, comprising:
 (a) a heavy chain variable region comprising an amino acid sequence at least about 90% identical to any one of SEQ ID NOs: 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, or 541; and   (b) a light chain variable region comprising an amino acid sequence at least about 90% identical to any one of SEQ ID NOs: 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, or 540.   
     
     
         12 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 11 , wherein the heavy chain variable region comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 503; and wherein the light chain variable region comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 502. 
     
     
         13 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 12 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 503; and wherein the light chain variable region comprises the amino acid of SEQ ID NO: 502. 
     
     
         14 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 11 , wherein the heavy chain variable region comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 511; and wherein the light chain variable region comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 510. 
     
     
         15 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 14 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 511; and wherein the light chain variable region comprises the amino acid of SEQ ID NO: 510. 
     
     
         16 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 11 , wherein the heavy chain variable region comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 493; and wherein the light chain variable region comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 492. 
     
     
         17 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 16 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 493; and wherein the light chain variable region comprises the amino acid of SEQ ID NO: 492. 
     
     
         18 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 11 , wherein the heavy chain variable region comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 501; and wherein the light chain variable region comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 500. 
     
     
         19 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 18 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 501; and wherein the light chain variable region comprises the amino acid of SEQ ID NO: 500. 
     
     
         20 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 11 , wherein the heavy chain variable region comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 515; and wherein the light chain variable region comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 514. 
     
     
         21 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 20 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 515; and wherein the light chain variable region comprises the amino acid of SEQ ID NO: 514. 
     
     
         22 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  21 , wherein the antibody binds human TL1A with a stronger affinity compared to the L8 clone, as determined by ELISA, wherein the L8 clone comprises a heavy chain variable region amino acid sequence as set forth by SEQ ID NO: 491, and a light chain variable region amino acid sequence as set forth by SEQ ID NO: 490. 
     
     
         23 . The antibody or antigen-binding fragment that specifically binds TL1A of  claim 22 , wherein the antibody binds human TL1A with at least a 2-fold stronger affinity compared to the L8 clone, as determined by ELISA, wherein the L8 clone comprises a heavy chain variable region amino acid sequence as set forth by SEQ ID NO: 491, and a light chain variable region amino acid sequence as set forth by SEQ ID NO: 490. 
     
     
         24 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  23 , wherein the antibody or antigen-binding fragment is chimeric or humanized. 
     
     
         25 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  23 , wherein the antibody or antigen-binding fragment is an IgG antibody. 
     
     
         26 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  25 , wherein the antibody or antigen-binding fragment comprises a Fab, F(ab) 2 , a single-domain antibody, a single chain variable fragment (scFv), or a nanobody. 
     
     
         27 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  26 , comprising a heavy chain constant region comprising an amino acid sequence as set forth by SEQ ID NO: 542 or 543. 
     
     
         28 . The antibody or antigen-binding fragment of any one of  claims 1  to  26 , comprising a heavy chain constant region comprising an amino acid sequence as set forth by SEQ ID NO: 542. 
     
     
         29 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  26 , comprising a light chain constant region comprising an amino acid sequence as set forth by SEQ ID NO: 544. 
     
     
         30 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  29 , wherein the antibody or antigen-binding fragment thereof inhibits TL1A induced secretion of interferon gamma from T lymphocytes. 
     
     
         31 . A pharmaceutical composition comprising the antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  30  and a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         32 . The pharmaceutical composition of  claim 31 , formulated for intravenous administration. 
     
     
         33 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  30  or the pharmaceutical composition of  claim 31  or  32  for use in treating inflammatory bowel disease, Crohn's disease, or colitis. 
     
     
         34 . A method of treating inflammatory bowel disease, Crohn's disease, or colitis in an individual comprising administering an effective amount of the antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  30  or the pharmaceutical composition of  claim 31  or  32  to the individual, wherein the individual is diagnosed with or suspected of being afflicted with inflammatory bowel disease, Crohn's disease, or colitis. 
     
     
         35 . The antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  30  or the pharmaceutical composition of  claim 31  or  32  for use in preventing or reducing interferon gamma secretion by T lymphocytes. 
     
     
         36 . A method preventing or reducing interferon gamma secretion by T lymphocytes in an individual comprising administering an effective amount of the antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  30  or the pharmaceutical composition of  claim 31  or  32  to the individual. 
     
     
         37 . A nucleic acid encoding the antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  30 . 
     
     
         38 . A cell comprising the nucleic acid of  claim 37 . 
     
     
         39 . The cell of  claim 38 , wherein the cell is a eukaryotic cell. 
     
     
         40 . The cell of  claim 38 , wherein the cell is a Chinese Hamster Ovary (CHO) cell. 
     
     
         41 . A method of preparing an inflammatory bowel disease, Crohn's disease, or colitis treatment comprising incubating a cell of any one of  claims 38  to  40  in a culture medium under conditions sufficient to secrete the antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  30  into the culture medium. 
     
     
         42 . The method of  claim 41 , further comprising subjecting the culture medium to at least one purification step. 
     
     
         43 . A method of preparing an inflammatory bowel disease, Crohn's disease, or colitis treatment comprising admixing the antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  30  and a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         44 . A method of treating a disease or a condition in an individual possessing a risk variant associated with the disease or the condition, the method comprising administering an effective amount of the antibody or antigen-binding fragment that specifically binds TL1A of any one of  claims 1  to  30  or the pharmaceutical composition of  claim 31  or  32  to the individual possessing the risk variant for the disease or the condition, wherein the disease or the condition comprises at least one of an inflammatory bowel disease (IBD), Crohn's disease (CD), or colitis. 
     
     
         45 . The method of  claim 44 , wherein the individual possesses a plurality of risk variants. 
     
     
         46 . The method of  claim 45 , wherein the plurality of risk variants is at least 3, 4, 5, or 10 risk variants. 
     
     
         47 . The method of any one of  claims 44  to  46 , wherein risk variant or the plurality of risk variants is associated with a subclinical phenotype of the disease or the condition. 
     
     
         48 . The method of  claim 44 , wherein the disease or the condition is a severe form of the at least one of the IBD, the CD, or the colitis.