Anti-light antibodies

Abstract

The present invention relates to anti-human LIGHT antibodies, new medical uses and methods.

1 . An antibody or a fragment thereof, that specifically binds to human lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes 214E allele (214E hLIGHT) and competes for binding to said 214E hLIGHT with an antibody selected from the group consisting of 1C02, 13H04 and 31A10. 
     
     
         2 . The antibody or antibody fragment according to  claim 1 ,
 wherein the antibody or fragment comprises variable domains that   i. specifically bind both 214E hLIGHT and lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes 214K allele (214K hLIGHT),   ii. compete with an antibody comprising the variable regions of 01C02 or 13H04 for binding 214E hLIGHT, and   iii. do not compete with an antibody comprising the variable regions of an antibody selected from 01C06 and 18E04 for binding to 214E hLIGHT; or   wherein the antibody or fragment comprises variable domains that   iv. specifically bind both 214E hLIGHT and 214K hLIGHT,   v. compete with an antibody comprising the variable regions of 31A10 for binding 214E hLIGHT and   vi. compete with an antibody comprising the variable regions of an antibody selected from 01C06 and 18E04 for binding to 214E hLIGHT.   
     
     
         3 . The antibody or fragment of  claim 1 , wherein (ii), (iii), (v) and (vi) are determined using the variable domains in a human IgG4 antibody format. 
     
     
         4 . The antibody or fragment of  claim 1 , wherein the antibody is in a human IgG4 format. 
     
     
         5 . The antibody or fragment of  claim 1 , comprising a VH domain that comprises an amino acid sequence of SEQ ID NO: 368, or comprise SEQ ID NO: 368. 
     
     
         6 . The antibody or fragment of  claim 1 , comprising a VL domain that comprises an amino acid sequence of SEQ ID NO: 370, or comprise SEQ ID NO: 370. 
     
     
         7 . The antibody or fragment of  claim 1  comprising lambda light chain variable domains. 
     
     
         8 . The antibody or fragment of  claim 1 , comprising a VH domain which comprises a HCDR1 sequence selected from the group consisting of the HCDR1 of:
 i. 1C02, and wherein the antibody or fragment competes with 1C02 for binding to said hLIGHT;   ii. 13H04, and wherein the antibody or fragment competes with 13H04 for binding to said hLIGHT; and   iii. 31A10, and wherein the antibody or fragment competes with 31A10 for binding to said hLIGHT.   
     
     
         9 . The antibody or fragment of  claim 1 , comprising a VH domain which comprises a HCDR2 sequence selected from the group consisting of the HCDR2 of:
 i. 1C02, and wherein the antibody or fragment competes with 1C02 for binding to said hLIGHT;   ii. 13H04, and wherein the antibody or fragment competes with 13H04 for binding to said hLIGHT; and   iii. 31A10, and wherein the antibody or fragment competes with 31A10 for binding to said hLIGHT.   
     
     
         10 . The antibody or fragment of  claim 1 , comprising a VH domain which comprises a HCDR3 sequence selected from the group consisting of the HCDR3 of:
 i. 1C02, and wherein the antibody or fragment competes with 1C02 for binding to said hLIGHT;   ii. 13H04, and wherein the antibody or fragment competes with 13H04 for binding to said hLIGHT; and   iii. 31A10, and wherein the antibody or fragment competes with 31A10 for binding to said hLIGHT.   
     
     
         11 . The antibody or fragment of  claim 1 , comprising a VH domain which comprises:
 i. The CDR1, 2 and 3 sequences recited in (a) of  claims 8 - 10 , and wherein the antibody or fragment competes with 1C02 for binding to said hLIGHT;   ii. The CDR1, 2 and 3 sequences recited in (a) of  claims 8 - 10 , and wherein the antibody or fragment competes with 13H04 for binding to said hLIGHT; or   iii. The CDR1, 2 and 3 sequences recited in (a) of  claims 8 - 10 , and wherein the antibody or fragment competes with 31A10 for binding to said hLIGHT.   
     
     
         12 . The antibody or fragment of  claim 1 , comprising a VL domain which comprises a LCDR1 sequence selected from the group consisting of the LCDR1 of:
 i. 1C02, and wherein the antibody or fragment competes with 1C02 for binding to said hLIGHT;   ii. 13H04, and wherein the antibody or fragment competes with 13H04 for binding to said hLIGHT; and   iii. 31A10, and wherein the antibody or fragment competes with 31A10 for binding to said hLIGHT.   
     
     
         13 . The antibody or fragment of  claim 1 , comprising a VL domain which comprises a LCDR2 sequence selected from the group consisting of the LCDR2 of:
 i. 1C02, and wherein the antibody or fragment competes with 1C02 for binding to said hLIGHT;   ii. 13H04, and wherein the antibody or fragment competes with 13H04 for binding to said hLIGHT; and   iii. 31A10, and wherein the antibody or fragment competes with 31A10 for binding to said hLIGHT.   
     
     
         14 . The antibody or fragment of  claim 1 , comprising a VL domain which comprises a LCDR3 sequence selected from the group consisting of the LCDR3 of:
 i. 1C02, and wherein the antibody or fragment competes with 1C02 for binding to said hLIGHT;   ii. 13H04, and wherein the antibody or fragment competes with 13H04 for binding to said hLIGHT; and   iii. 31A10, and wherein the antibody or fragment competes with 31A10 for binding to said hLIGHT.   
     
     
         15 . The antibody or fragment of  claim 1 , comprising a VL domain which comprises:
 i. The CDR1, 2 and 3 sequences recited in (a) of  claims 12 - 14 , and wherein the antibody or fragment competes with 1C02 for binding to said hLIGHT;   ii. The CDR1, 2 and 3 sequences recited in (a) of  claims 12 - 14 , and wherein the antibody or fragment competes with 13H04 for binding to said hLIGHT; or   iii. The CDR1, 2 and 3 sequences recited in (a) of  claims 12 - 14 , and wherein the antibody or fragment competes with 31A10 for binding to said hLIGHT.   
     
     
         16 . The antibody or fragment of  claim 1 , wherein the antibody or fragment competes with mAb664 for binding to 214E hLIGHT. 
     
     
         17 . The antibody or fragment of  claim 1 , wherein the hLIGHT is human cell surface-expressed hLIGHT. 
     
     
         18 . The antibody or fragment of  claim 1 , wherein the antibody or fragment decreases IL-8 secretion from human epithelial cells expressing a receptor for 214E hLIGHT in vitro. 
     
     
         19 . The antibody or fragment of  claim 18 , wherein the cells are primary cells. 
     
     
         20 . The antibody or fragment of  claim 1 , wherein the antibody or fragment specifically binds SEQ ID NO: 423 and SEQ ID NO: 308, wherein binding affinity to human LIGHT extracellular protein is at least the affinity of binding to rabbit LIGHT extracellular protein. 
     
     
         21 . The antibody or fragment of  claim 1 , wherein the antibody or fragment inhibits binding of 214E hLIGHT to a human HVEM and/or human lymphotoxin β receptor with an IC50 of 1×10 −8  or less in a HTRF assay. 
     
     
         22 . A pharmaceutical composition comprising the antibody or fragment of  claim 1  and a diluent, excipient or carrier; and optionally further comprising an anti-inflammatory drug. 
     
     
         23 . A kit comprising the antibody or fragment of  claim 1  and means for genotyping a human as positive or negative for a nucleotide sequence encoding 214E hLIGHT polypeptide and/or means for phenotyping a human as positive or negative for a 214E hLIGHT polypeptide. 
     
     
         24 . A kit comprising the antibody or fragment of  claim 1  and means for genotyping a human as positive or negative for a nucleotide sequence encoding 214K hLIGHT polypeptide and/or means for phenotyping a human as positive or negative for a 214K hLIGHT polypeptide. 
     
     
         25 . An isolated nucleic acid that encodes the HCDR3 of the antibody recited in  claim 1 . 
     
     
         26 . The isolated nucleic acid of  claim 25  comprising a nucleotide sequence that is at least 95% identical, or 100% identical, to a sequence selected from SEQ ID NOs: 375, 376, 147, 153, 7 and 13. 
     
     
         27 . An isolated nucleic acid that encodes the VH domain and/or a VL domain, or encodes a heavy chain or a LIGHT chain, of an antibody recited in  claim 1 . 
     
     
         28 . The isolated nucleic acid of  claim 27  comprising a nucleotide sequence that is at least 95% identical, to a sequence selected from SEQ ID NOs: 367, 1 and 141. 
     
     
         29 . The isolated nucleic acid of  claim 27  comprising a nucleotide sequence that is at least 95% identical to a sequence selected from SEQ ID NOs: 369, 15 and 155. 
     
     
         30 . A vector comprising the isolated nucleic acid of  claim 25 . 
     
     
         31 . A host cell comprising the isolated nucleic acid of  claim 25 . 
     
     
         32 . A method of treating or preventing a human lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (hLIGHT)-mediated disease or condition in a human by decreasing one, more or all of:
 i. the secretion of a cytokine selected from IL-2, TNF alpha and interferon gamma in the human;   ii. the proliferation of leukocytes of the human; and   iii. the binding of hLIGHT by human epithelial cells expressing a receptor for hLIGHT;
 wherein the method comprises administering to said human a therapeutically effective amount of an antibody or fragment that specifically binds to hLIGHT, wherein the antibody or fragment is according to  claim 1 . 
   
     
     
         33 . The method  claim 32 , wherein the human has been genotyped as positive for a nucleotide sequence encoding 214E hLIGHT polypeptide and/or wherein the human has been phenotyped as positive for a 214E hLIGHT polypeptide. 
     
     
         34 . The method of  claim 32 , wherein the disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogeneic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjogren's syndrome and airway inflammation.