Antibodies that Bind and Block Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1)

Abstract

The invention relates to antibodies that are capable of specifically binding TREM-1 and preventing the activation of TREM-1, a protein expressed on monocytes, macrophages and neutrophils. Such antibodies find utility in the treatment of individuals with an inflammatory disease, such as rheumatoid arthritis and inflammatory bowel disease.

1 . An antibody or fragment thereof that is capable of specifically binding to and blocking TREM-1. 
     
     
         2 . The antibody or fragment thereof according to  claim 1 , which is capable of blocking PGLYRP1-induced activation of TREM-1. 
     
     
         3 . The antibody or fragment thereof according to  claim 1 , which competes with mAb 0170 for binding to SEQ ID NO: 1 (human TREM-1). 
     
     
         4 . The antibody or fragment thereof according to  claim 1 , which competes with mAb 0170 for binding to SEQ ID NO: 12 or SEQ ID NO: 21 (cynomolgus monkey TREM-1). 
     
     
         5 . The antibody or fragment thereof according to  claim 1 , which is capable of specifically binding a polypeptide comprising amino acids D38 to F48 of SEQ ID NO: 1 (human TREM-1). 
     
     
         6 . The antibody or fragment thereof according to  claim 1 , which is capable of specifically binding a polypeptide comprising amino acid residues E19 to L26 of SEQ ID NO: 12 (cynomolgus monkey TREM-1). 
     
     
         7 . The antibody or fragment thereof according to  claim 1 , which has an epitope comprising one, two, three, four, five, six, seven or all of the amino acid residues D38, V39, K40, C41, D42, Y43, T44 and L45 and one, two or all of the amino acid residues E46, K47, F48 of SEQ ID NO: 1 (human TREM-1). 
     
     
         8 . The antibody or fragment thereof according to  claim 1  which has an epitope comprising one, two, three or all of the amino acid residues D42, E46, D92 and H93 of SEQ ID NO: 1 (human TREM-1). 
     
     
         9 . The antibody or fragment thereof according to  claim 7 , which has an epitope further comprising one, two or all of the amino acid residues L31, 186 and V101 of SEQ ID NO: 1 (human TREM-1). 
     
     
         10 . The antibody according to  claim 1 , which is capable of specifically binding SEQ ID NO: 13 (K20A-hTREM-1-Cmyc2-His6). 
     
     
         11 . The antibody according to  claim 1 , which is capable of specifically binding SEQ ID NO: 14 (A24T/Y28F/N305/R32Q/P70H-cTREM-1-Cmyc2-His6). 
     
     
         12 . The antibody according to  claim 1 , which is capable of specifically binding SEQ ID NO: 15 (A24T/Y28F/N305/R32Q/E54K-cTREM-1-Cmyc2-His6). 
     
     
         13 . The antibody according to  claim 1 , the heavy chain of which comprises a CDRH1 sequence corresponding to amino acid residues 31 to 35 (TYAMH) of SEQ ID NO: 4 or SEQ ID NO: 6, wherein one of these amino acid residues may be substituted by a different amino acid residue; and/or a CDRH2 sequence corresponding to amino acids 50 to 68 (RIRTKSSNYATYYAASVKG) of SEQ ID NO: 4 or SEQ ID NO: 6, wherein one, two or three of said amino acids may be substituted with a different amino acid residue; and/or a CDRH3 sequence corresponding to amino acid residues 101 to 110 (DMGIRRQFAY) of SEQ ID NO: 4 or amino acid residues 101 to 110 (DMGQRRQFAY) of SEQ ID NO: 6, wherein one, two or three of said amino acid residues may be substituted by a different amino acid; and the light chain of which comprises a CDRL1 sequence corresponding to amino acid residues 24 to 38 (RASESVDTFDYSFLH) of SEQ ID NO: 5 or SEQ ID NO: 7, wherein one, two or three of these amino acid residues may be substituted with a different amino acid; and/or a CDRL2 sequence corresponding to amino acid residues 54 to 60 (RASNLES) of SEQ ID NO: 5 or SEQ ID NO: 7, wherein one or two of these amino acid residues may be substituted with a different amino acid; and/or a CDRL3 sequence corresponding to amino acid residues 93 to 101 (QQSNEDPYT) of SEQ ID NO: 5 or SEQ ID NO: 7, wherein one or two of these amino acid residues may be substituted with a different amino acid. 
     
     
         14 . The antibody according to  claim 13 , the heavy chain of which comprises a CDRH1 sequence corresponding to amino acid residues 31 to 35 (TYAMH) of SEQ ID NO: 4 or SEQ ID NO: 6; and/or a CDRH2 sequence corresponding to amino acids 50 to 68 (RIRTKSSNYATYYAASVKG) of SEQ ID NO: 4 or SEQ ID NO: 6; and/or a CDRH3 sequence corresponding to amino acid residues 101 to 110 (DMGIRRQFAY) of SEQ ID NO: 4 or amino acid residues 101 to 110 (DMGQRRQFAY) of SEQ ID NO: 6; and the light chain of which comprises a CDRL1 sequence corresponding to amino acid residues 24 to 38 (RASESVDTFDYSFLH) of SEQ ID NO: 5 or SEQ ID NO: 7; and/or a CDRL2 sequence corresponding to amino acid residues 54 to 60 (RASNLES) of SEQ ID NO: 5 or SEQ ID NO: 7; and/or a CDRL3 sequence corresponding to amino acid residues 93 to 101 (QQSNEDPYT) of SEQ ID NO: 5 or SEQ ID NO: 7. 
     
     
         15 . The antibody or fragment thereof according to  claim 1  for use as a medicament. 
     
     
         16 . The antibody or fragment thereof according to  claim 8 , which has an epitope further comprising one, two or all of the amino acid residues L31, 186 and V101 of SEQ ID NO: 1 (human TREM-1).