Anti-cd14 antibody fusion protein

Abstract

A protein comprising (I) an anti-CD14 antibody or its active fragment, or a derivative thereof and (II) an inhibitor for a protease, or its active fragment, or a derivative thereof is provided.

1 . A fusion protein comprising:
 (I) an anti-CD14 antibody or its CD14 binding fragment, wherein said antibody or the fragment has an antigen binding activity and an inhibitory activity for LPS-induced IL-6 production in a TLR expressing cell and   (II) an inhibitor for a protease consisting of any one of an amino acid sequence selected from the group consisting of the amino acid sequences of the mutant UTI domain 2 of SEQ ID NOS: 27-106.   
     
     
         2 . A fusion protein comprising:
 (I) an anti-CD14 antibody or its CD14 binding fragment, wherein said antibody or the fragment has an antigen binding activity and an inhibitory activity for LPS-induced IL-6 production in a TLR expressing cell, and   (II) an inhibitor for a protease selected from a mutant of 4 amino acid substitutions (hereinafter referred to “UTI-D2(4)”) (R11S/R15I/Q19K/Y46D) represented by the amino acid sequence of SEQ ID NO:46,   UTI-D2(4) (R11S/R15L/Q19K/Y46D) represented by the amino acid sequence of SEQ ID NO: 47,   UTI-D2(4) (R11S/R15T/Q19/Y46D) represented by the amino acid sequence of SEQ ID NO: 48, or   UTI-D2 (4) (R11S/R15V/Q19K/Y46D) represented by the amino acid sequence of SEQ ID NO: 49.   
     
     
         3 . The fusion protein according to  claim 1 , wherein the protein has an inhibitory activity for LPS-induced IL-6 production in a TLR expressing cell, and an anti-inflammatory action or an inhibitory action for inflammatory protease. 
     
     
         4 . The fusion protein according to  claim 1 , wherein the protein has an elastase inhibitory action or TNF-α production inhibitory action. 
     
     
         5 . The fusion protein according to  claim 1 , wherein said fusion protein has the action of inhibiting the binding between CD14 and the TLR. 
     
     
         6 . The fusion protein according to  claim 1 , wherein said anti-CD14 antibody or its CD14 binding fragment in (I) has the action of inhibiting the binding between CD14 and the TLR. 
     
     
         7 . The fusion protein according to  claim 1 , wherein the anti CD14 antibody or its CD14 binding fragment in (I) recognizes at least a part of the region represented by from 269th to 315th amino acid residues of the amino acid sequence of human CD14. 
     
     
         8 . The fusion protein according to  claim 1 , wherein the anti CD14 antibody or its CD14 binding fragment in (I) recognizes at least a part of the region represented by from 294th to 296th amino acid residues of the amino acid sequence of human CD14. 
     
     
         9 . The fusion protein according to  claim 1 , wherein the anti CD14 antibody or its CD14 binding fragment in (I) comprises CDR1 consisting of SEQ ID NO: 173, CDR2 consisting of SEQ ID NO: 174, and CDR3 consisting of SEQ ID NO: 175 of the heavy chain as the CDR1, CDR2, and CDR3 in the heavy chain variable region, and
 CDR1 consisting of SEQ ID NO: 176, CDR2 consisting of SEQ ID NO: 177, CDR3 consisting of SEQ ID NO: 178 of the light chain as the CDR1, CDR2, and CDR3 in the light chain variable region.   
     
     
         10 . The fusion protein according to  claim 1 , wherein the anti-CD14 antibody or its CD14 binding fragment in (I) a chimeric antibody. 
     
     
         11 . The fusion protein according to  claim 1 , wherein the anti-CD14 antibody or its CD14 binding fragment in (I) is a humanized antibody. 
     
     
         12 . The fusion protein according to  claim 1 , wherein the anti-CD14 antibody or its CD14 binding fragment in (I) is monovalent. 
     
     
         13 . The fusion protein according to  claim 1 , wherein the anti-CD14 antibody or its CD14 binding fragment in (I) is divalent. 
     
     
         14 . The fusion protein according to  claim 1 , wherein the protease inhibitor in (II) is fused to the C terminal side of the heavy chain of an anti-CD14 antibody or its CD14 binding fragment in (I). 
     
     
         15 . A pharmaceutical composition comprising the fusion protein of  claim 1  as an active ingredient and a pharmaceutically acceptable additive. 
     
     
         16 . The pharmaceutical composition according to  claim 15  for sepsis, severe sepsis, septic ARDS, septic shock, SIRS related disease, endotoxin shock or ARDS. 
     
     
         17 . A therapeutic agent comprising the fusion protein of  claim 1  for sepsis, severe sepsis, septic ARDS, septic shock, SIRS related disease, endotoxin shock or ARDS.