Physiologically active protein originating in mammals

Abstract

The present invention provides novel physiologically active protein molecules originating in mammals, which are specifically expressed in arteriosclerosis and/or coronary restenosis, and are predicted to relate closely to the onset and progress of these diseases; DNAs encoding the protein molecules; antibodies reactive with the molecules; and pharmaceutical compositions comprising the above protein molecule or the antibody. The protein molecules, DNAs, and antibodies are useful for treating and preventing arteriosclerosis.

1 . A DNA encoding a protein having the amino acid sequence of SEQ ID NO: 4.  
     
     
         2 . A DNA encoding a protein fragment comprising the extracellular region of a protein having the amino acid sequence of SEQ ID NO: 4.  
     
     
         3 . A DNA comprising a nucleotide sequence corresponding to nucleotide residues 97 to 1419 of the nucleotide sequence of SeQ ID NO: 3.  
     
     
         4 . A DNA hybridizing with a DNA having the nucleotide sequence of SEQ ID NO: 3 under stringent conditions.  
     
     
         5 . A protein having the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence substantially the same as said amino acid sequence.  
     
     
         6 . A protein fragment comprising the extracellular region of a protein having the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence substantially the same as said amino acid sequence.  
     
     
         7 . A fusion protein between the extracellular region of the protein of  claim 5  and the constant region of the heavy chain of human immunoglobulin (Ig) or a portion of the constant region.  
     
     
         8 . An expression vector comprising the DNA of any one of  claims 1  to  4 .  
     
     
         9 . A transformant carrying the expression vector of  claim 8 .  
     
     
         10 . An antibody or its portion reactive with the protein of  claim 5  or the protein fragment of  claim 6 .  
     
     
         11 . The antibody or its portion of  claim 10 , wherein the antibody is a monoclonal antibody.  
     
     
         12 . A pharmaceutical composition comprising the protein fragment of  claim 6  or the fusion protein of  claim 7  and a pharmaceutically acceptable carrier.  
     
     
         13 . A pharmaceutical composition comprising the antibody or its portion of  claim 10  or  11  and a pharmaceutically acceptable carrier.  
     
     
         14 . A DNA encoding a protein having the amino acid sequence of SEQ ID NO: 10.  
     
     
         15 . A DNA encoding a protein fragment comprising the extracellular region of a protein having the amino acid sequence of SEQ ID NO: 10.  
     
     
         16 . A DNA having a nucleotide sequence corresponding to nucleotide residues 1 to 1785 of the nucleotide sequence of SEQ ID NO: 9.  
     
     
         17 . A DNA hybridizing with a DNA having the nucleotide sequence of SEQ ID NO: 9 under stringent conditions.  
     
     
         18 . A protein having the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence substantially the same as said amino acid sequence.  
     
     
         19 . A protein fragment comprising the extracellular region of a protein having the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence substantially the same as said amino acid sequence.  
     
     
         20 . A fusion protein comprising the extracellular region of the protein of  claim 18  and the constant region of the heavy chain of human immunoglobulin (Ig) or a portion of the constant region.  
     
     
         21 . An expression vector comprising the DNA of any one of  claims 14  to  17 .  
     
     
         22 . A transformant carrying the expression vector of  claim 21 .  
     
     
         23 . An antibody or its portion reactive with the protein of  claim 18  or the protein fragment of  claim 19 .  
     
     
         24 . The antibody or its portion of  claim 23 , wherein the antibody is a monoclonal antibody.  
     
     
         25 . A pharmaceutical composition comprising the protein fragment of  claim 19  or the fusion protein of  claim 20  and a pharmaceutically acceptable carrier.  
     
     
         26 . A pharmaceutical composition comprising the antibody or its portion of  claim 23  or  24  and a pharmaceutically acceptable carrier.  
     
     
         27 . A transgenic mouse in which the human-derived DNA comprising a DNA having a nucleotide sequence corresponding to nucleotide residues 97 to 1419 of the nucleotide sequence of SEQ ID NO: 3 is integrated into an endogenous gene of said mouse.  
     
     
         28 . A transgenic mouse in which the human-derived DNA comprising a DNA having a nucleotide sequence corresponding to nucleotide residues 1 to 1785 of the nucleotide sequence of SEQ ID NO: 9 is integrated into an endogenous gene of said mouse.  
     
     
         29 . A knockout mouse whose endogenous gene encoding a mouse-derived protein having the amino acid sequence of SEQ ID NO: 6 is inactivated so that said protein is not produced.  
     
     
         30 . A knockout mouse whose endogenous gene encoding a mouse-derived protein comprising the amino acid sequence of SEQ ID NO: 28 is inactivated so that said protein is not produced.