Novel Angiogenesis Inhibitor

Abstract

Because AK022567 has angiogenesis inhibitory activity, it is useful as an angiogenesis inhibitor. Furthermore, 4 splicing variants obtained from the same gene are also useful as an angiogenesis inhibitor. These 5 polypeptides, polynucleotides encoding the polypeptides and antibodies against the polypeptides are useful for screening of a candidate compound as an angiogenesis inhibitor or promoter. A compound obtained from the screening is useful as a medicine and can be used for a preventive or therapeutic agent for an angiogenesis related disease.

1 . An angiogenesis inhibitor comprising
 a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10,   a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having a deletion, substitution or addition of one or several amino acid residue(s) and angiogenesis inhibitory activity,   a protein or polypeptide that has an amino acid sequence that is a portion of an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having angiogenesis inhibitory activity,   
       or a salt thereof. 
     
     
         2 . An expression vector, comprising
 a polynucleotide which encodes:   a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10,   a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having a deletion, substitution or addition of one or several amino acid residue(s) and having angiogenesis inhibitory activity,   or a protein or polypeptide that has an amino acid sequence that is a portion of an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having angiogenesis inhibitory activity.   
     
     
         3 . An expression vector for inhibiting angiogenesis, comprising a polynucleotide hybridizing under a stringent condition with a polynucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, 3, 5, 7 and 9,
 that encodes a polypeptide having angiogenesis inhibitory activity.   
     
     
         4 . An angiogenesis promoter comprising a neutralizing antibody that specifically binds to a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10,
 a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having a deletion, substitution or addition of one or several amino acid residue(s) and having angiogenesis inhibitory activity,   a protein or polypeptide that has an amino acid sequence that is a portion of an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having angiogenesis inhibitory activity,   or a salt thereof.   
     
     
         5 . A method for screening a compound for activity as an angiogenesis inhibitor, comprising contacting a compound or a salt thereof, with:
 a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10,   a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having a deletion, substitution or addition of one or several amino acid residue(s) and having angiogenesis inhibitory activity,   a protein or polypeptide that has an amino acid sequence that is a portion of an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having angiogenesis inhibitory activity,   or a salt thereof,   comparing the angiogenesis inhibitory activity of said protein or polypeptide in the presence of said compound or salt of said compound with the angiogenesis inhibitory activity of said protein or polypeptide in the absence of said compound or salt of said compound, and   selecting as an angiogenesis inhibitor a compound or salt of said compound that increases the angiogenesis inhibitory activity of said protein or polypeptide.   
     
     
         6 . A method for screening a compound for activity as an angiogenesis inhibitor, comprising measuring the expression of a gene encoding:
 a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10,   a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having a deletion, substitution or addition of one or several amino acid residue(s) and having angiogenesis inhibitory activity,   or a protein or polypeptide that has an amino acid sequence that is a portion of an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having angiogenesis inhibitory activity   in a cell in the presence and in the absence of said compound or of a salt of said compound, and   selecting as an angiogenesis inhibitor a compound or a salt of said compound for which expression of said gene is higher in the presence of said compound or salt than in the absence of said compound or salt.   
     
     
         7 . A method for screening a compound for activity as an angiogenesis promoter, comprising contacting:
 a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10,   a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having a deletion, substitution or addition of one or several amino acid residue(s) and having angiogenesis inhibitory activity,   a protein or polypeptide that has an amino acid sequence that is a portion of an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having angiogenesis inhibitory activity,   or a salt thereof,   comparing the angiogenesis inhibitory activity of said protein or polypeptide in the presence of said compound or salt of said compound with the angiogenesis inhibitory activity of said protein or polypeptide in the absence of said compound or salt of said compound, and   selecting as an angiogenesis inhibitor a compound or salt of said compound that decreases the angiogenesis inhibitory activity of said protein or polypeptide.   
     
     
         8 . A method for screening a compound for activity as an angiogenesis promoter, comprising measuring the expression of a gene encoding:
 a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10,   a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having a deletion, substitution or addition of one or several amino acid residue(s) and having angiogenesis inhibitory activity, or   a protein or polypeptide that has an amino acid sequence that is a portion of an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having angiogenesis inhibitory activity   in a cell in the presence and in the absence of said compound or of a salt of said compound, and   selecting as an angiogenesis inhibitor a compound or a salt of said compound for which expression of said gene is lower in the presence of said compound or salt than in the absence of said compound or salt.   
     
     
         9 . A kit for the method for screening of  claim 5  or  claim 7 , comprising:
 a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10,   a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having a deletion, substitution or addition of one or several amino acid residue(s) and having angiogenesis inhibitory activity,   a partial peptide thereof having angiogenesis inhibitory activity,   or a salt thereof.   
     
     
         10 . A kit for the method for screening of  claim 6  or  claim 8 , comprising:
 a polynucleotide which encodes a protein having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10,   a polynucleotide that hybridizes under a stringent condition to a polynucleotide selected from the group consisting of SEQ ID NO: 1, 3, 5, 7 and 9, or   a polynucleotide that encodes a protein or polypeptide that has an amino acid sequence that is a portion of an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8 and 10 and having angiogenesis inhibitory activity.