Klotho variant polypeptides
View Patent ↗Disclosed are Klotho variant proteins in which residue Glu414 and/or residue Asp238 is substituted with an amino acid different than L-Glu or L-Asp, respectively, as well as polynucleotides encoding the variant proteins, and the use thereof in therapy, especially for the treatment of cancers, especially breast cancer and pancreatic cancer.
1. An isolated polypeptide comprising an amino-acid residue sequence selected from the group consisting of:
SEQ ID NO: 1 or a sequence at least 95% identical thereto;
residues 29-1012 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 1-980 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 29-980 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 1-568 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 29-568 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 34-549 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
SEQ ID NO:8 or a sequence at least 95% identical thereto;
residues 29-549 of SEQ ID NO:8 or a sequence at least 95% identical thereto; and
residues 34-549 of SEQ ID NO:8 or a sequence at least 95% identical thereto,
wherein:
the L-Glu of residue 414 is substituted with L-α-Gln.
2. An isolated polypeptide comprising a Klotho amino acid sequence selected from the group consisting of:
SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 29-1012 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 1-980 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 29-980 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 1-568 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 29-568 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
residues 34-549 of SEQ ID NO:1 or a sequence at least 95% identical thereto;
SEQ ID NO:8 or a sequence at least 95% identical thereto;
residues 29-549 of SEQ ID NO:8 or a sequence at least 95% identical thereto; and
residues 34-549 of SEQ ID NO:8 or a sequence at least 95% identical thereto,
and having at least one amino acid mutation in the catalytic domain of Klotho, wherein the isolated polypeptide inhibits IGF-1 signaling when expressed in MCF-7 cells in vitro, wherein said amino acid mutation is an amino acid substitution selected from the group consisting of Glu414Gln and Asp238Asn.