Chimeric polypeptides and uses thereof

Abstract

The disclosure provides nucleic acid molecules encoding chimeric polypeptides, chimeric polypeptides, pharmaceutical compositions comprising chimeric polypeptides, and methods for treating metabolic disorders such as diabetes and obesity using such nucleic acids, polypeptides, or pharmaceutical compositions.

What is claimed is: 
     
         1 . A chimeric polypeptide comprising a wild type mature FGF19 polypeptide scaffold comprising SEQ ID NO:4, further comprising a modification that decreases FGFR4-mediated signaling activity. 
     
     
         2 . The chimeric polypeptide of  claim 1 , wherein the modification comprises substituting one or more of the residues WGDPI at positions 16-20 of the FGF19 polypeptide scaffold with (a) no amino acid; or (b) an amino acid other than the amino acid located at the position in the wild type amino acid sequence. 
     
     
         3 . The chimeric polypeptide of  claim 2 , wherein the tryptophan residue of the WGDPI sequence is deleted. 
     
     
         4 . The chimeric polypeptide of  claim 2 , wherein the residues WGDPI are substituted with 1-5 contiguous residues present in a wild type FGF21 or a wild type FGF23 amino acid sequence. 
     
     
         5 . The chimeric polypeptide of  claim 4 , wherein the 1-5 contiguous residues are present in a wild type FGF21 amino acid sequence. 
     
     
         6 . The chimeric polypeptide of  claim 5 , wherein the 1-5 contiguous residues are GQV. 
     
     
         7 . The chimeric polypeptide of  claim 1 , wherein the modification comprises substituting one or more of the residues SGPHGLSS at positions 28-35 of the FGF19 polypeptide scaffold with (a) no amino acid; or (b) an amino acid other than the amino acid located at the position in the wild type amino acid sequence. 
     
     
         8 . The chimeric polypeptide of  claim 7 , wherein the residues SGPHGLSS are substituted with 1-8 contiguous residues present in a wild type FGF21 or a wild type FGF23 amino acid sequence. 
     
     
         9 . The chimeric polypeptide of  claim 8 , wherein the 1-8 contiguous residues are present in a wild type FGF21 amino acid sequence. 
     
     
         10 . The chimeric polypeptide of  claim 9 , wherein the 1-8 contiguous residues are DDAQQTE. 
     
     
         11 . The chimeric polypeptide of  claim 1 , wherein the modification comprises substituting one or more of the residues SSAKQRQLYKNRGFLPL at positions 124-140 of the FGF19 polypeptide scaffold with (a) no amino acid; or (b) an amino acid other than the amino acid located at the position in the wild type amino acid sequence. 
     
     
         12 . The chimeric polypeptide of  claim 11 , wherein the residues SSAKQRQLYKNRGFLPL are substituted with 1-17 contiguous residues present in either a wild type FGF21 or a wild type FGF23 amino acid sequence. 
     
     
         13 . The chimeric polypeptide of  claim 12 , wherein the 1-17 contiguous residues are present in a wild type FGF21 amino acid sequence. 
     
     
         14 . The chimeric polypeptide of  claim 13 , wherein the 1-17 contiguous residues are PGNKSPHRDPAPRGP. 
     
     
         15 . A chimeric polypeptide that exhibits decreased FGFR4-mediated signaling activity comprising a wild type FGF19 polypeptide scaffold comprising SEQ ID NO:4, wherein one or more of the residues WGDPI at positions 16-20 of SEQ ID NO:4 has been substituted with (a) no amino acid; or (b) an amino acid other than the amino acid located at the position in the wild type amino acid sequence; and one or both of:
 (i) one or more of the residues SGPHGLSS at positions 28-35 of SEQ ID NO:4 has been substituted with (1) no amino acid; or (2) an amino acid other than the amino acid located at the position in the wild type amino acid sequence; and   (ii) one or more of the residues SSAKQRQLYKNRGFLPL at positions 124-140 of SEQ ID NO:4 has been substituted with (1) no amino acid; or (2) an amino acid other than the amino acid located at the position in the wild type amino acid.   
     
     
         16 . The chimeric polypeptide of  claim 15 , wherein the tryptophan residue of the WGDPI sequence is deleted. 
     
     
         17 . The chimeric polypeptide of  claim 15 , wherein the residues WGDPI are substituted with 1-5 contiguous residues present in a wild type FGF21 or a wild type FGF23 amino acid sequence. 
     
     
         18 . The chimeric polypeptide of  claim 17 , wherein the 1-5 contiguous residues are present in wild type FGF21 amino acid sequence. 
     
     
         19 . The chimeric polypeptide of  claim 17 , wherein the 1-5 contiguous residues are GQV. 
     
     
         20 . The chimeric polypeptide of  claim 15 , wherein the residues SGPHGLSS are substituted with 1-8 contiguous residues present in a wild type FGF21 or a wild type FGF23 amino acid sequence. 
     
     
         21 . The chimeric polypeptide of  claim 20 , wherein the 1-8 contiguous residues are present in a wild type FGF21 amino acid sequence. 
     
     
         22 . The chimeric polypeptide of  claim 21 , wherein the 1-8 contiguous residues are DDAQQTE. 
     
     
         23 . The chimeric polypeptide of  claim 15 , wherein the residues SSAKQRQLYKNRGFLPL are substituted with 1-17 contiguous residues present in a wild type FGF21 or wild type FGF23 amino acid sequence. 
     
     
         24 . The chimeric polypeptide of  claim 23 , wherein the 1-17 contiguous residues are present in a wild type FGF21 amino acid sequence. 
     
     
         25 . The chimeric polypeptide of  claim 24 , wherein the 1-17 contiguous residues are PGNKSPHRDPAPRGP. 
     
     
         26 . The chimeric polypeptide of  claim 15 , wherein the residues WGDPI at positions 16-20 of SEQ ID NO:4 are substituted with GQV; and one or both of:
 (a) the residues SGPHGLSS at positions 28-35 of SEQ ID NO:4 are substituted with DDAQQTE; and   (b) the residues SSAKQRQLYKNRGFLPL at positions 124-140 of SEQ ID NO:4 are substituted with PGNKSPHRDPAPRGP.   
     
     
         27 . A nucleic acid molecule encoding the chimeric polypeptide of  claim 1  or  15 . 
     
     
         28 . A vector comprising the nucleic acid molecule of  claim 27 . 
     
     
         29 . A host cell comprising the nucleic acid molecule of  claim 27 . 
     
     
         30 . A pharmaceutical composition comprising the chimeric polypeptide of  claim 1  or  15  and a pharmaceutically acceptable carrier. 
     
     
         31 . A method of treating a metabolic disease selected from the group consisting of diabetes and obesity comprising administering to a human patient in need thereof the pharmaceutical composition of  claim 30 . 
     
     
         32 . An antigen binding protein that specifically binds to a chimeric polypeptide of  claim 1  or  15 . 
     
     
         33 . A chimeric fusion polypeptide comprising the chimeric polypeptide of  claim 1  or  15  fused to a heterogenous moiety. 
     
     
         34 . The chimeric fusion polypeptide of  claim 33 , wherein the heterogenous moiety is selected from the group consisting of an Fc region of an IgG molecule and a PEG molecule. 
     
     
         35 . The chimeric polypeptide of  claim 1  or  15 , wherein SEQ ID NO:4 is truncated on the N terminus by 1-15 amino acids, the C terminus by 1-15 amino acids, or on both the N terminus by 1-15 amino acids and the C terminus by 1-15 amino acids. 
     
     
         36 . The chimeric polypeptide of  claim 1  or  15 , which, except for the modification that decreases FGFR4-mediated signaling activity, comprises a polypeptide scaffold that is 95% or more identical to SEQ ID NO:4.