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US 10,377,805 B2Granted
Modified FGF-21 polypeptides comprising non-naturally encoding amino acids and their uses
AssigneeAmbrx, Inc.
InventorsThomas P. Cujec, Roberto Mariani, Anna-Maria A. Hays Putnam, William M. Keefe, Nick Knudsen, Lillian Skidmore, Jason Pinkstaff, Vadim Kraynov
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Abstract
Modified FGF-21 polypeptides and uses thereof are provided.
Claims21
A composition comprising a pharmaceutically acceptable carrier and a modified FGF-21 polypeptide comprising a non-naturally encoded amino acid, wherein:
- (a) the modified FGF-21 polypeptide comprises a sequence at least 90% identical to SEQ ID NO:
- 1, SEQ ID NO:
- 2, SEQ ID NO:
- 3, SEQ ID NO:
- 4, SEQ ID NO:
- 5, SEQ ID NO:
- 6, or SEQ ID NO:
- 7;
- (b) the non-naturally encoded amino acid has the structure:
- wherein the R group is any substituent other than the side chain found in alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, pyrrolysine, or selenocysteine;
- (c) the modified FGF-21 polypeptide contains a substitution of an amino acid with the non-naturally encoded amino acid at position 108 of SEQ ID NO:
- 1 or the corresponding amino acid position in SEQ ID NO:
- 2, SEQ ID NO:
- 3, SEQ ID NO:
- 4, SEQ ID NO:
- 5, SEQ ID NO:
- 6, or SEQ ID NO:
- 7;
- (d) the modified FGF-21 polypeptide maintains the biological activity of human FGF-21 polypeptides;
- (e) the non-naturally encoded amino acid is linked to a linker, polymer, or biologically active molecule;
- and
- (f) the modified FGF-21 polypeptide has an in vivo half-life at least two-fold greater than the human FGF-21 polypeptide of SEQ ID NO:
- 1.
20 more elements
A composition comprising a pharmaceutically acceptable carrier and a modified FGF-21 polypeptide comprising a non-naturally encoded amino acid, wherein:
- (a) the modified FGF-21 polypeptide comprises a sequence at least 95% identical to SEQ ID NO:
- 1, SEQ ID NO:
- 2, SEQ ID NO:
- 3, SEQ ID NO:
- 4, SEQ ID NO:
- 5, SEQ ID NO:
- 6, or SEQ ID NO:
- 7;
- (b) the non-naturally encoded amino acid has the structure:
- wherein the R group is any substituent other than the side chain found in alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, pyrrolysine, or selenocysteine;
- (c) the modified FGF-21 polypeptide contains a substitution of an amino acid with the non-naturally encoded amino acid at a position corresponding to residue 72, 77, 86, 108, 110, 131, or 146 of SEQ ID NO:
- 1 or the corresponding amino acid position in SEQ ID NO:
- 2, SEQ ID NO:
- 3, SEQ ID NO:
- 4, SEQ ID NO:
- 5, SEQ ID NO:
- 6, or SEQ ID NO:
- 7;
- (d) the modified FGF-21 polypeptide maintains the biological activity of human FGF-21 polypeptides;
- (e) the non-naturally encoded amino acid is linked to a linker, polymer, or biologically active molecule;
- and
- (f) the modified FGF-21 polypeptide has an in vivo half-life at least two-fold greater than the human FGF-21 polypeptide of SEQ ID NO:
- 1.
20 more elements
A composition comprising a pharmaceutically acceptable carrier and a modified FGF-21 polypeptide, wherein:
- (a) said modified FGF-21 polypeptide comprises the polypeptide of SEQ ID NO:1 except that an amino acid in the modified FGF-21 polypeptide is substituted by a non-naturally encoded amino acid at position 108 of SEQ ID NO:
- 1:
- (b) said non-naturally encoded amino acid comprises para-acetyl phenylalanine linked to a polymer comprising a poly(ethylene glycol), wherein said poly(ethylene glycol) has an average molecular weight of about 30 kDa;
- and
- (c) said non-naturally encoded amino acid is linked to said polymer through an oxime linkage.
2 more elements
Dependencies are inferred from the claim text.