Methods of treatment using modified FGF-21 polypeptides comprising non-naturally occurring amino acids
AssigneeAmbrx, Inc.
InventorsThomas P. Cujec, Roberto Mariani, Anna-Maria A. Hays Putnam, Wiliam M. Keefe, Nick Knudsen, Lillian Skidmore, Jason Pinkstaff, Vadim Kraynov
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Abstract
Modified FGF-21 polypeptides and uses thereof are provided.
Claims20
A method of treating a patient in need thereof, comprising administering an effective amount of a modified FGF-21 polypeptide to said patient, wherein said modified FGF-21 polypeptide maintains the biological activity of human FGF-21 polypeptides and comprises a non-naturally encoded amino acid, wherein:
- (a) the 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 polypeptide contains a substitution of an amino acid with the non-naturally encoded amino acid at a position in said modified FGF-21 polypeptide corresponding to residue 72, 77, 86, 108, 110, 131, or 146 of SEQ ID NO:
- 1;
- (d) the non-naturally encoded amino acid is linked to a linker, polymer, or biologically active molecule;
- and
- (e) the polypeptide has an in vivo half-life at least two-fold greater than the human FGF-21 polypeptide in SEQ ID NO:
- 1.
A method of treating a patient in need thereof, comprising administering an effective amount of a modified FGF-21 polypeptide to said patient, wherein said modified FGF-21 polypeptide maintains the biological activity of human FGF-21 polypeptides and comprises the polypeptide of SEQ ID NO:1 except that an amino acid in the polypeptide is substituted by a non-naturally encoded amino acid, wherein:
- (a) said non-naturally encoded amino acid is at a position corresponding to residue 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.
A method of treating a patient in need thereof, comprising administering an effective amount of a modified FGF-21 polypeptide to said patient, wherein said modified FGF-21 polypeptide maintains the biological activity of human FGF-21 polypeptides and comprises a non-naturally encoded amino acid, wherein:
- (a) the 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 polypeptide contains a substitution of an amino acid with the non-naturally encoded amino acid at a position in said modified FGF-21 polypeptide corresponding to residue 72, 77, 86, 108, 110, 131, or 146 of SEQ ID NO:
- 1;
- (d) the non-naturally encoded amino acid is linked to a linker, polymer, or biologically active molecule;
- and
- (e) the polypeptide has an in vivo half-life at least two-fold greater than the human FGF-21 polypeptide in SEQ ID NO:
- 1.
Dependencies are inferred from the claim text.