Relaxin polypeptides comprising non-naturally encoded amino acids
AssigneeAmbrx, Inc.
InventorsVadim Kraynov, Nick Knudsen, Ahma Hewet, Kristine De Dios, Jason Pinkstaff, Lorraine Sullivan
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Abstract
Modified relaxin polypeptides and their uses are provided. In one aspect, the disclosure provides a relaxin polypeptide comprising one or more non-naturally encoded amino acids. The polypeptide may be linked to a linker, polymer, or biologically active molecule. The serum half-life of the relaxin polypeptide may be enhanced relative to the unconjugated form. In another aspect, the disclosure provides methods of treating a patient having a disorder modulated by relaxin.
Claims58
A modified relaxin polypeptide comprising a non-naturally encoded amino acid, wherein:
- (a) the relaxin polypeptide comprises a relaxin A chain polypeptide and a relaxin B chain polypeptide, wherein said relaxin A chain polypeptide has a sequence at least 95% identical to SEQ ID NO:
- 4, and said relaxin B chain polypeptide has a sequence at least 95% identical to SEQ ID NO:
- 5 or SEQ ID NO:
- 6, and said non-naturally encoded amino acid is substituted in said A chain polypeptide at residue 1;
- and
- (b) the non-naturally encoded amino acid is linked to a linker, polymer, or biologically active molecule, wherein said non-naturally encoded amino acid comprises a first functional group and the linker, polymer, or biologically active molecule comprises a second functional group, wherein the first functional group and second functional group are not identical and each comprise a carbonyl group, an aminooxy group, a hydrazide group, a hydrazine group, a semicarbazide group, an azide group, or an alkyne group, and the resultant covalent linkage created by the reaction of the first and second functional groups comprises an oxime linkage or a triazole.
A modified relaxin polypeptide comprising a non-naturally encoded amino acid, wherein:
- (a) the relaxin polypeptide comprises the relaxin A chain polypeptide of SEQ ID NO:
- 4 and the relaxin B chain polypeptide of SEQ ID NO:
- 5 or SEQ ID NO:
- 6 which relaxin A and B chain polypeptide sequences contain up to two amino acid substitutions selected from substitution with natural or non-naturally encoded amino acids and further said relaxin A chain polypeptide is substituted with a non-naturally encoded amino acid at A chain residue 1;
- and
- (b) said non-naturally encoded amino acid at A chain residue 1 is linked to a linker, polymer, or biologically active molecule, wherein said non-naturally encoded amino acid comprises a first functional group and the linker, polymer, or biologically active molecule comprises a second functional group, wherein the first functional group and second functional group are not identical and each comprise a carbonyl group, an aminooxy group, a hydrazide group, a hydrazine group, a semicarbazide group, an azide group, or an alkyne group, and the resultant covalent linkage created by the reaction of the first and second functional groups comprises an oxime linkage or a triazole.
A modified relaxin polypeptide comprising a non-naturally encoded amino acid, wherein:
- (a) the relaxin polypeptide comprises the relaxin A chain polypeptide of SEQ ID NO:
- 4 and the relaxin B chain polypeptide of SEQ ID NO:
- 5 or SEQ ID NO:
- 6 which relaxin A and B chain polypeptide sequences each contain up to one natural amino acid substitution and further contain one non-naturally encoded amino acid substitution in said A chain polypeptide at residue 1;
- and
- (b) the non-naturally encoded amino acid is linked to a linker, polymer, or biologically active molecule, wherein said non-naturally encoded amino acid comprises a first functional group and the linker, polymer, or biologically active molecule comprises a second functional group, wherein the first functional group and second functional group are not identical and each comprise a carbonyl group, an aminooxy group, a hydrazide group, a hydrazine group, a semicarbazide group, an azide group, or an alkyne group, and the resultant covalent linkage created by the reaction of the first and second functional groups comprises an oxime linkage or a triazole.
A modified relaxin polypeptide comprising a non-naturally encoded amino acid, wherein:
- (a) the relaxin polypeptide comprises a relaxin A chain polypeptide and a relaxin B chain polypeptide, wherein the relaxin A chain polypeptide comprises SEQ ID NO:
- 4 containing a substitution of an amino acid with a non-naturally encoded amino acid at residue 1 and the relaxin B chain polypeptide comprises SEQ ID NO:
- 6 or SEQ ID NO:
- 5;
- (b) said non-naturally encoded amino acid is para-acetyl-L-phenylalanine;
- and
- (c) said para-acetyl-L-phenylalanine is linked to a poly(ethylene glycol) having an average molecular weight of about 20 kDa.
Dependencies are inferred from the claim text.