Therapeutic uses of modified relaxin polypeptides
First Claim
1. A method for treating a cardiovascular disease in a patient in need thereof, comprising administering to said patient an effective amount of a biologically active modified relaxin polypeptide, wherein (a) said modified relaxin polypeptide comprises an A chain and a B chain linked by at least one disulfide bond, wherein said A chain comprises SEQ ED NO:
- 4 substituted with a non-naturally encoded amino acid at position 1 and said B chain comprises SEQ ID NO;
5 or SEQ ID NO;
6, 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 non-naturally encoded amino acid is linked to the linker, polymer, or biologically active molecule by the resultant covalent linkage created by the reaction of the first and second functional groups.
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Abstract
Therapeutic uses of modified relaxin polypeptides for the treatment of cardiovascular disease, treatment of heart failure, and decreasing fibrotic disorders are provided. Exemplary embodiments provide for the use of relaxin polypeptides which include one or more amino acid substitutions with natural or non-naturally encoded amino acids, and/or linkage to a water-soluble polymer, such as polyethylene glycol.
348 Citations
20 Claims
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1. A method for treating a cardiovascular disease in a patient in need thereof, comprising administering to said patient an effective amount of a biologically active modified relaxin polypeptide, wherein (a) said modified relaxin polypeptide comprises an A chain and a B chain linked by at least one disulfide bond, wherein said A chain comprises SEQ ED NO:
- 4 substituted with a non-naturally encoded amino acid at position 1 and said B chain comprises SEQ ID NO;
5 or SEQ ID NO;
6, 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 non-naturally encoded amino acid is linked to the linker, polymer, or biologically active molecule by the resultant covalent linkage created by the reaction of the first and second functional groups. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
- 4 substituted with a non-naturally encoded amino acid at position 1 and said B chain comprises SEQ ID NO;
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10. A method of treating heart failure in a patient in need thereof, comprising administering to said patient an effective amount of a biologically active modified relaxin polypeptide, said modified relaxin polypeptide comprising an A chain and a B chain linked by at least one disulfide bond, wherein said A chain comprises SEQ ID NO:
- 4 substituted with a non-naturally encoded amino acid at position 1 and said B chain comprises SEQ ID NO;
6, wherein the non-naturally encoded amino acid at position 1 of the A chain is linked to a linker, polymer, or biologically active molecule, and said non-naturally encoded amino acid comprises para-acetyl-L-phenylalanine. - View Dependent Claims (11, 12, 13, 14)
- 4 substituted with a non-naturally encoded amino acid at position 1 and said B chain comprises SEQ ID NO;
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15. A method of decreasing or inhibiting the formation of cardiac fibrosis in a patient in need thereof, comprising administering to said patient an effective amount of a biologically active modified relaxin polypeptide, said modified relaxin polypeptide comprising an A chain and a B chain linked by at least one disulfide bond, wherein said A chain comprises SEQ ID NO:
- 4 substituted with a non-naturally encoded amino acid at position 1 and said B chain comprises SEQ ID NO;
5 or SEQ ID NO;
6, wherein the non-naturally encoded amino acid at position 1 of the A chain is linked to a linker, polymer, or biologically active molecule, and said non-naturally encoded amino acid comprises para-acetyl-L-phenylalanine. - View Dependent Claims (16, 17, 18, 19, 20)
- 4 substituted with a non-naturally encoded amino acid at position 1 and said B chain comprises SEQ ID NO;
Specification