Therapeutic uses of modified relaxin polypeptides
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.
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.
2. The method of claim 1 , wherein the non-naturally encoded amino acid at position 1 of the A chain is linked to a water soluble polymer.
3. The method of claim 2 wherein said water soluble polymer comprises a polyethylene glycol (PEG).
4. The method of claim 1 wherein said non-naturally encoded amino acid comprises a para-substituted phenylalanine, ortho-substituted phenylalanine, or meta-substituted phenylalanine.
5. The method of claim 1 wherein said non-naturally encoded amino acid comprises para-acetyl-L-phenylalanine.
6. The method of claim 1 wherein said cardiovascular disease is heart failure.
7. The method of claim 6 , wherein the heart failure comprises one or more of acute decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary valve insufficiency, heart failure associated with combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with cardiac storage disorders, diastolic heart failure, and systolic heart failure.
8. The method of claim 6 , wherein the heart failure comprises chronic heart failure.
9. The method of claim 6 , wherein the heart failure comprises acute heart failure.
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.
11. The method of claim 10 , wherein said non-naturally encoded amino acid is linked to said linker, polymer, or biologically active molecule by an oxime linkage produced by the reaction of a carbonyl moiety and aminooxy (hydroxylamine) moiety, or by a triazole linkage produced by the reaction of an azide moiety and an alkyne moiety.
12. The method of claim 10 , wherein the heart failure comprises one or more of acute decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary valve insufficiency, heart failure associated with combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with cardiac storage disorders, diastolic heart failure, and systolic heart failure.
13. The method of claim 10 , wherein the heart failure comprises chronic heart failure.
14. The method of claim 10 , wherein the heart failure comprises acute heart failure.
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.
16. The method of claim 15 , wherein said non-naturally encoded amino acid is linked to said linker, polymer, or biologically active molecule by an oxime linkage produced by the reaction of a carbonyl moiety and aminooxy (hydroxylamine) moiety, or by a triazole linkage produced by the reaction of an azide moiety and an alkyne moiety.
17. The method of claim 15 , wherein said patient has heart failure and the method treats said heart failure in said patient.
18. The method of claim 17 , wherein the heart failure comprises one or more of acute decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary valve insufficiency, heart failure associated with combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with cardiac storage disorders, diastolic heart failure, and systolic heart failure.
19. The method of claim 17 , wherein the heart failure comprises chronic heart failure.
20. The method of claim 17 , wherein the heart failure comprises acute heart failure.