Methods of treating kidney failure, and/or improving or stablizing renal function using modified relaxin polypeptides

Patent metadata

Field	Value
Publication number	US-12097241-B2
Application number	US-202217573238-A
Country	US
Kind code	B2
Filing date	Jan 11, 2022
Priority date	Feb 8, 2017
Publication date	Sep 24, 2024
Grant date	Sep 24, 2024

Abstract

The present disclosure generally relates to modified relaxin polypeptides, such as modified human relaxin 2 polypeptides, comprising a non-naturally encoded amino acid which is linked to a pharmacokinetic enhancer, and therapeutic uses of such polypeptides, such as for the treatment of cardiovascular conditions (such as heart failure) and/or conditions relating to fibrosis.

First claim

What is claimed is:

1. A method of treating kidney failure, or improving or stabilizing renal function in a patient with kidney failure, comprising administering a therapeutically effective amount of a modified relaxin polypeptide to said patient wherein:
(a) the modified 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, substituted with a non-naturally encoded amino acid at A chain residue 1, and having zero, one or two additional amino acid changes in said relaxin A chain and having zero, one or two additional amino acid changes in said relaxin B chain, wherein each of said amino acid changes is independently a substitution, insertion or deletion;
(b) said 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 or valine; and
(c) said non-naturally encoded amino acid is linked to a pharmacokinetic enhancer comprising a peptide component between 4 and 8 amino acids and a half-life extending moiety, comprising a fatty acid of Formula I:
-Cn-COOH  (Formula I)

wherein n is between 12 and 16, and
wherein said peptide component comprises Glu γ .

2. The method of claim 1 , wherein said non-naturally encoded amino acid comprises a carbonyl group, an aminooxy group, a hydrazide group, a hydrazine group, a semicarbazide group, an azide group, or an alkyne group.

3. The method of claim 1 , wherein said non-naturally encoded amino acid comprises a phenylalanine derivative.

4. The method of claim 1 , wherein said non-naturally encoded amino acid is directly linked to said peptide component.

5. The method of claim 1 , wherein said non-naturally encoded amino acid is linked to said pharmacokinetic enhancer through an oxime linkage or triazole linkage.

6. The method of claim 1 , wherein said relaxin A chain polypeptide comprises SEQ ID NO: 35, and said relaxin B chain polypeptide comprises SEQ ID NO: 5 or SEQ ID NO: 6.

7. The method of claim 1 , wherein said peptide component comprises GGGGS-Glu γ (SEQ ID NO: 139), DRDDRD (SEQ ID NO: 102), KKKKKK-Glu γ (SEQ ID NO: 103), GGGEEE-Glu γ (SEQ ID NO: 105), EEEGGG-Glu γ (SEQ ID NO: 106), KKKGGG-Glu γ (SEQ ID NO: 107), GGGKKK-Glu γ (SEQ ID NO: 109), Sar-Sar-Sar-Sar-Ser-Glu γ (SEQ ID NO: 112), Sar-Sar-Sar-Glu-Glu-Glu γ (SEQ ID NO: 113), KSGGSGG-Glu γ (SEQ ID NO: 117), dKdKdKdKdKdK-Gluγ (SEQ ID NO: 120), EEEGGG-d Glu γ (SEQ ID NO: 128), EGGGGSK-Glu γ (SEQ ID NO: 130), EEEEEE-Glu γ (SEQ ID NO: 131), KK-Glu γ (SEQ ID NO: 140), KGPKGP-Glu γ (SEQ ID NO: 146), SGGGS-Glu γ (SEQ ID NO: 147), KGGGS-Glu γ (SEQ ID NO: 148), KGGGSE-Glu γ (SEQ ID NO: 149), GSPGSP-Glu γ (SEQ ID NO: 150), GGGGP-Glu γ (SEQ ID NO: 151), EGGS-Glu γ (SEQ ID NO: 152), EGGGP-Glu γ (SEQ ID NO: 153), KGPGSE-Glu γ (SEQ ID NO: 154), Spermine-Glu γ , or KKGGS-Glu γ (SEQ ID NO: 156).

8. The method of claim 1 , wherein 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, substituted with a non-naturally encoded amino acid at A chain residue 1, wherein said non-naturally encoded amino acid is linked to said pharmacokinetic enhancer and said pharmacokinetic enhancer comprises the peptide component GGGGS-Glu γ (SEQ ID NO: 139).

9. The method of claim 1 , wherein said half-life extending moiety is covalently linked to the peptide component.

10. The method of claim 1 , wherein said half-life extending moiety comprises —C14-COOH.

11. The method of claim 1 , wherein said half-life extending moiety comprises a fatty acid of Formula I:
-Cn-COOH  (Formula I)

wherein n is between 12 and 14.

12. The method of claim 1 , wherein said pharmacokinetic enhancer comprises:

wherein the aminooxy group is linked to the non-natural amino acid in said modified relaxin polypeptide.

13. The method of claim 1 , wherein said half-life extending moiety is conjugated to said peptide component through an amide bond.

14. The method of claim 1 , wherein 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, substituted with a non-naturally encoded amino acid at A chain residue 1;
wherein said non-naturally encoded amino acid comprises para-acetyl-L-phenylalanine linked to said pharmacokinetic enhancer which comprises
a peptide component comprising GGGGS-Glu γ (SEQ ID NO: 139); and
a half-life extending moiety comprising —C14-COOH.

15. The method of claim 1 , wherein the modified relaxin comprises a relaxin A chain polypeptide of SEQ ID NO: 35, and a relaxin B chain polypeptide of SEQ ID NO:6, wherein a para-acetyl-L-phenylalanine is located at position 1 of the relaxin A chain polypeptide, which para-acetyl-L-phenylalanine is linked to the pharmacokinetic enhancer GGGGS-Glu γ (SEQ ID NO: 139)-C14-COOH, as depicted in Formula III:

16. The method of claim 1 , wherein the modified relaxin comprises a relaxin A chain polypeptide of SEQ ID NO: 35, and a relaxin B chain polypeptide of SEQ ID NO: 5, wherein a para-acetyl-L-phenylalanine is located at position 1 of the relaxin A chain polypeptide, which para-acetyl-L-phenylalanine is linked to the pharmacokinetic enhancer GGGGS-Glu γ (SEQ ID NO: 139)-C14-COOH, as depicted in Formula III:

17. The method of claim 1 , wherein said modified relaxin polypeptide exhibits an increased in vivo half-life of at least 2-fold compared to the wild-type relaxin polypeptide consisting of the relaxin A chain of SEQ ID NO: 4 linked to the relaxin B chain of SEQ ID NO: 5.

Assignees

• Bristol Myers Squibb Co

Inventors

• Dubowchik Gene M
• Gudmundsson Olafur S
• Han Xiaojun
• Lawrence R Michael
• Lipovsek Dasa
• Madsen Cort S
• Mapelli Claudio
• Morin Paul E
• Myers Michael C

Classifications

• A61K38/2221

  Relaxins · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K47/64

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title