# US 12,097,241 B2 · Methods of treating kidney failure, and/or improving or stablizing renal function using modified relaxin polypeptides

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- Number: US 12,097,241 B2
- Document ID: US12097241B2
- Status: Granted
- Kind: B2
- Application number: 17/573,238
- Filed: 2022-01-11
- Published: 2022-07-07
- Granted: 2024-09-24
- Earliest claimed: 2017-02-08
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Gene M. Dubowchik; Olafur S. Gudmundsson; Xiaojun Han; R. Michael Lawrence; Dasa Lipovsek; Cort S. Madsen; Claudio Mapelli; Paul E. Morin; Michael C. Myers
- Web page: https://patentgrep.com/patent/US12097241B2

## CPC

- A61K 38/18: Growth factors; Growth regulators
- A61K 38/2221: {Relaxins}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/06: Antihyperlipidemics
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/06: Antiarrhythmics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/02: for peripheral neuropathies
- A61P 27/02: Ophthalmic agents
- A61P 27/12: for cataracts
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 1/1077: {by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids}
- C07K 14/64: Relaxins
- A61K 38/00: 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)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/64: 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)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## 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.

## Claims

### Claim 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 Gluγ.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 1)

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.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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-Gluγ (SEQ ID NO: 139).

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 1)

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-Gluγ (SEQ ID NO: 139); and
a half-life extending moiety comprising —C14-COOH.

### Claim 15 (depends on 1)

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-Gluγ (SEQ ID NO: 139)-C14-COOH, as depicted in Formula III:

### Claim 16 (depends on 1)

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-Gluγ (SEQ ID NO: 139)-C14-COOH, as depicted in Formula III:

### Claim 17 (depends on 1)

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.