# US 2020/0399340 A1 · Novel growth hormone receptor antagonist and fusion protein thereof

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- Number: US 2020/0399340 A1
- Document ID: US20200399340A1
- Status: Published application
- Kind: A1
- Application number: 16/954,902
- Filed: 2018-12-20
- Published: 2020-12-24
- Earliest claimed: 2017-12-20
- Assignees: Alteogen, Inc.
- Applicants: Alteogen, Inc.
- Inventors: Soon Jae PARK; Jaehyeong KO; Sun-Ah YOU; Sang Hoon YUN
- Web page: https://patentgrep.com/patent/US20200399340A1

## CPC

- C07K 14/61: Growth hormone [GH], i.e. somatotropin
- C07K 14/72: for hormones {(for neuromediators C07K14/70571)}
- A61K 47/62: the modifying agent being a protein, peptide or polyamino acid
- C07K 14/8125: {Alpha-1-antitrypsin}
- 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)
- C07K 2319/00: Fusion polypeptide
- C07K 2319/61: containing an enzyme fusion for detection (lacZ, luciferase)
- 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)
- 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)

## Abstract

The present invention relates to a growth hormone receptor antagonist comprising a growth hormone variant which is modified by substitution of one or more amino acids of growth hormone. Further, the growth hormone receptor antagonist of the present invention may further comprise a long-acting carrier which is fused to the growth hormone variant. The growth hormone receptor antagonist may have strong binding potency to growth hormone receptor and may exhibit a long-lasting antagonistic action.

## Claims

### Claim 1

A growth hormone receptor antagonist comprising a growth hormone variant in which one or more amino acids in an amino acid sequence of growth hormone are substituted with another amino acid.

### Claim 2 (depends on 1)

The growth hormone receptor antagonist of claim 1, wherein the substitution with another amino acid comprises substitution of the 46th amino acid from the N-terminus with lysine, substitution of the 120th amino acid from the N-terminus with lysine or arginine, or a combination thereof.

### Claim 3 (depends on 2)

The growth hormone receptor antagonist of claim 2, wherein the substitution with another amino acid further comprises substitution at any one or more positions selected from the group consisting of the 18th amino acid, the 21st amino acid, the 54th amino acid, the 64th amino acid, the 167th amino acid, the 168th amino acid, the 171st amino acid, the 172nd amino acid, the 174th amino acid, the 176th amino acid, and the 179th amino acid from the N-terminus.

### Claim 4 (depends on 2)

The growth hormone receptor antagonist of claim 2, wherein the substitution with another amino acid further comprises substitution of the 174th amino acid from the N-terminus with serine, substitution of the 21st amino acid from the N-terminus with asparagine, or a combination thereof.

### Claim 5 (depends on 1)

The growth hormone receptor antagonist of claim 1, wherein the substitution with another amino acid comprises any one or more substitutions selected from the group consisting of substitution of the 18th amino acid from the N-terminus with aspartic acid, substitution of the 21st amino acid from the N-terminus with asparagine, substitution of the 46th amino acid from the N-terminus with lysine, substitution of the 54th amino acid from the N-terminus with proline, substitution of the 64th amino acid from the N-terminus with lysine, substitution of the 120th amino acid from the N-terminus with lysine or arginine, substitution of the 167th amino acid from the N-terminus with asparagine, substitution of the 168th amino acid from the N-terminus with alanine, substitution of the 171st amino acid from the N-terminus with serine, substitution of the 172nd amino acid from the N-terminus with arginine, substitution of the 174th amino acid from the N-terminus with serine, substitution of the 176th from the N-terminus with tyrosine, and substitution of the 179th amino acid from the N-terminus with threonine.

### Claim 6 (depends on 1)

The growth hormone receptor antagonist of claim 1, wherein a long-acting carrier is linked to the growth hormone variant.

### Claim 7 (depends on 6)

The growth hormone receptor antagonist of claim 6, wherein the long-acting carrier is fused to the N-terminus or the C-terminus of the growth hormone variant.

### Claim 8 (depends on 6)

The growth hormone receptor antagonist of claim 6, wherein the long-acting carrier is selected from the group consisting of polyethylene glycol, fatty acids, albumin or fragments thereof, albumin-binding substances, alpha-1 antitrypsin or variants thereof, immunoglobulin Fc or fragments thereof, a polymer of repeating units of a specific amino acid sequence, antibodies or fragments thereof, FcRn-binding substances, in vivo connective tissues or derivatives thereof, nucleotides, fibronectin, transferrin, saccharides, and polymers.

### Claim 9 (depends on 8)

The growth hormone receptor antagonist of claim 8, wherein the long-acting carrier is an alpha-1 antitrypsin or a variant thereof.

### Claim 10 (depends on 9)

The growth hormone receptor antagonist of claim 9, wherein the alpha-1 antitrypsin variant comprises substitution of one or more amino acids with another amino acid, and the substitution comprises substitution at one or more positions among the 1st and 25th amino acids from the N-terminus.

### Claim 11 (depends on 9)

The growth hormone receptor antagonist of claim 9, wherein the alpha-1 antitrypsin variant comprises any one or more substitutions selected from the group consisting of substitution of the 9th amino acid from the N-terminus with asparagine, substitution of the 232nd amino acid from the N-terminus with serine, substitution of the 37th amino acid from the N-terminus with asparagine, and substitution of the 359th amino acid from the N-terminus with threonine.

### Claim 12 (depends on 6)

The growth hormone receptor antagonist of claim 6, wherein the growth hormone variant is fused with the long-acting carrier directly or via a linker.

### Claim 13 (depends on 12)

The growth hormone receptor antagonist of claim 12, wherein the linker is a peptidyl linker or a non-peptidyl linker.

### Claim 14 (depends on 13)

The growth hormone receptor antagonist of claim 13, wherein the non-peptidyl linker is polyethylene glycol, polypropylene glycol, a copolymer of ethylene glycol and propylene glycol, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, polylactic acid (PLA), polylactic-glycolic acid (PLGA), a lipid polymer, chitins, hyaluronic acid, or a combination thereof.

### Claim 15 (depends on 13)

The growth hormone receptor antagonist of claim 13, wherein the peptidyl linker comprises two or more amino acids.

### Claim 16 (depends on 1)

A pharmaceutical composition for preventing or treating a disease caused by human growth hormone, comprising the growth hormone receptor antagonist of claim 1.

### Claim 17 (depends on 16)

The pharmaceutical composition of claim 16, wherein the disease is selected from the group consisting of acromegaly, gigantism, cancer, diabetic nephropathy, arthritis, lung inflammation, growth hormone deficiency (GHD), idiopathic short stature, Turner's syndrome, Prader-Willi syndrome, small for gestational age, and chronic renal insufficiency (CRI).

### Claim 18

A method of preparing a growth hormone receptor antagonist, the method comprising the step of culturing cells comprising a polynucleotide encoding the growth hormone variant in which one or more amino acids in an amino acid sequence of growth hormone are substituted with another amino acid.