# US 12,004,506 B2 · Pharmaceutical composition comprising a cyclic peptide of formula X1-GQRETPEGAEAKPWY-X2 and use for extracorporeal lung treatment

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- Number: US 12,004,506 B2
- Document ID: US12004506B2
- Status: Granted
- Kind: B2
- Application number: 16/941,074
- Filed: 2020-07-28
- Published: 2020-11-12
- Granted: 2024-06-11
- Earliest claimed: 2013-04-23
- Assignees: Apeptico Forschung Und Entwicklung GmbH
- Applicants: Apeptico Forschung Und Entwicklung GmbH
- Inventors: Hendrik Fischer; Helmut Pietschmann; Susan Jane Tzotzos; Bernhard Fischer; Rudolf Lucas
- Web page: https://patentgrep.com/patent/US12004506B2

## CPC

- A01N 1/126: Physiologically active agents, e.g. antioxidants or nutrients
- A01N 37/46: N-acyl derivatives
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 7/56: the cyclisation not occurring through 2,4-diamino-butanoic acid
- C07K 7/64: Cyclic peptides containing only normal peptide links
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- 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

A method of conditioning/improving lung functions extracorporeally by treatment of a non-ischemic donor lung ex vivo with a cyclized compound of the amino acid sequence of formula X1-GQRETPEGAEAKPWY-X2 I wherein X1 comprises an amino acid (sequence) with 1 to 4 members, comprising natural or unnatural amino acids, and X2 comprises one amino acid, selected from natural amino acids; and a pharmaceutical composition, comprising a peptide of formula I as defined in any one of claims 1 to 7, in in a form, which is appropriate for spraying to obtain an aerosol for inhalation, or which is appropriate for the preparation of a spray to obtain an aerosol upon spraying, which is appropriate for inhalation.

## Claims

### Claim 1

A method of improving the dynamic lung compliance and arterio-venous pO2 difference of a donor lung extracorporeally during ventilating and perfusing of the donor lung, the method comprising:
conditioning the donor lung extracorporeally prior to implantation to improve ventilation performance of the donor lung, wherein conditioning of the donor lung comprises applying into said donor lung ex vivo a cyclized compound of the amino acid sequence (SEQ ID NO: 9) of formula I:
X1-GQRETPEGAEAKPWY-X2 (I)
wherein,
X1 comprises an amino acid sequence with 1 to 4 members, comprising natural or unnatural amino acids, and
X2 comprises one amino acid, selected from natural amino acids,
and wherein the compound is applied into the donor lung during ventilating and perfusing of said donor lung.

### Claim 2 (depends on 1)

The method according to claim 1 wherein X1 in a compound of formula I is selected from the group consisting of C, KSP, K, ornithine, 4-amino butanoic acid, and β-alanine.

### Claim 3 (depends on 1)

The method according to claim 1, wherein X2 is selected from the group consisting of C, D, G, and E.

### Claim 4 (depends on 1)

The method according to claim 1, wherein cyclization of the cyclized compound is between the first amino acid residue in X1 and the last amino acid residue in X2.

### Claim 5 (depends on 1)

The method according to claim 1, wherein cyclization of the cyclized compound is via an amide bond or via a disulfide bridge.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the compound of formula I is selected from the group consisting of:
SEQ ID NO: 1
Cyclo(CGQRETPEGAEAKPWYC)
wherein both terminal cysteine residues form a disulfide bridge;
SEQ ID NO: 2
Cyclo(KSPGQRETPEGAEAKPWYE)
wherein an amide bond is formed between the amino group attached to the ε-carbon atom of the N-terminal lysine residue and the side chain carboxyl group attached to the γ-carbon of the C-terminal glutamic acid residue;
SEQ ID NO: 3
Cyclo(KGQRETPEGAEAKPWYG)
wherein an amide bond is formed between the amino group attached to the ε-carbon atom of the side chain of the N-terminal lysine residue and the carboxyl group of the C-terminal glycine residue;
SEQ ID NO: 4
Cyclo(ornithine-GQRETPEGAEAKPWYG)
wherein an amide bond is formed between the amino group attached to the δ-carbon of the side chain of the N-terminal ornithine residue and the carboxyl group of the C-terminal glycine residue;
SEQ ID NO: 5
Cyclo(4-aminobutanoic acid-GQRETPEGAEAKPWYD)
wherein an amide bond is formed between the amino group of the N-terminal 4-aminobutanoic acid residue and the side chain carboxyl group attached to the β-carbon of the C-terminal aspartic acid residue;
and
SEQ ID NO: 6
Cyc1o(β-a1anine-GQRETPEGAEAKPWYE)
wherein an amide bond is formed between the amino group of the N-terminal β-alanine residue and the side chain carboxyl group attached to the γ-carbon of the C-terminal glutamic acid residue.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the cyclized compound of formula I is in the form of a salt.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the cyclized compound of formula I is administered by spraying.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the cyclized compound of formula I is administered by use of a nebulizer.

### Claim 10 (depends on 1)

The method according to claim 1 wherein X1 comprises an amino acid sequence with 1 to 3 members, comprising natural or unnatural amino acids.

### Claim 11 (depends on 1)

The method of claim 1, wherein the donor lung comprises a pO2 greater than 100 mm Hg.

### Claim 12 (depends on 11)

The method of claim 11, further comprising nebulizing the cyclized compound into the donor lung during ventilation, prior to implantation.

### Claim 13

A method of improving the dynamic lung compliance and arterio-venous pO2 difference of a human donor lung extracorporeally, comprising:
conditioning the human donor lung extracorporeally prior to implantation to improve ventilation performance of the human donor lung, wherein conditioning of the human donor lung comprises treating the human donor lung ex vivo prior to implantation with a nebulized treatment composition comprising a cyclized compound of the amino acid sequence (SEQ ID NO: 9) of formula I:
(I)
X1-GQRETPEGAEAKPWY-X2
wherein,
X1 comprises an amino acid sequence with 1 to 4 members, comprising natural or unnatural amino acids, and
X2 comprises one amino acid, selected from natural amino acids,
and wherein the compound is applied into the human donor lung together with ventilating and perfusing said human donor lung.

### Claim 14

A method of improving the dynamic lung compliance and arterio-venous pO2 difference of a donor lung, comprising:
conditioning the donor lung extracorporeally prior to implantation to improve ventilation performance of the donor lung, wherein conditioning of the donor lung comprises treating the donor lung with an aerosol comprising a cyclized compound of the amino acid sequence (SEQ ID NO: 9) of formula I:
(I)
X1-GQRETPEGAEAKPWY-X2
wherein,
X1 comprises an amino acid sequence with 1 to 4 members, comprising natural or unnatural amino acids, and
X2 comprises one amino acid, selected from natural amino acids,
and wherein the compound is applied into the donor lung together with ventilating and perfusing said donor lung.

### Claim 15 (depends on 14)

The method according to claim 14, wherein treating the donor lung occurs immediately before implantation of the donor lung into a recipient.