# US 2014/0037626 A1 · Metal Abstraction Peptide With Release of Metal

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- Number: US 2014/0037626 A1
- Document ID: US20140037626A1
- Status: Published application
- Kind: A1
- Application number: 13/945,769
- Filed: 2013-07-18
- Published: 2014-02-06
- Earliest claimed: 2012-07-18
- Assignees: Echogen, Inc.; University of Kansas
- Applicants: Echogen, Inc.; University of Kansas
- Inventors: Jennifer Ann Stowell Laurence; Mary Elizabeth Krause; George Laurence
- Web page: https://patentgrep.com/patent/US20140037626A1

## CPC

- C07K 7/06: having 5 to 11 amino acids
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- 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

Compositions comprising peptides that are capable of binding a metal in a square planar orientation, a square pyramidal orientation, or both, are disclosed. Such compositions can be used for binding and releasing a metal in a variety of contexts and environments, such as the treatment of cancer.

## Claims

### Claim 1

A pharmaceutical composition comprising:
i) a metal-binding peptide, wherein the metal-binding peptide comprises a sequence Z1—XZ3C1Z4C2—Z2, wherein X is any natural or non-natural amino acid or amino acid analogue, and wherein C1 and C2 are each individually chosen from a cysteine and a sulfur-containing alpha or beta amino acid, and wherein Z1, Z2, Z3, and Z4 are each individually a sequence of 1-5 residues, or absent, wherein each residue is independently a natural or non-natural amino acid or analogue thereof;
ii) a metal bound to the metal-binding peptide; and
iii) a pharmaceutically-acceptable excipient,
wherein the composition is a unit dosage form.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the metal-binding peptide binds the metal to yield a concentration of peptide with bound metal and a concentration of peptide without bound metal and a ratio of the concentrations, wherein the ratio is at least two times greater at a pH above 7 than the ratio at a pH below 6 for a constant concentration of metal-binding peptide and metal.

### Claim 3 (depends on 2)

The pharmaceutical composition of claim 2, wherein the ratio of the concentrations is about 2 to about 1.

### Claim 4 (depends on 2)

The pharmaceutical composition of claim 2, wherein the ratio is at least five times greater at a pH above 7 than the ratio at a pH below 6.

### Claim 5 (depends on 2)

The pharmaceutical composition of claim 2, wherein the ratio of the concentrations is at least five times greater at a pH between 7 and 8 than the ratio at a pH between 4 and 6.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the metal-binding peptide comprises at least 20 amino acid residues.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein X is a basic amino acid.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein at least one of C1 and C2 is cysteine.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein at least one of Z1 and Z2 includes a basic amino acid adjacent to X or C2.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein at least one of Z3 and Z4 includes a basic amino acid adjacent to X, C1, or C2.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, wherein Z2, Z3, and Z4 are absent, wherein Z1 is any natural or non-natural amino acid or sequence of natural or non-natural amino acids.

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, wherein a basic amino acid of Z1 is adjacent to X.

### Claim 13 (depends on 1)

The pharmaceutical composition of claim 1, wherein Z1 and Z2 are absent.

### Claim 14 (depends on 1)

The pharmaceutical composition of claim 1, wherein Z1, Z2, Z3, and Z4 are absent.

### Claim 15 (depends on 1)

The pharmaceutical composition of claim 1, wherein Z3 and Z4 are absent.

### Claim 16 (depends on 1)

The pharmaceutical composition of claim 1, wherein the metal-binding peptide is linked to an antibody.

### Claim 17 (depends on 16)

The pharmaceutical composition of claim 16, wherein the metal-binding peptide is linked to the antibody through an amide bond.

### Claim 18 (depends on 1)

The pharmaceutical composition of claim 1, wherein the metal is platinum.

### Claim 19 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutically-acceptable excipient is a phosphate buffer.

### Claim 20 (depends on 1)

The pharmaceutical composition of claim 1, wherein the unit dosage form provides a therapeutically-effective amount of the metal bound to the metal-binding peptide to a subject, after administration to the subject.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, wherein the therapeutically-effective amount of the metal bound to the metal-binding peptide is from about 1 mg to about 100 mg.

### Claim 22 (depends on 20)

The pharmaceutical composition of claim 20, wherein the therapeutically-effective amount of the metal bound to the metal-binding peptide is from about 100 mg to about 5000 mg.

### Claim 23 (depends on 20)

The pharmaceutical composition of claim 20, wherein the subject is a human.

### Claim 24

A method of treating cancer, the method comprising administering to a subject in need or want thereof a therapeutically-effective amount of a composition comprising:
i) a metal-binding peptide, wherein the metal-binding peptide comprises a sequence Z1—XZ3C1Z4C2—Z2, wherein X is any natural or non-natural amino acid or amino acid analogue, and wherein C1 and C2 are each individually chosen from a cysteine and a sulfur-containing alpha or beta amino acid, and wherein Z1, Z2, Z3, and Z4 are each individually a sequence of 1-5 residues, or absent, wherein each residue is independently a natural or non-natural amino acid or analogue thereof;
ii) a metal bound to the metal-binding peptide; and
iii) a pharmaceutically-acceptable excipient,
wherein the composition is a unit dosage form.

### Claim 25 (depends on 24)

The method of claim 24, wherein the metal-binding peptide binds the metal to yield a concentration of peptide with bound metal and a concentration of peptide without bound metal and a ratio of the concentrations, wherein the ratio is at least two times greater at a pH above 7 than the ratio at a pH below 6 for a constant concentration of metal-binding peptide and metal.

### Claim 26 (depends on 25)

The method of claim 25, wherein the ratio of the concentrations is about 2 to about 1.

### Claim 27 (depends on 25)

The method of claim 25, wherein the ratio is at least five times greater at a pH above 7 than the ratio at a pH below 6.

### Claim 28 (depends on 25)

The method of claim 25, wherein the ratio of the concentrations is at least five times greater at a pH between 7 and 8 than the ratio at a pH between 4 and 6.

### Claim 29 (depends on 24)

The method of claim 24, wherein the metal-binding peptide comprises at least 20 amino acid residues.

### Claim 30 (depends on 24)

The method of claim 24, wherein X is a basic amino acid.

### Claim 31 (depends on 24)

The method of claim 24, wherein at least one of C1 and C2 is cysteine.

### Claim 32 (depends on 24)

The method of claim 24, wherein at least one of Z1 and Z2 includes a basic amino acid adjacent to X or C2.

### Claim 33 (depends on 24)

The method of claim 24, wherein at least one of Z3 and Z4 includes a basic amino acid adjacent to X, C1, or C2.

### Claim 34 (depends on 24)

The method of claim 24, wherein Z2, Z3, and Z4 are absent, wherein Z1 is any natural or non-natural amino acid or sequence of natural or non-natural amino acids.

### Claim 35 (depends on 34)

The method of claim 34, wherein a basic amino acid of Z1 is adjacent to X.

### Claim 36 (depends on 24)

The method of claim 24, wherein Z1 and Z2 are absent.

### Claim 37 (depends on 24)

The method of claim 24, wherein Z1, Z2, Z3, and Z4 are absent.

### Claim 38 (depends on 24)

The method of claim 24, wherein Z3 and Z4 are absent.

### Claim 39 (depends on 24)

The method of claim 24, wherein the metal-binding peptide is linked to an antibody.

### Claim 40 (depends on 39)

The method of claim 39, wherein the metal-binding peptide is linked to the antibody through an amide bond.

### Claim 41 (depends on 24)

The method of claim 24, wherein the metal is platinum.

### Claim 42 (depends on 24)

The method of claim 24, wherein the pharmaceutically-acceptable excipient is a phosphate buffer.

### Claim 43 (depends on 24)

The method of claim 24, wherein the administering is intravenous.

### Claim 44 (depends on 24)

The method of claim 24, wherein the therapeutically-effective amount of peptide with bound metal is from about 1 mg to about 100 mg.

### Claim 45 (depends on 24)

The method of claim 24, wherein the therapeutically-effective amount of peptide with bound metal is from about 100 mg to about 5000 mg.

### Claim 46 (depends on 24)

The method of claim 24, wherein the subject is a human.

### Claim 47

A method of providing a metal to a subject in need or want thereof, the method comprising administering to the subject:
i) a metal-binding peptide, wherein the metal-binding peptide comprises a sequence Z1—XZ3C1Z4C2—Z2, wherein X is any natural or non-natural amino acid or amino acid analog, and wherein C1 and C2 are each individually chosen from a cysteine and a sulfur-containing alpha or beta amino acid, and wherein Z1, Z2, Z3, and Z4 are each individually a sequence of 1-5 residues, or absent, wherein each residue is independently a natural or non-natural amino acid or analogue thereof; and
ii) the metal, wherein the metal is bound to the metal-binding peptide,
wherein the metal-binding peptide releases the metal in a physiological environment, wherein the release is associated with a decrease in pH.

### Claim 48 (depends on 47)

The method of claim 47, wherein the metal is released at a pH below 7.

### Claim 49 (depends on 47)

The method of claim 47, wherein the metal is released at a pH of 6 or below.

### Claim 50 (depends on 47)

The method of claim 47, wherein the metal is released at a pH of 5 or below.

### Claim 51 (depends on 47)

The method of claim 47, wherein the physiological environment is a tumor cell.

### Claim 52 (depends on 47)

The method of claim 47, wherein the physiological environment is a cancer cell.

### Claim 53 (depends on 47)

The method of claim 47, wherein X is a basic amino acid.

### Claim 54 (depends on 47)

The method of claim 47, wherein at least one of C1 and C2 is cysteine.

### Claim 55 (depends on 47)

The method of claim 47, wherein at least one of Z1 and Z2 includes a basic amino acid adjacent to X or C2.

### Claim 56 (depends on 47)

The method of claim 47, wherein at least one of Z3 and Z4 includes a basic amino acid adjacent to X, C1, or C2.

### Claim 57 (depends on 47)

The method of claim 47, wherein Z2, Z3, and Z4 are absent, wherein Z1 is any natural or non-natural amino acid or sequence of natural or non-natural amino acids.

### Claim 58 (depends on 57)

The method of claim 57, wherein a basic amino acid of Z1 is adjacent to X.

### Claim 59 (depends on 47)

The method of claim 47, wherein Z1 and Z2 are absent.

### Claim 60 (depends on 47)

The method of claim 47, wherein Z1, Z2, Z3, and Z4 are absent.

### Claim 61 (depends on 47)

The method of claim 47, wherein Z3 and Z4 are absent.

### Claim 62 (depends on 47)

The method of claim 47, wherein the metal-binding peptide is linked to an antibody.

### Claim 63 (depends on 62)

The method of claim 62, wherein the metal-binding peptide is linked to the antibody through an amide bond.

### Claim 64 (depends on 47)

The method of claim 47, wherein the metal is platinum.

### Claim 65 (depends on 47)

The method of claim 47, wherein the administering is intravenous

### Claim 66 (depends on 47)

The method of claim 47, wherein the subject is a human.