# US 11,028,137 B2 · Mutant islet amyloid polypeptides with improved solubility and methods for using the same

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- Number: US 11,028,137 B2
- Document ID: US11028137B2
- Status: Granted
- Kind: B2
- Application number: 16/482,471
- Filed: 2018-02-01
- Published: 2019-11-21
- Granted: 2021-06-08
- Earliest claimed: 2017-02-01
- Assignees: The Research Foundation for The State University of New York
- Applicants: The Research Foundation for The State University of New York
- Inventors: Daniel Raleigh; Rehana Akter; Andisheh Abedini
- Web page: https://patentgrep.com/patent/US11028137B2

## CPC

- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- C07K 14/4711: {Alzheimer's disease; Amyloid plaque core protein}
- A61K 38/28: Insulins
- 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)
- 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

Isolated non-naturally occurring, mutant-human islet amyloid polypeptides (IAPP) polypeptides, which are more soluble at neutral pH than the wild-type human islet amyloid polypeptide (hIAPP) protein are disclosed. These polypeptides can be formulated or co-formulated at physiological pH, which enable the polypeptides to be delivered to a subject in a single injection with an insulin agent. Methods and pharmacological compositions for treating an abnormal condition, such as an amyloid-based disease or type-1 diabetes in a subject are also disclosed.

## Claims

### Claim 1

An isolated mutant-human islet amyloid polypeptide hIAPP comprising an amino acid sequence that comprises at least two amino acid substitutions relative to the wild-type hIAPP polypeptide set forth in SEQ ID NO: 1 at positions 21, 22, 31 and 35, wherein said at least two amino acid substitutions comprise a substitution with lysine or arginine.

### Claim 2 (depends on 1)

The isolated mutant-hIAPP of claim 1, wherein said mutant-hIAPP comprises an amino acid substitution at positions 21 and 35 relative to the wild-type hIAPP polypeptide set forth in SEQ ID NO: 1 as set forth in SEQ ID NOs: 3 or 7.

### Claim 3 (depends on 1)

The isolated mutant-hIAPP of claim 1, wherein said mutant-hIAPP comprises an amino acid substitution at positions 22 and 31 relative to the wild-type hIAPP polypeptide set forth in SEQ ID NO: 1 as set forth in SEQ ID NOs: 5 or 9.

### Claim 4 (depends on 1)

The isolated mutant-hIAPP of claim 1, wherein said mutant-hIAPP further comprises at least one proline substitution relative to the wild-type hIAPP polypeptide set forth in SEQ ID NO: 1 at positions 24, 26 or 28.

### Claim 5 (depends on 4)

The isolated mutant-hIAPP of claim 4, wherein said mutant-hIAPP further comprises at least one proline substitution at position 24 or 26 relative to the wild-type hIAPP polypeptide set forth in SEQ ID NO: 1.

### Claim 6 (depends on 4)

The isolated mutant-hIAPP of claim 4, comprising amino acid substitutions at positions 21 and 35 and a single proline substitution at position 24, 26 or 28 relative to the wild-type hIAPP polypeptide set forth in SEQ ID NO: 1.

### Claim 7 (depends on 4)

The isolated mutant-hIAPP of claim 4, comprising amino acid substitutions at positions 22 and 31 and a single proline substitution at position 24, 26 or 28 relative to the wild-type hIAPP polypeptide set forth in SEQ II) NO: 1.

### Claim 8 (depends on 4)

The isolated mutant-hIAPP of claim 4, wherein said mutant-hIAPP comprises an amino acid substitution at positions 22, 28 and 31 as set forth in SEQ. ID NOs: 16 or 22.

### Claim 9 (depends on 4)

The isolated mutant-hIAPP of claim 4, wherein said mutant-hIAPP comprises an amino acid substitution at positions 21, 24, 26 and 35 as set forth in SEQ ID NOs: 4 or 8.

### Claim 10 (depends on 4)

The isolated mutant-hIAPP of claim 4, wherein said mutant-hIAPP comprises an amino acid substitution at positions 22, 24, 26 and 31 as set forth in SEQ ID NOs: 6 or 10.

### Claim 11 (depends on 1)

The isolated mutant-hIAPP of claim 1, wherein said isolated mutant-hIAPP is a synthetic peptide.

### Claim 12 (depends on 1)

The isolated mutant-hIAPP of claim 1, wherein said isolated mutant-hIAPP is a recombinant peptide.

### Claim 13 (depends on 1)

A pharmacological formulation comprising at least one of the isolated mutant-hIAPP of claim 1, wherein said pharmacological formulation has a neutral pH.

### Claim 14 (depends on 13)

The pharmacological formulation of claim 13, wherein said neutral pH is between 7.0 and 7.8.

### Claim 15 (depends on 13)

The pharmacological formulation of claim 13, wherein said neutral pH is 7.4.

### Claim 16 (depends on 13)

The pharmacological formulation of claim 13, further comprising insulin.

### Claim 17 (depends on 16)

The pharmacological formulation of claim 16, wherein said insulin is synthetic insulin.

### Claim 18 (depends on 1)

A method for treating a subject comprising administering to the subject a therapeutically effective amount of an isolated mutant-hIAPP of claim 1, wherein said administration treats an abnormal condition in the subject, and wherein said abnormal condition is an amyloid based disease or type-1 diabetes.

### Claim 19 (depends on 18)

The method of claim 18, further comprising administering to the subject a therapeutically effective amount of insulin, wherein said insulin and said isolated mutant-hIAPP is administered at neutral pH.