# US 2014/0155316 A1 · Fibroblast growth factor 1 protein fragments and methods of use

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- Number: US 2014/0155316 A1
- Document ID: US20140155316A1
- Status: Published application
- Kind: A1
- Application number: 14/176,992
- Filed: 2014-02-10
- Published: 2014-06-05
- Earliest claimed: 2012-06-07
- Assignees: New York University; The Salk Institute for Biological Studies
- Applicants: New York University; Salk Institute for Biological Studies
- Inventors: Moosa Mohammadi; Regina M. Goetz; Ronald M. Evans; Michael Downes; Jae Myoung Suh
- Web page: https://patentgrep.com/patent/US20140155316A1

## CPC

- C07K 14/50: Fibroblast growth factor [FGF]
- A61K 38/1825: {Fibroblast growth factor [FGF]}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07K 14/501: {acidic FGF [aFGF]}
- C07K 14/503: {basic FGF [bFGF]}
- C07K 2319/00: Fusion polypeptide
- 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 chimeric protein that includes an N-terminus coupled to a C-terminus, where the N-terminus includes a portion of a paracrine fibroblast growth factor (“FGF”) and the C-terminus includes a C-terminal portion of an FGF19 molecule. The portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. The present invention also relates to pharmaceutical compositions including chimeric proteins according to the present invention, methods for treating a subject suffering from diabetes, obesity, or metabolic syndrome, and methods of screening for compounds with enhanced binding affinity for the βKlotho-FGF receptor complex involving the use of chimeric proteins of the present invention.

## Claims

### Claim 1

A method of treating diabetes, obesity and/or metabolic syndrome in a subject, comprising:
administering to a subject having diabetes, obesity and/or metabolic syndrome an FGF1 peptide fragment comprising at least 95% sequence identity to an amino acid sequence consisting of:
amino acids 25-155 of SEQ ID NO: 1 (FGF1ΔNT);
amino acids 1-155 of SEQ ID NO: 1 with a K127D, K128Q and K133V substitution (FGF1ΔHBS); or
amino acids 25-155 of SEQ ID NO: 1 with a K127D, K128Q and K133V substitution (FGF1ΔNT ΔHBS),
thereby treating the diabetes, obesity and/or metabolic syndrome.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject has one or more of type 1 diabetes, type 2 diabetes, gestational diabetes, drug-induced diabetes, high blood glucose, metabolic syndrome, lipodystrophy syndrome, dyslipidemia, insulin resistance, leptin resistance, atherosclerosis, vascular disease, inflammatory disease, fibrotic disease, hypercholesterolemia, hypertriglyceridemia, non-alcoholic fatty liver disease, overweight, and obesity.

### Claim 4 (depends on 1)

The method of claim 1, wherein the method lowers blood glucose in the subject.

### Claim 5 (depends on 1)

The method of claim 1, wherein the FGF1 peptide fragment is administered at a dose of 0.1 to 10 mg/kg once or twice a day.

### Claim 6 (depends on 1)

The method of claim 1, wherein the FGF1 peptide fragment is administered at a dose of 0.5 mg/kg.

### Claim 7 (depends on 1)

The method of claim 1, wherein administering comprises oral, parenteral, subcutaneous, intravenous, intramuscular, or intraperitoneal administration.

### Claim 8 (depends on 1)

The method of claim 1, wherein the FGF1 peptide fragment is administered with a pharmaceutically-acceptable carrier.

### Claim 9 (depends on 1)

The method of claim 1, wherein the FGF1 peptide fragment is co-administered with one or more agents selected from the group consisting of an anti-inflammatory agent, an antifibrotic agent, an antihypertensive agent, an antidiabetic agent, a triglyceride-lowering agent, and a cholesterol-lowering agent.

### Claim at position 10

-11. (canceled)

### Claim 12 (depends on 1)

The method of claim 1, wherein the subject is a mammal.

### Claim 13 (depends on 12)

The method of claim 12, wherein the mammal is a human.

### Claim 14 (depends on 1)

The method of claim 1, wherein the FGF1 peptide fragment consists of the amino acid sequence shown in:
amino acids 25-155 of SEQ ID NO: 1 (FGF1ΔNT);
amino acids 1-155 of SEQ ID NO: 1 with a K127D, K128Q and K133V substitution (FGF1ΔHBS); or
amino acids 25-155 of SEQ ID NO: 1 with a K127D, K128Q and K133V substitution (FGF1ΔNT ΔHBS).