# US 8,771,682 B2 · Methods and compositions for reducing interleukin-4 or interleukin-13 signaling

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- Number: US 8,771,682 B2
- Document ID: US8771682B2
- Status: Granted
- Kind: B2
- Application number: 13/457,029
- Filed: 2012-04-26
- Published: 2013-04-04
- Granted: 2014-07-08
- Earliest claimed: 2011-04-26
- Assignees: Technische Universtität Dresden
- Applicants: Christian Bökel; Thomas Weidemann
- Inventors: Christian Bökel; Thomas Weidemann
- Web page: https://patentgrep.com/patent/US8771682B2

## CPC

- A61K 38/45: Transferases (2)
- A61K 31/415: 1,2-Diazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/02: Peptides of undefined number of amino acids; Derivatives thereof
- G01N 33/6893: {related to diseases not provided for elsewhere}
- G01N 2333/5406: IL-4
- G01N 2333/5437: IL-13
- G01N 2800/122: Chronic or obstructive airway disorders, e.g. asthma COPD
- G01N 2800/24: Immunology or allergic disorders
- 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)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates generally to methods and compositions for reducing Interleukin-4 or Interleukin-13 signaling, in particular to treat asthma and atopic dermatitis. The inventors have found that Rac/PAK mediated endocytosis of the ligand bound type I (IL-4R with the chains IL-4Ra and IL-2-Rg) and/or type II receptor (IL-13R with the chains IL-4Ra and IL-13Ra1) is needed for the IL-4 and/or IL-13 mediated activation of downstream signalling events including phosphorylation of Stat family transcrition factors. These discoveries enable new methods of screening compounds that modulate Interleukin-4 and Interleukin-13 signalling, as well as new methods for treating conditions characterized by increased Interleukin-4 and Interleukin-13 levels. These conditions include inflammatory conditions, asthma bronchiale, atopic dermatitis, allergies, atopic syndromes, allergic rhinitis, and th2-induced conditions.

## Claims

### Claim 1

A method for reducing Interleukin-4 (IL-4R) or Interleukin-13 (IL-13R) signaling in a cell or subject comprising administering an inhibitor of Rac/Pak driven endocytosis in an amount sufficient to reduce or inhibit endocytosis of IL-4R or IL-13R, wherein, the IL-4R or IL-13R signaling is associated with Rac/Pak driven endocytosis.

### Claim 2 (depends on 1)

The method of claim 1, wherein said inhibitor of Rac/Pak driven endocytosis is administered in amount effective to reduce or inhibit phosphorylation of Stat family transcription factors.

### Claim 3 (depends on 1)

The method of claim 1, wherein the inhibitor of Rac/Pak driven endocytosis is selected from agents inhibiting Rac-1 or Pak1/2.

### Claim 4 (depends on 1, 2)

The method of claim 1 or 2, wherein the inhibitor is selected from the group consisting of
peptides inhibiting Rac-1,
peptides inhibiting PAK1, PAK2 or PAK4 including the Pak inhibitor domain (PID), small hairpin RNA (shRNA), small interference RNA (siRNA) inhibiting Rac1, PAK1, PAK2 and PAK4, and combinations thereof.

### Claim 5 (depends on 4)

The method of claim 4, wherein said peptide inhibiting Rac-1 is N17Rac.

### Claim 6 (depends on 4)

The method of claim 4, wherein said peptide inhibiting PAK1 comprises amino acids 83-149 of PAK1.

### Claim 7

A method of treating a condition characterized by increased Interleukin-4 (IL-4R) or Interleukin-13 (IL-13R) levels in a subject in need thereof comprising administering an inhibitor of Rac/Pak driven endocytosis in a therapeutically effective amount, wherein, the increase in IL-4R or IL-13R levels is associated with Rac/Pak driven endocytosis.

### Claim 8 (depends on 7)

The method of claim 7, wherein the inhibitor of Rac/Pak driven endocytosis is selected from agents inhibiting Rac-1 or Pak1/2.

### Claim 9 (depends on 4, 8)

The method of claim 8, wherein the inhibitor is selected from inhibitors as defined in claim 4.

### Claim 10 (depends on 7)

The method of claim 7, wherein the condition characterized by increased Interleukin-4 or Interleukin-13 levels is selected from the group consisting of inflammatory conditions, asthma bronchiale, atopic dermatitis, and allergies, atopic syndromes, allergic rhinitis, th2-induced conditions, and combinations thereof.

### Claim 11

A method of treating atopic dermatitis in a subject in need thereof comprising administering an inhibitor of Rac/Pak driven endocytosis in a therapeutically effective amount, wherein, the atopic dermatitis is associated with Rak/Pak driven endocytosis.

### Claim 12 (depends on 11)

The method of claim 11, wherein the inhibitor of Rac/Pak driven endocytosis is selected from agents inhibiting rac-1 or Pak1/2.

### Claim 13 (depends on 4, 11)

The method of claim 11, wherein the inhibitor is selected from inhibitors as defined in claim 4.