METHODS FOR TREATING INFLAMMATION

• US 20090274696A1
• Filed: 04/29/2009
• Published: 11/05/2009
• Est. Priority Date: 04/29/2008
• Status: Abandoned Application

• Current Assignee: Wyeth LLC (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Mason, Lawrence, Jacobson, Bruce A., Chen, Hang, Bowman, Michael R.
• Application Number:
  US12/432,617
• Publication Number:
  US 20090274696A1
• Time in Patent Office: Days
• US Class Current: 424/135.100
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 38/1703 from vertebrates
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07K 14/4702 : Regulators; Modulating activity
• CPC Class Codes: C07K 14/575 : Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: G01N 2333/52 : Assays involving cytokines
• CPC Class Codes: G01N 33/5088 : of vertebrates

Abstract

Provided are methods and compositions for reducing airway hyperresponsiveness and other inflammatory diseases, disorders and conditions in a mammal by decreasing FIZZ1 (Found in Inflammatory Zone 1) activity. Also provided are methods and compositions for identifying modulators of airway inflammation and/or inhibitors of FIZZ1. The present invention encompasses modulators of airway inflammation and/or inhibitors of FIZZ1 and uses thereof. In addition, the present invention provides methods and compositions for enhancing an immune response based on FIZZ1 protein.

Claims

1. A method to reduce airway hyperresponsiveness in a mammal, the method comprising a step of decreasing Found in Inflammatory Zone (FIZZ1) activity.

2. The method of claim 1, wherein the step of decreasing the FIZZ1 activity comprises reducing transcription of FIZZ1 gene.

3. The method of claim 1, wherein the step of decreasing the FIZZ1 activity comprises reducing translation of an mRNA sequence encoding FIZZ1 protein.

4. The method of claim 1, wherein the step of decreasing the FIZZ1 activity comprises administering an interfering RNA.

5. The method of claim 4, wherein the interfering RNA is selected from siRNA, shRNA or miRNA.

6. The method of claim 5, wherein the interfering RNA is siRNA.

7. The method of claim 6, wherein said siRNA comprises a sequence substantially complementary to at least a portion of the mRNA encoding the FIZZ1 protein.

8. The method of claim 6, wherein said siRNA is double-stranded.

9. The method of claim 6, wherein said siRNA is single-stranded.

10. The method of claim 6, wherein said siRNA comprises a sequence having between about 20 and about 25 nucleotide bases.

11. The method of claim 1, wherein the step of decreasing the FIZZ1 activity comprises administering an antibody, or a fragment thereof, that specifically binds the FIZZ1 protein.

12. The method of claim 10, wherein the antibody, or a fragment thereof, is selected from the group consisting of intact IgG, F(ab′

)2, F(ab)₂, Fab′

, Fab, ScFvs, diabodies, triabodies and tetrabodies.

13. The method of claim 12, wherein the antibody is a monoclonal antibody.

14. The method of claim 13, wherein the antibody is a humanized monoclonal antibody.

15. The method of claim 1, wherein the step of decreasing the FIZZ1 activity comprises administering an aptamer that specifically binds the FIZZ1 protein.

16. The method of claim 15, wherein the aptamer is an RNA aptamer.

17. The method of claim 1, wherein the step of decreasing the FIZZ1 activity comprises administering a small molecule that inhibits the FIZZ1 activity.

18. The method of claim 1, wherein the step of decreasing the FIZZ1 activity comprises reducing the FIZZ1 activity in tracheal smooth muscle of the mammal.

19. The method of claim 1, wherein the step of decreasing the FIZZ1 activity comprises reducing the FIZZ1 activity in airway epithelium.

20. The method of claim 1, wherein the airway hyperresponsiveness is associated with asthma.

21. A method for treating inflammation, the method comprising a step of decreasing FIZZ1 activity in a mammal in need of the treatment.

22-44. -44. (canceled)

45. A method for evaluating the ability of an agent to modulate airway inflammation, the method comprising the steps of:

(1) providing a trachea sample;

(2) culturing the trachea sample in a medium in the presence of FIZZ1;

(3) providing an agent to the medium;

(4) determining the histology of the trachea sample; and

(5) comparing the histology result from step (4) to a control to evaluate the ability of the agent to modulate airway inflammation.

46-50. -50. (canceled)

51. A method for evaluating the ability of an agent to modulate airway hyperresponsiveness, the method comprising the steps of:

(1) providing a trachea sample;

(2) culturing the trachea sample in a medium in the presence of FIZZ1;

(3) providing an agent to the medium;

(4) providing carbachol to the medium;

(5) determining a contractile response to carbachol of the trachea sample; and

(6) comparing the contractile response to carbachol determined in step (5) to a control to evaluate the ability of the agent to modulate airway hyperresponsiveness.

52-54. -54. (canceled)

55. A method of screening inhibitors of FIZZ1, the method comprising the steps of:

(1) providing a plurality of trachea samples, each of which is cultured in a medium in the presence of FIZZ1;

(2) providing a plurality of inhibitor candidates;

(3) determining a phenotype associated with FIZZ1-mediated airway inflammation or hyperresponsiveness in each of the plurality of trachea samples;

(4) comparing the phenotype determined in step (3) to a control; and

(5) identifying one or more inhibitors of FIZZ1 that reduce the phenotype based on the comparison result in step (4).

56-63. -63. (canceled)

66. A method for enhancing an immune response in a mammal, the method comprising administering a polypeptide encoding FIZZ1 protein (SEQ ID NO:

4), a fragment thereof, or a variant having at least 90% sequence identity to the FIZZ1 protein (SEQ ID NO;

4).

67. A vaccine comprising a polypeptide encoding FIZZ1 protein (SEQ ID NO:

4), a fragment thereof, or a variant having at least 90% sequence identity to the FIZZ1 protein (SEQ ID NO;

4).