Long term disease modification using immunostimulatory oligonucleotides

• US 8,815,817 B2
• Filed: 05/15/2009
• Issued: 08/26/2014
• Est. Priority Date: 05/15/2008
• Status: Active Grant

• Current Assignee: Dynamax Technologies Limited
• Original Assignee: Dynamax Technologies Limited
• Inventors: Hessel, Edith M., Coffman, Robert L.
• Primary Examiner(s): ZARA, JANE J
• Application Number:
  US12/992,590
• Publication Number:
  US 20110118341A1
• Time in Patent Office: 1,929 Days
• Field of Search: 435/6, 435/91.1, 435/455, 435/6.1, 435/91.31, 514/1, 514/2, 514/44, 514/1.1, 514/44.R, 536/23.1
• US Class Current: 514/44
• CPC Class Codes: A01K 2207/10 Animals modified by protein administration, for non-therapeutic purpose
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0387 Animal model for diseases of the immune system
• CPC Class Codes: A01K 67/027 New or modified breeds of vertebrates
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/57 characterised by the type of response, e.g. Th1, Th2
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 39/35 Allergens
• CPC Class Codes: A61K 39/36 from pollen
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14

Abstract

The invention provides methods for treating asthma by using multiple rounds of administration of ISS over a period of time to confer long term disease modification.

Claims

1. A method for treating an individual in need thereof comprising administering to the individual multiple administrations of an effective amount of a CpG-containing ISS wherein the CpG-containing ISS is administered at least 5 times and wherein the administration results in a long term disease modification of allergic rhinitis, wherein the long term disease modification is determined by the reduction of one or more allergic rhinitis symptoms for a period of at least 3 weeks after the last administration of the ISS, and wherein the ISS is administered to the individual from about 3 days to about 4 weeks in between the dosages.

2. The method of claim 1 wherein the multiple administrations occur on a weekly basis.

3. The method of claim 1 wherein the ISS is administered every 14 days.

4. The method of claim 1 wherein the long term disease modification is a decrease of Th2 response in the individual.

5. The method of claim 4 wherein the decrease of Th2 response in the individual is a decrease of any one of the cytokines selected from group consisting of IL-4, IL-5, IL-10, and IL-13.

6. The method of claim 1 wherein the long term disease modification lasts at least 13 weeks after the last administration of the ISS.

7. The method of claim 1 wherein the individual in need thereof has allergic rhinitis.

8. The method of claim 1 wherein the ISS is selected from the group consisting of 1018 ISS (SEQ ID NO:

1) and a chimeric immunomodulatory compound.

9. The method of claim 1 wherein the ISS is 1018 ISS (SEQ ID NO:

1).

10. The method of claim 1 wherein the ISS is administered in the presence of an allergen.

11. The method of claim 10 wherein the allergen is an adventitious allergen.

12. The method of claim 11 wherein the adventitious allergen is ragweed.

13. The method of claim 10 wherein the allergen is a seasonal allergen.

14. The method of claim 1 wherein the individual is a human with allergic rhinitis but not asthma.

15. The method of claim 4 wherein the decrease of Th2 response in an individual is a decrease in eosinophil infiltration in the airways.

16. The method of claim 1 wherein the modification lasts at least 8 weeks after the last administration of the ISS.

17. The method of claim 1 wherein the ISS is 5′

-N_x(TCG(N_q)_yN_w(X₁X₂CGX₂′

X₁′

(CG)_p)_z (SEQ ID NO;

14) wherein N are nucleosides with x=0-3, y=1-4, w=−

2, −

1, 0, 1 or 2, p=0 or 1, q=0, 1 or 2, and z=1-20, wherein X₁ and X₁′

, X₂ and X₂′

are self-complimentary, and wherein the 5′

T of the (TCG(N_q))_y (SEQ ID NO;

3) sequence is 0-3 bases from the 5′

end of the polynucleotide.

18. The method of claim 1 wherein the ISS comprises (1) at least one palindromic sequence of at least 8 bases in length, wherein the palindromic sequence comprises at least one CG dinucleotide, and (2) at least one TCG trinucleotide sequence at or near the 5′

end of the polynucleotide.

19. The method of claim 1 or 8 or 17 or 18 wherein the ISS is an unconjugated ISS.

20. The method of claim 1 or 8 or 17 or 18 wherein the ISS comprises phosphorothioate linkages.

21. The method of claim 1 or 8 or 17 or 18 wherein the CpG-containing ISS is administered at least 8 times.

22. The method of claim 1 or 8 or 17 or 18 wherein the ISS is less than 200 bases in length.