Methods of treating cancer using immunostimulatory oligonucleotides

• US 8,008,266 B2
• Filed: 11/21/2003
• Issued: 08/30/2011
• Est. Priority Date: 07/15/1994
• Status: Expired due to Fees

• Current Assignee: United States As Represented By The Secretary Department of Health and Human Services, University of Iowa Research Foundation
• Original Assignee: United States Department Of Health And Human Services (Government of the United States of America), Iowa Research Foundation, Coley Pharmaceutical Group, Inc. (Pfizer Inc.)
• Inventors: Krieg, Arthur M., Klinman, Dennis, Steinberg, Alfred D.
• Primary Examiner(s): GUSSOW, ANNE
• Application Number:
  US10/719,493
• Publication Number:
  US 20040087538A1
• Time in Patent Office: 2,839 Days
• Field of Search: 514/44, 536/23.1, 530/387.1, 530/387.3, 530/388.22, 530/388.8, 424/130.1, 424/136.1, 424/142.1, 424/143.1, 424/155.1
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/711 Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/117 : Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
• CPC Class Codes: C12N 2310/17 : Immunomodulatory nucleic acids
• CPC Class Codes: C12N 2310/315 : Phosphorothioates
• CPC Class Codes: C12Q 1/68 : involving nucleic acids
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Nucleic acid sequences containing unmethylated CpG dinucleotides that modulate an immune response including stimulating a Th1 pattern of immune activation, cytokine production, NK lytic activity, and B cell proliferation are disclosed. The sequences are also useful as a synthetic adjuvant.

Claims

1. A method for treating cancer, comprising:

administering to a human subject an effective amount for treating cancer of a CpG immunostimulatory oligonucleotide having at least one unmethylated CpG dinucleotide, wherein at least one nucleotide of the stabilized CpG immunostimulatory oligonucleotide has a phosphate backbone modification and wherein the oligonucleotide is 8 to 100 nucleotides in length, wherein the phosphate backbone modification is a phosphorothioate modification, further comprising administering an antigen.

2. The method of claim 1, further comprising administering a chemotherapeutic agent.

3. The method of claim 1, further comprising administering a cancer immunotherapeutic agent.

4. The method of claim 1, wherein the cancer is brain cancer.

5. The method of claim 1, wherein the cancer is lung cancer.

6. The method of claim 1, wherein the cancer is ovarian cancer.

7. The method of claim 1, wherein the cancer is breast cancer.

8. The method of claim 1, wherein the cancer is prostate cancer.

9. The method of claim 1, wherein the cancer is colon cancer.

10. The method of claim 1, wherein the cancer is leukemia.

11. The method of claim 1, wherein the cancer is carcinoma.

12. The method of claim 1, wherein the cancer is sarcoma.

13. The method of claim 1, wherein the CpG immunostimulatory oligonucleotide comprises:

5′

X₁X₂CGX₃X₄3′

wherein X₁X₂ and X₃X₄ are nucleotides.

14. The method of claim 13, wherein X₃X₄ are nucleotides selected from the group consisting of:

TpT, and TpC.

15. The method of claim 13, wherein X₁X₂ are GpA and X₃X₄ are TpT.

16. The method of claim 13, wherein X₁X₂ are both purines and X₃X₄ are both pyrimidines.

17. The method of claim 13, wherein X₁X₂ are GpA and X₃X₄ are both pyrimidines.

18. The method of claim 13, wherein the oligonucleotide is 8 to 40 nucleotides in length.

19. The method of claim 13, wherein 5′

X₁ X₂CGX₃ X₄3′

is not palindromic.

20. The method of claim 1, wherein the CpG immunostimulatory oligonucleotide includes at least two CpG motifs.

21. The method of claim 20, wherein at least one of the at least two CpG motifs is not palindromic.

22. The method of claim 1, wherein the oligonucleotide is administered prior to a chemotherapy.

23. The method of claim 1, wherein the oligonucleotide is administered subcutaneously.

24. A method for treating non small cell lung carcinoma (NSCLC) in a human subject, comprising

administering to a human subject having NSCLC an effective amount to treat NSCLC of an immunostimulatory oligonucleotide that includes at least one unmethylated CpG dinucleotide, wherein the immunostimulatory oligonucleotide includes a phosphate backbone modification and, wherein the oligonucleotide is 8 to 100 nucleotides in length, wherein the phosphate backbone modification is a phosphorothioate modification, further comprising administering an antigen.

25. The method of claim 24, further comprising administering a chemotherapeutic agent.

26. The method of claim 24, further comprising administering an immunotherapeutic agent.

27. The method of claim 24, wherein the oligonucleotide is 8 to 40 nucleotides in length.

28. The method of claim 24, wherein the CpG immunostimulatory oligonucleotide includes at least two CpG motifs.

29. The method of claim 28, wherein at least one of the at least two CpG motifs is not palindromic.

30. The method of claim 24, wherein the oligonucleotide is administered subcutaneously.