Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines

• US 6,218,371 B1
• Filed: 04/02/1999
• Issued: 04/17/2001
• Est. Priority Date: 04/03/1998
• Status: Expired due to Fees

• Current Assignee: University of Iowa Research Foundation
• Original Assignee: University of Iowa Research Foundation
• Inventors: Weiner, George, Krieg, Arthur M.
• Primary Examiner(s): Yucel, Remy
• Assistant Examiner(s): ZARA, JANE J
• Application Number:
  US09/286,098
• Time in Patent Office: 746 Days
• Field of Search: 424/180.1, 424/184.1, 424/185.1, 424/192.1, 424/193.1, 424/278.1, 435/91.1, 435/91.5, 435/325, 435/455, 435/6, 514/44, 530/300, 530/350, 530/351, 536/23.1, 536/23.4, 536/23.5, 536/23.51, 536/23.52, 536/25.3
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 2039/55522 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 2039/55527 Interleukins
• CPC Class Codes: A61K 2039/55538 IL-12
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• 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 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/04 Immunostimulants
• 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

Abstract

The present invention relates to synergistic combinations of immunostimulatory CpG oligonucleotides and immunopotentiating cytokines. In particular, the invention relates to methods of stimulating an immune response using the synergistic combination of compounds and products related thereto.

Claims

1. A method for stimulating an immune response in a subject, comprising:

administering to a subject exposed to an antigen an effective amount for inducing a synergistic antigen specific immune response of an immunopotentiating cytokine selected from the group consisting of GM-CSF, IL-2, IL-4 and IFN-γ

, and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula;

2. A The method of claim 1, wherein the immunopotentiating cytokine is an antigen-cytokine fusion protein.

3. The method of claim 2, wherein the antigen-cytokine fusion protein is an antigen-GM-CSF fusion protein.

4. The method of claim 1, wherein the antigen is selected from the group consisting of a tumor antigen, a microbial antigen, and an allergen.

5. The method of claim 4, wherein the antigen is a tumor antigen.

6. The method of claim 1, wherein the antigen is administered to the subject in conjunction with the immunostimulatory CpG oligonucleotide and the immunopotentiating cytokine.

7. The method of claim 1, wherein the subject is passively exposed to the antigen.

8. The method of claim 1, wherein the subject has a neoplastic disorder.

9. The method of claim 1, wherein the subject has a viral infection.

10. The method of claim 1, wherein the subject is a non-human animal.

11. The method of claim 10, wherein the non-human animal is a vertebrate animal selected from the group consisting of a dog, a cat, a horse, a cow, a pig, a sheep, a goat, a chicken, and a primate.

12. A composition, comprising:

an effective amount for synergistically activating a dendritic cell of an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula;

13. The composition of claim 12, wherein the cytokine is GM-CSF.

14. The composition of claim 12, further comprising an antigen and wherein the antigen and the CpG oligonucleotide are not conjugated.

15. The composition of claim 14, wherein the antigen is selected from the group consisting of a cancer antigen, a microbial antigen, and an allergen.

16. A method for activating a dendritic cell, comprising:

contacting a dendritic cell exposed to an antigen with an effective amount for synergistically activating a dendritic cell of an immunopotentiating cytokine selected from the group consisting of GM-CSF, IL-2, IL-4 and IFN-γ

, and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula;

17. The method of claim 16, wherein the antigen is a tumor antigen.

18. A method for treating a subject having a neoplastic disorder, comprising:

administering to the tumor of a subject having a neoplastic disorder an immunopotentiating cytokine selected from the group consisting of GM-CSF, IL-2, IL-4 and IFN-γ

, and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula;

19. The method of claim 18, wherein the tumor is selected from the group consisting of a lymphoma and a tumor of the brain, lung, ovary, breast, prostate, colon, and skin.

20. The method of claim 18, wherein the immunostimulatory CpG oligonucleotide and the immunopotentiating cytokine are injected directly into the tumor.

21. The method of claim 18, wherein the subject is a non-human animal.

22. The method of claim 21, wherein the non-human animal is a vertebrate animal selected from the group consisting of a dog, a cat, a horse, a cow, a pig, a sheep, a goat, a chicken, and a primate.

23. The method of claim 22, wherein the tumor is selected from the group consisting of lymphoma an a tumor of the brain, lung, ovary, breast, prostate, colon, and skin.