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

• US 20050197314A1
• Filed: 04/19/2005
• Published: 09/08/2005
• Est. Priority Date: 04/03/1998
• Status: Abandoned Application

• Current Assignee: University of Iowa Research Foundation
• Original Assignee: University of Iowa Research Foundation
• Inventors: Krieg, Arthur M., Weiner, George
• Application Number:
  US11/110,189
• Publication Number:
  US 20050197314A1
• Time in Patent Office: Days
• 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

1-20. -20. (canceled)

21. 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 a Flt3 ligand, and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula;

22. The method of claim 21, wherein the Flt3 ligand and the antigen are fused to form an antigen-Flt3 ligand fusion protein.

23. The method of claim 21, wherein the antigen is selected from the group consisting of a tumor antigen, a microbial antigen, and an allergen.

24. The method of claim 23, wherein the antigen is a tumor antigen.

25. The method of claim 21, wherein the antigen is administered to the subject in conjunction with the immunostimulatory CpG oligonucleotide and the Flt3 ligand.

26. The method of claim 21, wherein the subject is passively exposed to the antigen.

27. The method of claim 21, wherein the subject has a neoplastic disorder.

28. The method of claim 21, wherein the subject has a viral infection.

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

30. The method of claim 29, 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.

31. 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;

5′

X₁CGX₂ 3′

wherein the oligonucleotide is 8 to 100 nucleotides long, wherein C is unmethylated and wherein X₁ and X₂ are nucleotides; and

a Flt3 ligand.

32. The composition of claim 31, further comprising an antigen and wherein the antigen and the CpG oligonucleotide are not conjugated.

33. The composition of claim 33, wherein the antigen is selected from the group consisting of a cancer antigen, a microbial antigen, and an allergen.

34. 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 a Flt3 ligand, and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula;

5′

X₁CGX₂ 3′

wherein the oligonucleotide is 8 to 100 nucleotides long, wherein C is unmethylated and wherein X₁ and X₂ are nucleotides, whereby an antigen is optionally additionally administered, and wherein the antigen and the CpG oligonucleotide are not conjugated.

35. The method of claim 34, wherein the antigen is a tumor antigen.

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

administering to the tumor of a subject having a neoplastic disorder a Flt3 ligand, and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula;

5′

X₁CGX₂ 3′

wherein the oligonucleotide is 8 to 100 nucleotides long, wherein C is unmethylated and wherein X₁ and X₂ are nucleotides, in an amount effective for synergistically increasing survival time of the subject with respect to a subject administered the immunostimulatory CpG oligonucleotide or the Flt3 ligand alone.

37. The method of claim 36, 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.

38. The method of claim 36, wherein the immunostimulatory CpG oligonucleotide and the Flt3 ligand are injected directly into the tumor.

39. The method of claim 36, wherein the subject is a non-human animal.

40. The method of claim 39, 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.