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

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.

We claim:  
     
         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 and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula:   5′X 1 CGX 2 3′   wherein the oligonucleotide includes at least 8 nucleotides wherein C and G are unmethylated and wherein X 1  and X 2  are nucleotides.    
     
     
         2 . The method of  claim 1 , wherein the cytokine is selected from the group consisting of GM-CSF, IL-3, IL-5, IL-12, and interferon-γ.  
     
     
         3 . The method of  claim 1 , wherein the immunopotentiating cytokine is an antigen-cytokine fusion protein.  
     
     
         4 . The method of  claim 3 , wherein the antigen-cytokine fusion protein is an antigen-GM-CSF fusion protein.  
     
     
         5 . The method of  claim 1 , wherein the antigen is a selected from the group consisting of a tumor antigen, a microbial antigen, and an allergen.  
     
     
         6 . The method of  claim 5 , wherein the antigen is a tumor antigen.  
     
     
         7 . The method of  claim 1 , wherein the antigen is administered to the subject in conjunction with the immunostimulatory CpG oligonucleotide and the immunopotentiating cytokine.  
     
     
         8 . The method of  claim 1 , wherein the subject is passively exposed to the antigen.  
     
     
         9 . The method of  claim 1 , wherein the subject has a neoplastic disorder.  
     
     
         10 . The method of  claim 1 , wherein the subject has a viral infection.  
     
     
         11 . 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′X 1 CGX 2 3′   wherein the oligonucleotide includes at least 8 nucleotides wherein C and G are unmethylated and wherein X 1  and X 2  are nucleotides; and    a cytokine selected from the group consisting of GM-CSF, IL-4, TNFα, Flt3 ligand, and IL-3.    
     
     
         11 . The composition of  claim 10 , wherein the cytokine is GM-CSF.  
     
     
         12 . The composition of  claim 10 , further comprising an antigen.  
     
     
         13 . The composition of  claim 12 , wherein the antigen is selected from the group consisting of a cancer antigen, a microbial antigen, and an allergen.  
     
     
         14 . 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 and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula:   5′X 1 CGX 2 3′   wherein the oligonucleotide includes at least 8 nucleotides wherein C and G are unmethylated and wherein X 1  and X 2  are nucleotides.    
     
     
         15 . The method of  claim 14 , wherein the cytokine is selected from the group consisting of GM-CSF, IL-3, IL-5, IL-12, and interferon-γ.  
     
     
         16 . The method of  claim 14 , wherein the antigen is a tumor antigen.  
     
     
         17 . 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 and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula:   5′X 1 CGX 2 3′   wherein the oligonucleotide includes at least 8 nucleotides wherein C and G are unmethylated and wherein X 1  and X 2  are nucleotides, in an amount effective for synergistically increasing survival time of the subject with respect to a subject administered the immunostimulatory CpG oligonculeotide or the immunopotentiating cytokine alone.    
     
     
         18 . The method of  claim 17 , wherein the tumor is selected from the group consisting of a tumor of the brain, lung, ovary, breast, prostate, colon, skin, and blood.  
     
     
         19 . The method of  claim 17 , wherein the immunostimulatory CpG oligonucleotide and the immunopotentiating cytokine are injected directly into the tumor.  
     
     
         20 . A contraceptive method, comprising: 
 administering to a subject an antigen, an immunopotentiating cytokine and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula:   5′X 1 CGX 2 3′   wherein the oligonucleotide includes at least 8 nucleotides wherein C and G are unmethylated and wherein X 1  and X 2  are nucleotides, wherein the antigen is an antigen selected from the group consisting of a gonadal cell antigen and an antigen from a cytokine or hormone required for the maintenance of a gonadal cell.