Modulation of immunostimulatory properties of oligonucleotide-based compounds by utilizing modified immunostimulatory dinucleotides

Abstract

The invention relates to the therapeutic use of oligonucleotides as immunostimulatory agents in immunotherapy applications. More particularly, the invention provides immunomers and immunostimulatory oligonucleotides for use in methods for generating an immune response or for treating a patient in need of immunostimulation. The immunomers and immunostimulatory oligonucleotides of the invention preferably comprise novel purines. The immunomers according to the invention further comprise at least two oligonucleotides linked at their 3′ ends, internucleoside linkages or functionalized nucleobase or sugar to a non-nucleotidic linker, at least one of the oligonucleotides being an immunomodulatory oligonucleotide and having an accessible 5′ end.

1 . An immunostimulatory oligonucleotide having the structure 5′-TCTGTCG 2 TTCT-X-TCTTG 2 CTGTCT-5′; 5′-TCTGTC 2 GTTCT-X-TCTTGC 2 TGTCT-5′; 5′-CTGTCG 1 TTCTC-X-CTCTTG 1 CTGTC-5′; 5′-TCTGTCG 2 TTCT-X-TCTTG 2 CTGTCT-5′; 5′-TCG 2 TCG 2 TTCTG-X-GTCTTG2CTG 2 CT-5′ and 5′-TC 2 GTC 2 GTTCTG-X-GTCTTGC 2 TGC 2 T-5′; wherein X is a glycerol linker and G 1  is 2′-deoxy-7-deazaguanosine, G 2  is arabinoguanosine and C 2  is arabinocytidine. 
     
     
         2 . A composition comprising the oligonucleotide according to  claim 1  and a physiologically acceptable carrier. 
     
     
         3 . A method for generating an immune response in a vertebrate, the method comprising administering to the vertebrate an immunostimulatory oligonucleotide having the structure 5″-TCTGTCG 2 TTCT-X-TCTTG 2 CTGTCT-5′; 5′-TCTGTC 2 GTTCT-X-TCTTGC 2 TGTCT-5′; 5′-CTGTCG 1 TTCTC-X-CTCTTG 1 CTGTC-5′; 5′-TCTGTCG 2 TTCT-X-TCTTG 2 CTGTCT-5′; 5′-TCG 2 TCG 2 TTCTG-X-GTCTTG 2 CTG 2 CT-5′ and 5′-TC 2 GTC2GTTCTG-X-GTCTTGC 2 TGC 2 T-5′; wherein X is a glycerol linker and G 1  is 2′-deoxy-7-deazaguanosine, G 2  is arabinoguanosine and C 2  is arabinocytidine. 
     
     
         4 . A composition comprising an oligonucleotide according to  claim 1  and an antibody, antisense oligonucleotide, protein, antigen, allergen, chemotherapeutic agent or adjuvant. 
     
     
         5 . The composition according to  claim 2 , further comprising an antibody, antisense oligonucleotide, protein, antigen, allergen, chemotherapeutic agent or adjuvant. 
     
     
         6 . The method according to  claim 3 , further comprising administering an antibody, antisense oligonucleotide, protein, antigen, allergen, chemotherapeutic agent or adjuvant. 
     
     
         7 . The method according to  claim 3 , wherein the route of administration is selected from parenteral, oral, sublingual, transdermal, topical, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop and mouthwash.