Modulation of immunostimulatory activity of immunostimulatory oligonucleotide analogs by positional chemical changes
The invention relates to the therapeutic use of oligonucleotides or oligonucleotide analogs as immunostimulatory agents in immunotherapy applications. The invention provides methods for enhancing the immune response caused by immunostimulatory oligonucleotide compounds.
1. A method for modulating the immunostimulatory effect of an immunostimulatory oligonucleotide compound having an immunostimulatory dinucleotide selected from the group consisting of C*pG, CpG*, and C*pG*, wherein C is 2′-deoxycytidine, C* is selected from 5-hydroxycytosine, 5-hydroxymethylcytosine, N4-alkylcytosine, and 4-thiouracil, G is 2′-deoxyguanosine and G* is selected from 7-deazaguanosine and 6-thioguanosine, comprising introducing a 1′,2′-dideoxyribose, C3-linker, Spacer 9, Spacer 18, β-L-deoxynucleoside, or 2′-O-propargyl-ribonucleoside into the 5′ and/or 3′ side of the immunostimulatory dinucleotide.
2. The method according to claim 1 , comprising introducing into the oligonucleotide a 1′,2′-dideoxyribose.
3. The method according to claim 1 , comprising introducing into the oligonucleotide a C3-linker.
4. The method according to claim 1 , comprising introducing into the oligonucleotide a Spacer 9.
5. The method according to claim 1 , comprising introducing into the oligonucleotide a Spacer 18.
6. The method according to claim 1 , wherein the C3 linker is 2-aminobutyl-1,3-propanediol.
7. The method according to claim 1 , comprising introducing into the oligonucleotide a β-L-deoxynucleoside.
8. The method according to claim 1 , comprising introducing into the oligonucleotide a 2′-O-propargyl-ribonucleoside.
9. The method according to claim 1 , wherein G* is 7-deazaguanosine.
10. An immunostimulatory oligonucleotide produced by the method according to claim 1 .