Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides
View Patent ↗The invention provides methods for modulating the immune response caused by CpG-containing oligonucleotides. The methods according to the invention enable both decreasing the immunostimulatory effect for antisense applications, as well as increasing the immunostimulatory effect for immunotherapy applications.
1. A method for increasing the immunostimulatory effect of a CpG-containing oligonucleotide, the method comprising introducing into the oligonucleotide a 2′-5′ internucleoside linkage at a position selected from the group consisting of 3rd nucleoside 5′ to the CpG dinucleotide, 4th nucleoside 5′ to the CpG dinucleotide, 5th nucleoside 5′ to the CpG dinucleotide, 6th nucleoside 5′ to the CpG dinucleotide, 2 nd nucleoside 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
2. The method according to claim 1 , wherein the 2′-5′ intemucleoside linkage is an alkyiphosphonate.
3. A CpG-containing oligonucleotide having increased immunostimulatory effects, the oligonucleotide comprising a 2′-5′ intemucleoside linkage at a position selected from the group consisting of 3rd nucleoside 5′ to the CpG dinucleotide, 4th nucleoside 5′ to the CpG dinucleotide, 5th nucleoside 5′ to the CpG dinucleotide, 6th nucleoside 5′ to the CpG dinucleotide, 2 nd nucleoside 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
4. The oligonucleotide according to claim 3 , wherein the oligonucleotide is not an antisense oligonucleotide.
5. The oligonucleotide according to claim 3 , wherein the oligonucleotide is from about 6 to about 50 nucleotides in length.
6. The oligonucleotide according to claim 3 , wherein the oligonucleotide further comprise modified intemucleotide linkages or modified sugars to improve stability.
7. A method for inducing an immune response in a mammal, the method comprising administering to the mammal an oligonucleotide comprising a 2′-5′ intemucleoside linkage at a position selected from the group consisting of 3rd nucleoside 5′ to the CpG dinucleotide, 4th nucleoside 5′ to the CpG dinucleotide, 5th nucleoside 5′ to the CpG dinucleotide, 6th nucleoside 5′ to the CpG dinucleotide, 2 nd nucleoside 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
8. The method according to claim 7 , wherein the oligonucleotide is not an antisense oligonucleotide.
9. The method according to claim 2 , wherein the alkylphosphonate is a methylphosphonate.
10. The oligonucleotide according to claim 3 , wherein the 2′-5′ intemucleoside linkage is an alkylphosphonate.
11. The oligonucleotide according to claim 10 , wherein the alkylphosphonate is a methylphosphonate.
12. The method according to claim 7 , wherein the 2′-5′ intemucleoside linkage is an alkylphosphonate.
13. The method according to claim 12 , wherein the alkylphosphonate is a methylphosphonate.