Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides
AssigneeHybridon, Inc.
InventorSudhir Agrawal
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Abstract
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.
Claims60
A method for reducing the immunostimulatory effect of a CpG-containing oligonucleotide, the method comprising introducing a 3′ substituted nucleoside into the oligonucleotide at a position adjacent to, and on the 5′ side of the CpG dinucleotide.
A CpG-containing oligonucleotide having a reduced immunostimulatory effect, wherein the oligonucleotide comprises a 3′ substituted nucleoside at a position adjacent to, and on the 5′ side of the CpG dinucleotide.
A method for obtaining an antisense-specific reduction in the expression of a gene in a mammal, the method comprising administering to the mammal a CpG-containing oligonucleotide having a reduced immunostimulatory effect, wherein the oligonucleotide comprises a 3′ substituted nucleoside at a position adjacent to, and on the 5′ side of the CpG dinucleotide.
A method for increasing the immunostimulatory effect of a CpG-containing oligonucleotide, the method comprising introducing into the oligonucleotide a 3′ substituted nucleoside 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 nucleosides 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
A CpG-containing oligonucleotide having increased immunostimulatory effects, the oligonucleotide comprising a 3′ substituted nucleoside 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 nucleosides 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
A method for inducing an immune response in a mammal, the method comprising administering to the mammal an oligonucleotide comprising a 3′ substituted nucleoside 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 nucleosides 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
A method for increasing the immunostimulatory effect of a CpG-containing oligonucleotide, the method comprising introducing into the oligonucleotide an uncharged 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 nucleosides 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
A CpG-containing oligonucleotide having increased immunostimulatory effects, the oligonucleotide comprising an uncharged 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 nucleosides 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
A method for inducing an immune response in a mammal, the method comprising administering to the mammal an oligonucleotide comprising an uncharged 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 nucleosides 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
A method for reducing the immunostimulatory effect of a CpG-containing oligonucleotide, the method comprising introducing a 2′-5′ internucleoside linkage into the oligonucleotide at a position adjacent to, and on the 5′ side of the CpG dinucleotide.
A CpG-containing oligonucleotide having a reduced immunostimulatory effect, wherein the oligonucleotide comprises a 2′-5′ internucleoside linkage at a position adjacent to, and on the 5′ side of the CpG dinucleotide.
A method for obtaining an antisense-specific reduction in the expression of a gene in a mammal, the method comprising administering to the mammal a CpG-containing oligonucleotide having a reduced immunostimulatory effect, wherein the oligonucleotide comprises a 2′-5′ internucleoside linkage at a position adjacent to, and on the 5′ side of the CpG dinucleotide.
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 nucleosides 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
A CpG-containing oligonucleotide having increased immunostimulatory effects, the oligonucleotide comprising 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 nucleosides 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
A method for inducing an immune response in a mammal, the method comprising administering to the mammal an oligonucleotide comprising 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 nucleosides 3′ to the CpG dinucleotide, 3rd nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, 5th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3 ′ to the CpG dinucleotide, 6th nucleoside 3′ to the CpG dinucleotide, 4th nucleoside 3′ to the CpG dinucleotide, and combinations thereof.
Dependencies are inferred from the claim text.