Nucleic acid derivative having immunostimulatory activity
The purpose of the present invention is to provide double-stranded oligonucleotides comprising the CpG oligonucleotide mentioned below, as a nucleic acid derivative having an immunostimulatory activity. An adjuvant comprising a double-stranded oligonucleotide, wherein a first strand is a CpG oligonucleotide consisting of 8 to 50 nucleotides, a second strand is an oligonucleotide consisting of 8 to 60 nucleotides and comprising a sequence capable of hybridizing with the first strand, and a lipid binds to the second strand through a linker.
1. A double-stranded oligonucleotide, wherein
a first strand consists of a CpG oligonucleotide consisting of 8 to 50 nucleotides,
a second strand of the double-stranded oligonucleotide is 8 to 60 nucleotides and capable of hybridizing with the first strand,
wherein the second strand is not an oligonucleotide all of which nucleosides consist of an RNA nucleoside,
wherein the length of the second strand is 50% or more of that of the first strand, and
wherein a lipid comprising C12 to C30 hydrocarbon chain(s) is bound to the second strand through a linker.
2. The double-stranded oligonucleotide of claim 1 , wherein the oligonucleotide of the second strand is an oligonucleotide consisting of DNA nucleosides and/or nucleoside derivatives.
3. The double-stranded oligonucleotide of claim 2 , wherein the nucleoside derivative is a nucleoside having a substituent at the 2′ position of the sugar and/or a nucleoside having a bridge structure between the 4′ and 2′ positions of the sugar.
4. The double-stranded oligonucleotide of claim 3 , wherein the bridge structure between the 4′ and 2′ positions of the sugar is 4′-(CH 2 )m-O-2′, wherein m is an integer of 1 to 4.
5. The double-stranded oligonucleotide of claim 1 , wherein the lipid is a diacyl lipid.
6. The double-stranded oligonucleotide of claim 1 , wherein the lipid binds at the 3′ end and/or 5′ end of the second strand.
7. The double-stranded oligonucleotide of claim 1 , wherein the linker is an oligonucleotide linker.
8. The double-stranded oligonucleotide of claim 7 , wherein the linker is -(dX 1 )u-, wherein X 1 is each independently, A, G, C or T, and u is an integer of 1 to 8.
9. A method for treating a cancer or an infectious disease, comprising administering the double-stranded oligonucleotide of claim 1 to a subject in need thereof.
10. The method of claim 9 , wherein the double-stranded oligonucleotide is administered in combination with an antigen.
11. The double-stranded oligonucleotide of claim 5 , wherein the diacyl lipid is
wherein p and q are each independently an integer of 10 to 28.
12. The double-stranded oligonucleotide of claim 1 , wherein the first strand has the sequence set forth in SEQ ID NO:13.
13. A double-stranded oligonucleotide having a first strand and a second strand, wherein the first strand is represented by the formula:
and wherein the second strand is represented by the formula:
14. A method for treating a cancer or an infectious disease, comprising administering the double-stranded oligonucleotide of claim 11 to a subject in need thereof.
15. The method of claim 14 , wherein the double-stranded oligonucleotide is administered in combination with an antigen.
16. A method for treating a cancer or an infectious disease, comprising administering the double-stranded oligonucleotide of claim 12 to a subject in need thereof.
17. The method of claim 16 , wherein the double-stranded oligonucleotide is administered in combination with an antigen.
18. A method for treating a cancer or an infectious disease, comprising administering the double-stranded oligonucleotide of claim 13 to a subject in need thereof.
19. The method of claim 18 , wherein the double-stranded oligonucleotide is administered in combination with an antigen.