Oligonucleotides for reduction of PD-L1 expression

1. An antisense oligonucleotide of formula CCtatttaacatcAGAC (SEQ ID NO: 640), wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine and all internucleoside linkages are phosphorothioate internucleoside linkages.

2. An antisense oligonucleotide conjugate comprising the oligonucleotide of claim 1 and a conjugate moiety covalently attached to the oligonucleotide, wherein a linker is present between the oligonucleotide and the conjugate moiety.

3. The antisense oligonucleotide conjugate of claim 2 , wherein the conjugate moiety comprises an asialoglycoprotein receptor targeting moiety.

4. The antisense oligonucleotide conjugate of claim 2 , wherein the linker is a physiologically labile linker.

5. The antisense oligonucleotide conjugate of claim 4 , wherein the physiologically labile linker is a nuclease susceptible linker.

6. The antisense oligonucleotide conjugate of claim 3 wherein the asialoglycoprotein receptor targeting moiety is a tri-valent N-acetylgalactosamine (GalNAc) moiety; and wherein the linker is a physiologically labile linker that comprises a cytidine- adenosine dinucleotide.

7. A pharmaceutical composition comprising the antisense oligonucleotide of claim 1 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

8. A pharmaceutical composition comprising the antisense oligonucleotide conjugate of claim 6 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

9. The pharmaceutical composition according to claim 7 , wherein the pharmaceutically acceptable diluent is sterile phosphate buffered saline.

10. The pharmaceutical composition according to claim 7 , wherein the pharmaceutically acceptable salt is sodium.

11. The pharmaceutical composition according to claim 8 , wherein the pharmaceutically acceptable diluent is sterile phosphate buffered saline.

12. The pharmaceutical composition according to claim 8 , wherein the pharmaceutically acceptable salt is sodium.

13. An in vivo or in vitro method for modulating PD-L1 expression in a target cell which is expressing PD-L1, said method comprising administering the antisense oligonucleotide of claim 1 in an effective amount to said cell.

14. An in vivo or in vitro method for modulating PD-L1 expression in a target cell which is expressing PD-L1, said method comprising administering the antisense oligonucleotide conjugate of claim 6 in an effective amount to said cell.

15. A method for restoration of immune response against a virus, said method comprising administering a therapeutically effective amount of the antisense oligonucleotide of claim 1 to a subject infected with a virus.

16. A method for restoration of immune response against a virus, said method comprising administering a therapeutically effective amount of the antisense oligonucleotide conjugate of claim 6 to a subject infected with a virus.

17. The method according to claim 15 , wherein the virus is HBV.

18. The method according to claim 16 , wherein the virus is HBV.

19. The method according to claim 15 , wherein the restoration of the immune response is an increase in the liver of CD 8 + T cells specific to one or more HBV antigens when compared to a control.

20. The method according to claim 16 , wherein the restoration of the immune response is an increase in the liver of CD 8 + T cells specific to one or more HBV antigens when compared to a control.

21. A method for restoration of immune response against a parasite, the method comprising administering a therapeutically effective amount of the antisense oligonucleotide of claim 1 to a subject infected with a parasite.

22. A method for restoration of immune response against a parasite, the method comprising administering a therapeutically effective amount of the antisense oligonucleotide conjugate of claim 6 to a subject infected with a parasite.

23. A method for treating HBV infection comprising administering a therapeutically effective amount of the antisense oligonucleotide of claim 1 to a subject suffering from HBV infection.

24. A method for treating HBV infection comprising administering a therapeutically effective amount of the antisense oligonucleotide conjugate of claim 6 to a subject suffering from HBV infection.

25. A pharmaceutically acceptable salt of an antisense oligonucleotide of formula CCtatttaacatcAGAC (SEQ ID NO: 640), wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine and all internucleoside linkages are phosphorothioate internucleoside linkages.

26. The pharmaceutically acceptable salt of the antisense oligonucleotide of claim 25 , which is a sodium salt.

27. A pharmaceutically acceptable salt of an antisense oligonucleotide conjugate comprising an antisense oligonucleotide of formula CCtatttaacatcAGAC (SEQ ID NO: 640), wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine and all internucleoside linkages are phosphorothioate internucleoside linkages, wherein a linker is present between the oligonucleotide and the conjugate moiety; further wherein the conjugate moiety comprises a asialoglycoprotein receptor targeting moiety that is a tri-valent N-acetylgalactosamine (GalNAc) moiety; further wherein the linker is a physiologically labile linker that comprises a cytidine-adenosine dinucleotide.

28. The pharmaceutically acceptable salt of the antisense oligonucleotide conjugate of claim 27 , which is a sodium salt.

29. The antisense oligonucleotide conjugate of claim 3 , wherein the asialoglycoprotein receptor targeting moiety is a tri-valent N-acetylgalactosamine (GalNAc) moiety.

30. The antisense oligonucleotide conjugate of claim 5 , wherein the nuclease susceptible linker is a cytidine-adenosine dinucleotide.