Oligonucleotides for reduction of PD-L1 expression
The present invention relates to antisense oligonucleotides that are capable of reducing expression of PD-L1 in a target cell. The oligonucleotides hybridize to PD-L1 mRNA. The present invention further relates to conjugates of the oligonucleotide and pharmaceutical compositions and methods for treatment of viral liver infections such as HBV, HCV and HDV; parasite infections such as malaria, toxoplasmosis, leishmaniasis and trypanosomiasis or liver cancer or metastases in the liver using the oligonucleotide.
1. An antisense oligonucleotide of formula CTAattgtagtagtaCTC (SEQ ID NO: 466), 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 said oligonucleotide.
3. The antisense oligonucleotide conjugate of claim 2 , wherein a linker is present between the oligonucleotide and the conjugate moiety.
4. The antisense oligonucleotide conjugate of claim 3 , wherein the conjugate moiety is an asialoglycoprotein receptor targeting moiety.
5. The antisense oligonucleotide conjugate of claim 4 , wherein the asialoglycoprotein receptor targeting moiety is a tri-valent N-acetylgalactosamine (GalNAc) moiety.
6. The antisense oligonucleotide conjugate of claim 3 , wherein the linker is a physiologically labile linker.
7. The antisense oligonucleotide conjugate of claim 6 , wherein the physiologically labile linker is a nuclease susceptible linker.
8. The antisense oligonucleotide conjugate of claim 6 , wherein the physiologically labile linker comprises a cytidine-adenosine dinucleotide.
9. The antisense oligonucleotide conjugate of claim 2 , wherein a linker is present between the oligonucleotide and the conjugate moiety; further wherein the conjugate moiety is an asialoglycoprotein receptor targeting moiety that is a tri-valent N-acetylgalactosamine (GalNAc) moiety; wherein the linker is a physiologically labile linker; further wherein the physiologically labile linker comprises a cytidine-adenosine dinucleotide.
10. A pharmaceutical composition comprising the antisense oligonucleotide conjugate of claim 2 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.
11. The pharmaceutical composition according to claim 10 wherein the pharmaceutically acceptable diluent is sterile phosphate buffered saline.
12. The pharmaceutical composition according to claim 10 , wherein the pharmaceutically acceptable salt is sodium.
13. The pharmaceutical composition according to claim 10 , wherein the pharmaceutically acceptable salt is potassium.
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 2 in an effective amount to said cell.
15. A method for restoration of immune response against a virus, said method comprising administering a therapeutically or prophylactically effective amount of the antisense oligonucleotide conjugate of claim 2 to a subject infected with a virus.
16. The method according to claim 15 , wherein the virus is HBV.
17. A method for restoration of immune response against a parasite, said method comprising administering a therapeutically or prophylactically effective amount of the oligonucleotide conjugate of claim 2 to a subject infected with a parasite.
18. The method according to claim 15 , wherein the restoration of the immune response is an increase in the liver of CD8+ T cells specific to one or more HBV antigens when compared to a control.
19. A method for treating or preventing HBV infection comprising administering a therapeutically or prophylactically effective amount of the antisense oligonucleotide conjugate of claim 2 to a subject suffering from or susceptible to HBV infection.
20. A pharmaceutically acceptable salt of the antisense oligonucleotide conjugate of claim 2 .
21. A pharmaceutically acceptable sodium salt of the antisense oligonucleotide conjugate of claim 2 .
22. A pharmaceutically acceptable potassium salt of the antisense oligonucleotide conjugate of claim 2 .