Oligonucleotides for reduction of PD-L1 expression

Patent metadata

Field	Value
Publication number	US-10745480-B2
Application number	US-201916664749-A
Country	US
Kind code	B2
Filing date	Oct 25, 2019
Priority date	Mar 14, 2016
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Pedersen Lykke
• Javanbakht Hassan
• Jackerott Malene
• Ottosen Søren
• Luangsay Souphalone

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C12N2310/322

  2'-R Modification · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N15/1131 Primary

  against viruses · CPC title

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title