Compositions and methods for modulating HBV expression

Patent metadata

Field	Value
Publication number	US-9932580-B2
Application number	US-201514822493-A
Country	US
Kind code	B2
Filing date	Aug 10, 2015
Priority date	May 1, 2013
Publication date	Apr 3, 2018
Grant date	Apr 3, 2018

Abstract

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.

First claim

The invention claimed is:

1. A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide has a nucleobase sequence consisting of any one of the nucleobase sequences of SEQ ID NOs: 4, 5, 6, 7, 8, 9, or 11, and wherein the conjugate group comprises:

2. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar.

3. The compound of claim 2 , wherein at least one modified sugar is a bicyclic sugar.

4. The compound of claim 2 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a constrained ethyl, a 3′-fluoro-HNA or a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2.

5. The compound of claim 2 , wherein at least one modified sugar is 2′-O-methoxyethyl.

6. The compound of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.

7. The compound of claim 6 , wherein the modified nucleobase is a 5-methylcytosine.

8. The compound of claim 1 , wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide.

9. The compound of claim 1 , wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide.

10. The compound of claim 1 , wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage.

11. The compound of claim 10 , wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages.

12. The compound of claim 10 , wherein the modified oligonucleotide comprises at least two phosphorothioate internucleoside linkages.

13. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded.

14. The compound of claim 1 , wherein the modified oligonucleotide is double stranded.

15. The compound of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

16. The compound of claim 15 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.

17. The compound of claim 16 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.

18. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded and consists of 20 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 4, and wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, and wherein each cytosine residue is a 5-methylcytosine.

19. The compound of claim 18 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.

20. The compound of claim 19 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.

21. The compound of claims 20 , wherein the modified oligonucleotide further comprises at least 2 phosphodiester internucleoside linkages.

22. The compound of claim 18 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.

23. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded and consists of 20 linked nucleosides having a nucleobase sequence consisting of any of SEQ ID NOs: 7, 6, or 8, and wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 6 linked nucleosides; and
a 3′ wing segment consisting of 4 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, and wherein each cytosine residue is a 5-methylcytosine.

24. The compound of claim 23 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.

25. The compound of claim 24 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.

26. The compound of claims 25 , wherein the modified oligonucleotide further comprises at least 2 phosphodiester internucleoside linkages.

27. The compound of claim 23 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.

28. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded and consists of 17 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 5, and wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 3 linked nucleosides; and
a 3′ wing segment consisting of 4 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, and wherein each cytosine residue is a 5-methylcytosine.

29. The compound of claim 28 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.

30. The compound of claim 29 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.

31. The compound of claims 30 , wherein the modified oligonucleotide further comprises at least 2 phosphodiester internucleoside linkages.

32. The compound of claim 28 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.

33. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded and consists of 16 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 9, and wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 3 linked nucleosides; and
a 3′ wing segment consisting of 3 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein the 3 linked nucleosides of the 5′ wing segment comprise a 2′-O-methoxyethyl sugar, a constrained ethyl sugar, and a constrained ethyl sugar in the 5′ to 3′ direction; wherein the 3 linked nucleosides of the 3′ wing segment comprise a constrained ethyl sugar, a constrained ethyl sugar, and a 2′-O-methoxyethyl sugar in the 5′ to 3′ direction; and wherein each cytosine residue is a 5-methylcytosine.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Prakash Thazha P
• Seth Punit P
• Swayze Eric E

Classifications

• A61K47/59

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C12Y301/03048

  Protein-tyrosine-phosphatase (3.1.3.48) · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title