Oligomers and oligomer conjugates

Patent metadata

Field	Value
Publication number	US-10767181-B2
Application number	US-201916530765-A
Country	US
Kind code	B2
Filing date	Aug 2, 2019
Priority date	May 15, 2014
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

The present invention relates to an oligomer conjugate for use in the treatment of a viral disorder. The oligomer conjugate comprises: a) an oligomer capable of modulating a target sequence in HBx and/or HBsAg of Hepatitis B Virus (HBV) to treat said viral disorder; and b) a carrier component capable of delivering the oligomer to the liver which is linked, preferably conjugated, to the oligomer.

First claim

The invention claimed is:

1. An oligomer conjugate comprising:
a) at least a first oligomer that is 10 to 20 nucleotides in length and comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 24; 25; 26; 27; 28; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196 and 197;
b) a carrier component comprising an asialoglycoprotein receptor (ASGP-R) targeting moiety, wherein the carrier component is covalently attached to the first oligomer.

2. The oligomer conjugate of claim 1 , wherein the first oligomer is a gapmer oligomer of W—X—Y, wherein X represents at least 6 contiguous 2′-deoxyribonucleotides and each of W and Y independently represent at least one modified nucleotides selected from the group consisting of: 2′-O-alkyl-RNA units, 2′-amino-DNA units, 2′-fluoro-DNA units, LNA units, arabino nucleic acid (ANA) units, 2′-fluoro-ANA units, HNA units, intercalating nucleic acid (INA) units, 2′MOE units, ethylene nucleic acid (ENA) units, unlinked nucleic acid (UNA) units, tricyclo DNA units and cET-LNA units.

3. The oligomer conjugate of claim 2 , wherein the modified nucleotides are selected from MOE or LNA units.

4. The oligomer conjugate of claim 3 , wherein the LNA units are selected from the group consisting of β-Doxy-LNA, α-L-oxy-LNA, β-D-thio-LNA, β-D-ENA, and β-D-amino.

5. The oligomer conjugate of claim 2 , wherein W and Y independently consist of 3, 4 or 5 2′-O-methoxyethylribose sugar (2′-MOE) or units and region X consists of 8, 9, 10, 11 or 12 2′-deoxyribonucleotides.

6. The oligomer conjugate of claim 2 , wherein regions W—X—Y have 3-9-3, 3-10-3, 5-10-5 or 4-12-4 units.

7. The oligomer conjugate of claim 1 , wherein said ASGP-R targeting moiety is selected from the group consisting of galactose, galactosamine, N-formyl-galactosamine, N-acetylgalactosamine (GalNAc), N-propionyl-galactosamine, N-n-butanoyl-galactosamine, N-isobutanoylgalactose-amine or a cluster of any one or more thereof.

8. The oligomer conjugate of claim 1 , wherein the carrier component is a GalNAc cluster comprising two to four terminal GalNAc moieties.

9. The oligomer conjugate of claim 8 , wherein the GalNAc cluster is a trivalent GalNAc selected from the group consisting of Conj 1, 2, 1a and 2a.

10. The oligomer conjugate of claim 1 , wherein the carrier component comprises GalNAc2.

11. The oligomer conjugate of claim 1 , wherein the covalent attachment comprises a phosophodiester nucleotide linker comprising 2-5 phosphodiester linked DNA or RNA nucleosides.

12. The oligomer conjugate of claim 11 , wherein the phosphodiester nucleotide linker comprises the sequence CA.

13. A pharmaceutical composition comprising the oligomer conjugate of claim 1 and a pharmaceutically acceptable carrier or excipient.

Assignees

• Hoffmann La Roche

Inventors

• Javanbakh Hassan
• Ottosen Søren
• Lindow Morten

Classifications

• C12N15/1133 Primary

  against herpetoviridae, e.g. HSV · CPC title

• A61K31/713 Primary

  Double-stranded nucleic acids or oligonucleotides · CPC title

• C12N2310/3515

  Lipophilic moiety, e.g. cholesterol · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N2310/351

  Conjugate · CPC title