Oligomers and oligomer conjugates

• US 10,421,967 B2
• Filed: 05/15/2015
• Issued: 09/24/2019
• Est. Priority Date: 05/15/2014
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Javanbakh, Hassan, Ottosen, Soren, Lindow, Morten
• Primary Examiner(s): Chestnut, Barry A
• Application Number:
  US14/714,004
• Publication Number:
  US 20160010093A1
• Time in Patent Office: 1,593 Days
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 15/1133 against herpetoviridae, e.g. HSV
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

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.

Claims

1. An oligomer conjugate comprising:

a) at least a first oligomer that is 10 to 20 nucleotides in length and is perfectly complementary to a sequence from positions 1530 to 1598 of SEQ ID NO;

3; and

b) a carrier component comprising an asialoglycoprotein receptor (ASGP-R) targeting moiety.

2. The oligomer conjugate of claim 1, wherein the first oligomer comprises a 2′

-deoxyribonucleotide gap region flanked on each side by a wing, wherein each wing independently comprises one or more LNA units.

3. 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.

4. The oligomer conjugate of claim 1, wherein the carrier component is a GalNAc cluster comprising two to four terminal GalNAc moieties and a PEG spacer linking each GalNAc moiety to a branch point group.

5. The oligomer conjugate of claim 4, wherein the GalNAc cluster is a trivalent GalNAc selected from the group consisting of Conj 1, 2, 1a and 2a.

6. The oligomer conjugate of claim 2, wherein the carrier component comprises GalNAc2.

7. The oligomer conjugate of claim 2, further comprising a phosphodiester nucleotide linker comprising two, three, four or five phosphodiester linked DNA or RNA nucleosides.

8. The oligomer conjugate of claim 7, wherein the phosphodiester nucleotide linker comprises the sequence CA.

9. The oligomer conjugate of claim 1, wherein the first oligomer comprises a sequence selected from the group consisting of:

10. The oligomer conjugate of claim 9, wherein said first oligomer comprises a sequence selected from the group consisting of:

11. The oligomer conjugate of claim 10, wherein the first oligomer region is based on a sequence selected from the group consisting of any one or more of:

12. The oligomer conjugate of claim 9, selected from the group consisting of:

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

14. The oligomer conjugate of claim 1 wherein the first oligomer is perfectly complementary to a sequence from positions 1530 to 1544 of SEQ ID NO:

3.

15. The oligomer conjugate of claim 14, wherein said first oligomer comprises a sequence selected from the group consisting of:

16. The oligomer conjugate of claim 15 selected from the group consisting of:

17. The oligomer conjugate of claim 1 wherein the first oligomer is complementary to a sequence from positions 1577 to 1598 of SEQ ID NO:

3.

18. The oligomer conjugate of claim 17, wherein said first oligomer comprises a sequence selected from the group consisting of:

19. The oligomer conjugate of claim 17 selected from the group consisting of: