Targeting ligands for therapeutic compounds

• US 10,246,709 B2
• Filed: 03/07/2017
• Issued: 04/02/2019
• Est. Priority Date: 03/07/2016
• Status: Active Grant

• Current Assignee: Alnylam Pharmaceuticals Incorporated, Arrowhead Pharmaceuticals, Inc.
• Original Assignee: Arrowhead Pharmaceuticals, Inc.
• Inventors: Rozema, David B., Wakefield, Darren H., Blokhin, Andrei V., Benson, Jonathan D., Li, Zhen, Pei, Tao, Fleitz, Fred
• Primary Examiner(s): Whiteman, Brian
• Application Number:
  US15/452,423
• Publication Number:
  US 20170253875A1
• Time in Patent Office: 756 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/317 with an inverted bond, e.g. a cap structure
• CPC Class Codes: C12N 2310/32 of the sugar
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2310/3533 Halogen

Abstract

Described are novel targeting ligands that may be linked to compounds, such therapeutic compounds, that are useful in directing the compounds to the target in vivo. The targeting ligands disclosed herein can serve to target expression-inhibiting oligomeric compounds, such as RNAi agents, to liver cells to modulate gene expression. The targeting ligands disclosed herein, when conjugated to an expression-inhibiting oligomeric compound, may be used in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Compositions including the targeting ligands disclosed herein when linked to expression-inhibiting oligomeric compounds are capable of mediating expression of target nucleic acid sequences in liver cells, such as hepatocytes, which may be useful in the treatment of diseases or conditions that respond to inhibition of gene expression or activity in a cell, tissue, or organism.

Claims

1. A targeting ligand comprising the structure of Formula B:

2. The targeting ligand of claim 1, comprising the following structure:

3. The targeting ligand of claim 1, wherein the targeting ligand comprises the structure selected from:

4. The targeting ligand of claim 1, wherein the Targeting Moiety is

5. The targeting ligand of claim 1, wherein n is 6.

6. The targeting ligand of claim 1, wherein the targeting ligand is linked to an expression-inhibiting oligomeric compound.

7. The targeting ligand of claim 6, wherein the expression-inhibiting oligomeric compound is an RNAi agent.

8. The targeting ligand of claim 7, wherein the RNAi agent is double stranded.

9. The targeting ligand of claim 8, wherein the RNAi agent comprises one or more modified nucleotides.

10. The targeting ligand claim 7, wherein the targeting ligand is linked at the 3′

or 5′

terminal end of the RNAi agent.

11. The targeting ligand of claim 10, wherein the RNAi agent is double stranded.

12. The targeting ligand of claim 11, wherein the double-stranded RNAi agent is linked to the targeting ligand at the 5′

terminal end of the sense strand of the RNAi agent.

13. The targeting ligand of claim 7, wherein the RNAi agent is linked to targeting ligand via a phosphate group, phosphorothioate group, or a phosphonate group.

14. A composition comprising the targeting ligand of claim 1, wherein the targeting ligand is linked to an expression-inhibiting oligomeric compound, wherein the structure of the targeting ligand and expression-inhibiting oligomeric compound is represented by the structure selected from the group consisting of:

15. The composition of claim 14, wherein the expression-inhibiting oligomeric compound is a double-stranded RNAi agent.

16. The composition of claim 15, wherein the double-stranded RNAi agent is attached to the targeting ligand at the 5′

end of the sense strand of the RNAi agent.

20. A method of inhibiting expression of a target nucleic acid in a subject, the method comprising administering a therapeutic amount of an expression-inhibiting oligomeric compound conjugated to the targeting ligand of claim 1.

21. A method of introducing an expression-inhibiting oligomeric compound into a mammalian cell, the method comprising contacting a mammalian cell with the targeting ligand of claim 1, linked to the expression-inhibiting oligomeric compound.

22. The method of claim 21, wherein the cell is present in a subject.

23. The method of claim 22, wherein the subject is a human.

24. The method of claim 21, wherein the expression-inhibiting oligomeric compound is an RNAi agent.

25. A method of treating a disease or disorder that would benefit from administration of an expression-inhibiting oligomeric compound, the method comprising administering a therapeutic amount of the targeting ligand of claim 1 linked to an expression-inhibiting oligomeric compound to a subject in need of treatment thereof.

26. The method of claim 25, wherein the expression-inhibiting oligomeric compound is an RNAi agent.

27. A method of treating a disease or disorder that would benefit from administration of an expression-inhibiting oligomeric compound, the method comprising administering a therapeutic amount of the composition of claim 14 to a subject in need of treatment thereof.

17. A compound having the structure of:

18. The compound of claim 17, having the structure selected from the group consisting of:

19. The compound of claim 18, wherein the compound is: