Galactose cluster-pharmacokinetic modulator targeting moiety for siRNA

• US 9,796,756 B2
• Filed: 12/17/2015
• Issued: 10/24/2017
• Est. Priority Date: 12/17/2010
• Status: Active Grant

• Current Assignee: Arrowhead Pharmaceuticals, Inc.
• Original Assignee: Arrowhead Pharmaceuticals, Inc.
• Inventors: Hadwiger, Philipp, Hoffmann, Torsten, Kitas, Eric A, Mohr, Peter, Roehl, Ingo, Valis, Linda, Rozema, David B, Lewis, David L, Wakefield, Darren H
• Primary Examiner(s): ZARA, JANE J
• Application Number:
  US14/972,385
• Publication Number:
  US 20160102120A1
• Time in Patent Office: 677 Days
• Field of Search: 435 61, 435 911, 435 9131, 435455, 435458, 514 44, 530397, 536 231, 536 245
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07K 5/1021 with the first amino acid being acidic

Abstract

The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to cell in vivo. The pharmacokinetic modulator improve in vivo targeting compared to the targeting ligand alone. Targeting ligand-pharmacokinetic modulator targeting moiety targeted RNAi polynucleotides can be administered in vivo alone or together with co-targeted delivery polymers.

Claims

1. A composition for delivering an RNA interference polynucleotide to a liver cell in vivo comprising the structure represented by:

2. The composition of claim 1 wherein R¹ comprises cholesterol.

3. The composition of claim 1 wherein R¹ comprises hexadec-8-enoyl.

4. The composition of claim 1 wherein R¹ comprises oleyl.

5. The composition of claim 1 wherein R¹ comprises (9E,12E)-octadeca-9,12-dienoyl.

6. The composition of claim 1 wherein R¹ comprises dioctanoyl.

7. The composition of claim 1 wherein R¹ comprises C16-C20 acyl.

8. The composition of claim 7 wherein R¹ comprises C16 acyl.

9. The composition of claim 7 wherein R¹ comprises C18 acyl.

10. The composition of claim 7 wherein R¹ comprises C80 acyl.

11. The composition of claim 1 wherein R³ comprises:

galactosamine, N-formyl-galactosamine, N-acetylgalactosamine, N-propionyl-galactosamine, N-n-butanoyl-galactosamine, or N-iso-butanoylgalactosamine.

12. The composition of claim 1 wherein R³ comprises N-formyl-galactosamine.

13. The composition of claim 1 wherein R³ comprises N-acetylgalactosamine.

14. The composition of claim 1 wherein R³ comprises N-propionyl-galactosamine.

15. The composition of claim 1 wherein R³ comprises N-n-butanoyl-galactosamine.

16. The composition of claim 1 wherein R³ comprises N-iso-butanoylgalactosamine.

17. The composition of claim 1 wherein the composition further comprises a polynucleotide delivery polymer.

18. The composition of claim 17 wherein the polynucleotide delivery polymer comprises a reversibly modified membrane active polyamine.

19. The composition of claim 1 wherein R² comprises:

DNA, RNA, dsRNA, siRNA, or miRNA.

20. The composition of claim 1 wherein R² comprises siRNA.