Galactose cluster-pharmacokinetic modulator targeting moiety for siRNA

Patent metadata

Field	Value
Publication number	US-9796756-B2
Application number	US-201514972385-A
Country	US
Kind code	B2
Filing date	Dec 17, 2015
Priority date	Dec 17, 2010
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

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.

First claim

The invention claimed is:

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

wherein R 1 comprises a hydrophobic group having 16 or more carbon atoms, R 2 comprises the RNA interference polynucleotide, and R 3 comprises a galactose or galactose derivative having affinity for the asialoglycoprotein receptor equal to or greater than that of galactose.

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

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

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

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

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

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

8. The composition of claim 7 wherein R 1 comprises C16 acyl.

9. The composition of claim 7 wherein R 1 comprises C18 acyl.

10. The composition of claim 7 wherein R 1 comprises C80 acyl.

11. The composition of claim 1 wherein R 3 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 R 3 comprises N-formyl-galactosamine.

13. The composition of claim 1 wherein R 3 comprises N-acetylgalactosamine.

14. The composition of claim 1 wherein R 3 comprises N-propionyl-galactosamine.

15. The composition of claim 1 wherein R 3 comprises N-n-butanoyl-galactosamine.

16. The composition of claim 1 wherein R 3 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 R 2 comprises: DNA, RNA, dsRNA, siRNA, or miRNA.

20. The composition of claim 1 wherein R 2 comprises siRNA.

Assignees

• Arrowhead Madison Inc
• 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

Classifications

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P31/12

  Antivirals · CPC title

• C07K5/1021 Primary

  with the first amino acid being acidic · CPC title

• C07H21/02

  with ribosyl as saccharide radical · CPC title

• C12N15/11 Primary

  DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity} · CPC title