GALACTOSE CLUSTER-PHARMACOKINETIC MODULATOR TARGETING MOIETY FOR siRNA

• US 20120157509A1
• Filed: 12/15/2011
• Published: 06/21/2012
• Est. Priority Date: 12/17/2010
• Status: Active Grant

• Current Assignee: Arrowhead Madison Inc (Arrowhead Pharmaceuticals, Inc.)
• Original Assignee: Arrowhead Research Corporation
• Inventors: Hadwiger, Philipp, Hoffmann, Torsten, Kitas, Eric A., Mohr, Peter, Roehl, Ingo, Valis, Linda, Rozema, David B., Lewis, David L., Wakefield, Darren H.
• Granted Patent: US 9,249,179 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• 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 oligonucleotide to a cell in vivo comprising:

an RNA interference polynucleotide covalently linked to a targeting ligand-pharmacokinetic modulator targeting moiety.

3. The composition of claim 1 wherein pharmacokinetic modulator consists of a hydrophobic group having 16 or more carbon atoms.

4. The composition of claim 3 wherein pharmacokinetic modulator consists of a hydrophobic group having 16-20 carbon atoms.

5. The composition of claim 3 wherein pharmacokinetic modulator is selected from the group consisting of:

palmitoyl, hexadec-8-enoyl, oleyl, (9E,12E)-octadeca-9,12-dienoyl, dioctanoyl, and C16-C20 acyl.

6. The composition of claim 3 wherein pharmacokinetic modulator consists of cholesterol.

7. The composition of claim 1 wherein targeting ligand consists of a cell receptor ligand.

8. The composition of claim 7 wherein cell receptor ligand comprises an asialoglycoprotein receptor targeting moiety.

9. The composition of claim 8 wherein asialoglycoprotein receptor targeting moiety is selected from the group consisting of:

galactose, galactosamine, N-formyl-galactosamine, N-acetylgalactosamine, N-propionyl-galactosamine, N-n-butanoyl-galactosamine, and N-iso-butanoylgalactos-amine.

10. The composition of claim 8 wherein asialoglycoprotein receptor targeting moiety comprises a galactose cluster.

11. The composition of any of claims 10 wherein the galactose cluster consists of an N-acetylgalactosamine trimer.

12. The composition of claim 7 wherein cell receptor ligand comprises folate.

13. The composition of claim 1 wherein the composition further comprises and polynucleotide delivery polymer.

14. The composition of claim 13 wherein the polynucleotide delivery polymer comprises and reversibly modified membrane active polyamine.

15. The composition of claim 1 wherein the RNA interference polynucleotide is selected from the group consisting of DNA, RNA, dsRNA, RNA interference polynucleotide, siRNA, and miRNA.

2. The composition of 1 wherein the RNA interference polynucleotide is covalently linked to targeting-ligand-pharmacokinetic modulator targeting moiety via a physiologically labile linkage.

16. A composition for delivering an polynucleotide to a liver cell in vivo comprising:

said polynucleotide covalently linked to an ASGPr targeting moiety-pharmacokinetic modulator targeting moiety.

17. The composition of claim 16 wherein the ASGPr targeting moiety is selected from the group consisting of galactose, galactosamine, N-formyl-galactosamine, N-acetylgalactosamine, N-propionyl-galactosamine, N-n-butanoyl-galactosamine, N-iso-butanoylgalactos-amine, galactose cluster, and N-acetylgalactosamine trimer.

18. The composition of claim 16 wherein the pharmacokinetic modulator is selected from the group consisting of hydrophobic group having 16 or more carbon atoms, hydrophobic group having 16-20 carbon atoms, palmitoyl, hexadec-8-enoyl, oleyl, (9E,12E)-octadeca-9,12-dienoyl, dioctanoyl, and C16-C20 acyl, and cholesterol.

19. The composition of claim 16 wherein the ASGPr targeting moiety-pharmacokinetic modulator targeting moiety is linked to the polynucleotide via a physiologically labile bond.

20. The composition of claim 16 wherein the ASGPr targeting moiety and pharmacokinetic modulator are linked to the polynucleotide via a scaffold molecule.