Galactose cluster-pharmacokinetic modulator targeting moiety for siRNA

• US 9,249,179 B2
• Filed: 12/15/2011
• Issued: 02/02/2016
• Est. Priority Date: 12/17/2010
• Status: Active Grant

• Current Assignee: Arrowhead Pharmaceuticals, Inc.
• Original Assignee: 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.
• Primary Examiner(s): ZARA, JANE J
• Application Number:
  US13/327,271
• Publication Number:
  US 20120157509A1
• Time in Patent Office: 1,510 Days
• Field of Search: 435/6, 435/91.1, 435/91.31, 435/458, 435/6.1, 435/455, 514/44, 536/23.1, 536/24.5, 536/1.11, 536/123, 536/123.1, 536/126, 530/397
• US Class Current: 1/1
• 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 said galactose derivative having affinity for the asialoglycoprotein receptor equal to or greater than that of galactose is selected from the group consisting of:

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

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

4. The composition of claim 3 wherein the polynucleotide delivery polymer comprises a reversibly modified membrane active polyamine.

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