RNAi vitamin D conjugates

• US 9,789,197 B2
• Filed: 10/21/2015
• Issued: 10/17/2017
• Est. Priority Date: 10/22/2014
• Status: Active Grant

• Current Assignee: Extend Biosciences, Inc.
• Original Assignee: Extend Biosciences, Inc.
• Inventors: Soliman, Tarik, Hales, Laura M., Hall, Daniel B., Sard, Howard P., Hegde, Vishnumurthy
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US14/919,671
• Publication Number:
  US 20160114049A1
• Time in Patent Office: 727 Days
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/551 one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Abstract

The invention provides non-hormonal vitamin D conjugated to therapeutic RNA compounds that result in the compounds having increased absorption, bioavailability or circulating half-life when compared to non-conjugated forms. The vitamin D targeting groups are coupled to the therapeutic RNA compounds via the third carbon on the vitamin D backbone.

Claims

1. A carrier-drug conjugate comprising a targeting group that is a non-hormonal vitamin D conjugated to a therapeutic RNA compound at the carbon 3 position of said non-hormonal vitamin D targeting group.

2. The carrier-drug conjugate of claim 1, wherein said non-hormonal vitamin D is not hydroxylated at the carbon 1 position.

3. The carrier-drug conjugate of claim 1, wherein said targeting group is conjugated to said therapeutic RNA compound via a scaffold that is selected from the group consisting of poly(ethylene glycol), polylysine, polyethyleneimine, poly(propyleneglycol), a peptide, serum albumin, thioredoxin, an immunoglobulin, an amino acid, a nucleic acid, a glycan, a modifying group that contains a reactive linker, a water-soluble polymer, a small carbon chain linker, and an additional therapeutic peptide.

4. A pharmaceutical composition comprising a carrier-drug conjugate comprising a targeting group that is a non-hormonal vitamin D conjugated via a scaffold at the carbon 3 position to a therapeutic RNA compound having a nucleic acid sequence with at least a 90% sequence identity to SEQ ID NO:

1.

5. The pharmaceutical composition of claim 4, wherein said carrier increases the cellular uptake, absorption, bioavailability, or half-life of said therapeutic RNA compound in circulation.

6. The pharmaceutical composition of claim 4, wherein said non-hormonal vitamin D is not hydroxylated at the carbon 1 position.

7. The pharmaceutical composition of claim 5, wherein said scaffold is selected from the group consisting of poly(ethylene glycol), polylysine, polyethyleneimine, poly(propyleneglycol), a peptide, serum albumin, thioredoxin, an immunoglobulin, an amino acid, a nucleic acid, a glycan, a modifying group that contains a reactive linker, a water-soluble polymer, a small carbon chain linker, and an additional therapeutic peptide.

8. The pharmaceutical composition of claim 7, wherein said scaffold is poly(ethylene glycol).

9. A carrier-drug conjugate comprising a targeting group that is vitamin D non-releasably conjugated to a therapeutic RNA compound, wherein said therapeutic RNA compound is conjugated at the carbon 3 position of said non-hormonal vitamin D targeting group.

10. The carrier-drug conjugate of claim 9, wherein said vitamin D is non-hormonal.

11. The carrier-drug conjugate of claim 9, wherein said non-hormonal vitamin D is not hydroxylated at the carbon 1 position.

12. The carrier-drug conjugate of claim 9, wherein said therapeutic RNA compound retains about the same activity as said therapeutic RNA compound not conjugated to said targeting group as measured by a functional assay.

13. The carrier-drug conjugate of claim 9, wherein said targeting group is conjugated to said therapeutic RNA compound via a scaffold that is selected from the group consisting of poly(ethylene glycol), polylysine, polyethyleneimine, poly(propyleneglycol), a peptide, serum albumin, thioredoxin, an immunoglobulin, an amino acid, a nucleic acid, a glycan, a modifying group that contains a reactive linker, a water-soluble polymer, a small carbon chain linker, and an additional therapeutic peptide.

14. The carrier-drug conjugate of claim 13, wherein said scaffold is approximately the same mass as said therapeutic RNA compound.