Therapeutic vitamin D conjugates

• US 9,585,934 B2
• Filed: 10/21/2015
• Issued: 03/07/2017
• 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., So, Christopher, Sard, Howard P., Hegde, Vishnumurthy
• Primary Examiner(s): Alstrum Acevedo, James H
• Assistant Examiner(s): MARTINEZ, TARA L
• Application Number:
  US14/919,601
• Publication Number:
  US 20160113993A1
• Time in Patent Office: 503 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• 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
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00

Abstract

The invention provides non-hormonal vitamin D conjugated to apelin proteins that result in increased absorption, bioavailability or circulating half-life when compared to non-conjugated forms. In some embodiments, the vitamin D targeting groups are coupled to the apelin proteins 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 that is not hydroxylated at the carbon 1 position, conjugated at the carbon 3 position to a protein having apelin activity comprising an amino acid sequence with at least a 90% sequence identity to SEQ ID NO:

1.

2. The carrier-drug conjugate of claim 1, wherein said targeting group is conjugated to said protein via a scaffold that is poly(ethylene glycol).

3. A pharmaceutical composition comprising a carrier-drug conjugate comprising a targeting group that is a non-hormonal vitamin D that is not hydroxylated at the carbon 1 position, conjugated at the carbon 3 position via a scaffold to a protein having apelin activity comprising an amino acid sequence with at least a 90% sequence identity to SEQ ID NO:

1.

4. The pharmaceutical composition of claim 3 wherein said scaffold is poly(ethylene glycol).

5. The pharmaceutical composition of claim 3, wherein said amino acid sequence of said protein is SEQ ID NO:

1.

6. The pharmaceutical composition of claim 3, wherein said scaffold has a mass of about 2 kDa.

7. A pharmaceutical composition, comprising:

a) a protein having apelin activity comprising an amino acid sequence with at least a 90% sequence identity to SEQ ID NO;

1,

b) a stably attached scaffold,

c) a targeting group that is a non-hormonal vitamin D that is not hydroxylated at the carbon 1 position, conjugated at the carbon 3 position,

wherein after administration to a first test subject, said protein has a half life measured by Enzyme Linked Immunosorbant Assay (ELISA) analysis of blood samples taken at a plurality of time points that is greater than a half life of said protein administered to a second test subject without said stably attached scaffold moiety and targeting group as measured by said ELISA analysis of blood samples taken at said plurality of time points.

8. The pharmaceutical composition of claim 7, wherein said administration to said first and second subjects is accomplished by subcutaneous injection.

9. The pharmaceutical composition of claim 7, wherein said protein stably attached to said scaffold and targeting group retains about the same activity as said protein not stably attached to said scaffold and targeting group as measured by a functional assay.

10. The pharmaceutical composition of claim 7, wherein said amino acid sequence of said protein is SEQ ID NO:

1.

11. The pharmaceutical composition of claim 7, wherein the scaffold has a mass of about 500 Da to 5,000 Da.

12. The pharmaceutical composition of claim 7, wherein said scaffold is approximately the same mass as the protein.

13. A carrier-drug conjugate, comprising a targeting group that is vitamin D that is not hydroxylated at the carbon 1 position, non-releasably conjugated at the carbon 3 position to a protein having apelin activity comprising an amino acid sequence with at least a 90% sequence identity to SEQ ID NO:

1.

14. The carrier-drug conjugate of claim 13, wherein said vitamin D is non-hormonal.

15. The carrier-drug conjugate of claim 13, wherein said protein retains about the same activity as said protein not conjugated to said targeting group as measured by a functional assay.

16. The carrier-drug conjugate of claim 13, wherein said targeting group is conjugated to said protein via a scaffold that is poly(ethylene glycol).

17. The carrier-drug conjugate of claim 13, wherein said scaffold is approximately the same mass as the protein.