Therapeutic vitamin D conjugates
The invention provides non-hormonal vitamin D conjugated via the third carbon on the vitamin D backbone to parathyroid hormone (PTH) proteins that result in increased absorption, bioavailability or circulating half-life when compared to non-conjugated forms.
1. A carrier-drug conjugate, comprising a targeting group that is a non-hormonal secosteroid vitamin D that is not hydroxylated at the carbon 1 position conjugated at the carbon 3 position to a protein having parathyroid hormone (PTH) activity, wherein said protein comprises an amino acid sequence with at least a 90% sequence identity to SEQ ID NO:10.
2. The carrier-drug conjugate of claim 1 , wherein said activity is a binding of said protein to parathyroid hormone receptor 1 or parathyroid hormone receptor 2.
3. The carrier-drug conjugate of claim 1 , wherein said activity increases the concentration of calcium (Ca 2+ ) in the blood.
4. The carrier-drug conjugate of claim 1 , wherein said protein is an 84 amino acid protein.
5. The carrier-drug conjugate of claim 1 , wherein said targeting group is conjugated to said protein via a scaffold.
6. The carrier-drug conjugate of claim 5 , wherein said scaffold is poly(ethylene glycol).
7. A pharmaceutical composition comprising a carrier-drug conjugate comprising a targeting group that is a non-hormonal secosteroid vitamin D that is not hydroxylated at the carbon 1 position conjugated at the carbon 3 position via a scaffold to a protein having PTH activity, wherein said protein comprises an amino acid sequence with at least a 90% sequence identity to SEQ ID NO:10.
8. The pharmaceutical composition of claim 7 , wherein said activity is a binding of said protein to parathyroid hormone receptor 1 or parathyroid hormone receptor 2.
9. The pharmaceutical composition of claim 7 , wherein said activity increases the concentration of calcium (Ca 2+ ) in the blood.
10. The pharmaceutical composition of claim 7 , wherein said protein is an 84 amino acid protein.
11. The pharmaceutical composition of claim 7 , wherein said non-hormonal vitamin D is not hydroxylated at the carbon 1 position.
12. The pharmaceutical composition of claim 7 , wherein said scaffold is poly(ethylene glycol).
13. A pharmaceutical composition, comprising:
a) a protein having PTH activity,
b) a targeting group that is a non-hormonal secosteroid vitamin D that is not hydroxylated at the carbon 1 position conjugated at the carbon 3 position,
c) a scaffold stably attached to said targeting group,
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, wherein said protein comprises an amino acid sequence with at east a 90% sequence identity to SEQ ID NO: 10.
14. The pharmaceutical composition of claim 13 , wherein said amino acid sequence of said protein is SEQ ID NO:10.
15. The pharmaceutical composition of claim 13 , wherein said protein has 84 amino acids.
16. The pharmaceutical composition of claim 13 , wherein said administration to said first and second subjects is accomplished by subcutaneous injection.
17. The pharmaceutical composition of claim 13 , 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.
18. The pharmaceutical composition of claim 13 , wherein the scaffold has a mass of about 500 Da to 5,000 Da.
19. The pharmaceutical composition of claim 13 , wherein said amino acid sequence of said protein is SEQ ID NO:17 or 18.
20. A carrier-drug conjugate, comprising a targeting group that is a secosteroid vitamin D that is not hydroxylated at the carbon 1 position non-releasably conjugated at the carbon 3 position to a protein having PTH activity comprising an amino acid sequence with at least a 90% sequence identity to SEQ ID NO:10.
21. The carrier-drug conjugate of claim 20 , wherein said vitamin D is non-hormonal.
22. The carrier-drug conjugate of claim 21 , wherein said non-hormonal vitamin D is not hydroxylated at the carbon 1 position.
23. The carrier-drug conjugate of claim 20 , wherein said protein retains about the same activity as said protein not conjugated to said targeting group as measured by a functional assay.
24. The carrier-drug conjugate of claim 20 , wherein said targeting group is conjugated to said protein via a scaffold that is poly(ethylene glycol).
25. The carrier-drug conjugate of claim 20 , wherein said scaffold is approximately the same mass as the protein.
26. The carrier-drug conjugate of claim 20 , wherein said protein comprises the sequence selected from the group consisting of SEQ ID NO: 10, 17, and 18.