Fusion proteins of collagen-binding domain and parathyroid hormone
Fusion proteins containing active agonist or antagonist fragments of parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP) coupled to a collagen-binding domain are presented. The fusion proteins can be used to promote bone growth, to promote hair growth, to prevent cancer metastasis to bone, to promote immune reconstitution with a bone marrow stem cell transplant, to promote mobilization of bone marrow stem cells for collection for autologous stem cell transplant, and to treat renal osteodystrophy. Pharmaceutical agents comprising a collagen-binding polypeptide segment linked to a non-peptidyl PTH/PTHrP receptor agonist or antagonist are also presented.
1. A composition comprising: a collagen-binding polypeptide segment covalently linked to a PTH/PTHrP receptor agonist; wherein the collagen-binding polypeptide segment is a bacterial collagen binding polypeptide segment, Wherein the PTH/PTHrP receptor agonist comprises residues 1-14 of SEQ ID NO: 1, and wherein the collagen-binding polypeptide segment comprises a polypeptide selected from the group consisting of: SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, polypeptides at least 90% identical to SEQ ID NOs 13-17 and fragments consisting of at least 10 consecutive amino acids of any one of SEQ ID NOs: 13-17.
2. The composition of claim 1 , wherein the collagen-binding polypeptide segment and the PTH/PTHrP receptor agonist are chemically cross-linked to each other or are polypeptide portions of a fusion protein.
3. The composition of claim 1 , wherein the composition has at least 50% greater activity than PTH(1-34) as measured by increased bone mineral density after eight weeks of weekly administration of the composition to a subject in need thereof at equal molar doses of the PTH.
4. The composition of claim 1 , wherein the PTH/PTHrP receptor agonist is a polypeptide and the N-terminus of the collagen-binding polypeptide segment is linked directly or through a linker polypeptide segment to the C-terminus of the PTH/PTHrP receptor agonist polypeptide.
5. The composition of claim 1 , wherein the PTH/PTHrP receptor agonist comprises residues 1-33 of SEQ ID NO: 1, SEQ ID NO: 7, or residues 1-34 of SEQ ID NO: 7.
6. The composition of claim 1 , wherein the composition further comprises residues 807-900 of SEQ ID NO: 6 covalently linked to at least one of the collagen-binding polypeptide segment and the PTH/PTHrP receptor agonist.
7. The composition of claim 1 , wherein the collagen-binding polypeptide segment is selected from the group consisting of: SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17.
8. A method of treating a medical condition selected from the group consisting of: promoting hone growth, promoting hair growth, promoting tissue growth, promoting immune reconstitution, promoting bone marrow stem cell mobilization and treating myocardial infarction, comprising administering an effective amount of the composition of claim 1 to a mammal in need thereof.
9. The method of claim 8 , wherein administering the composition to the mammal increases trabecular bone mineral density or cortical bone mineral density or trabecular bone mineral volume or cortical bone mineral volume.
10. The method of claim 8 , wherein the composition is administered before, during or after administration of an implant or in combination with an implant.
11. The method of claim 8 , wherein the implant is a dental implant or a bone graft.
12. The method of claim 8 , wherein the implant comprises intact bone, bone cement, hydroxyapatite, demineralized bone, osteoblasts or combinations thereof.
13. The method of claim 8 , wherein the composition is administered by injection.
14. The method of claim 8 , wherein the composition is administered in aqueous solution at pH below about 5.0.