Delivery of therapeutic agents by a collagen binding protein
Methods of delivering therapeutic agents by administering compositions including a bacterial collagen-binding polypeptide segment linked to the therapeutic agent to subjects in need of treatment with the therapeutic agent are provided. In these methods, the therapeutic agent is not a PTH/PTHrP receptor agonist or antagonist, basic fibroblast growth factor (bFGF) or epidermal growth factor (EGF). The bacterial collagen-binding polypeptide segment delivers the agent to sites of partially untwisted or under-twisted collagen. Methods of treating collagenopathies using a composition including a collagen-binding polypeptide and a PTH/PTHrP receptor agonist are also provided. In addition, methods of treating hyperparathyroidism, and hair loss using compositions comprising a collagen binding polypeptide and a PTH/PTHrP receptor agonist are provided. Finally, methods of reducing hair regrowth by administering a composition including a collagen binding polypeptide and a PTH/PTHrP receptor antagonist are provided.
1. A method of treating a subject having alopecia that is not chemotherapy-induced comprising administering a composition comprising a bacterial collagen-binding polypeptide segment linked to a PTH/PTHrP receptor agonist to the subject to increase hair growth in the subject in need thereof for treatment of alopecia that is not chemotherapy-induced, wherein the bacterial collagen-binding polypeptide segment comprises a collagen-binding polypeptide derived from an M9 peptidase from Clostridium, Bacillus and Vibrio selected from the group consisting of one of SEQ ID NOs: 13-34 or a fragment of at least 8 consecutive amino acids of SEQ ID NOs: 13-34, residues 34-158 of SEQ ID NO: 1, a fragment of at least 8 consecutive amino acids from residues 34-158 of SEQ ID NO: 1, or a peptide that is at least 90% identical to residues 34-158 of SEQ ID NO: 1 or SEQ ID NOs: 13-34 and wherein the PTH/PTHrP receptor agonist comprises residues 1-33 of SEQ ID NO: 1, PTH (SEQ ID NO: 7), residues 1-14 of SEQ ID NO: 1, residues 1-34 of SEQ ID NO: 7 or a fragment of at least 8 consecutive amino acids from residues 1-34 of SEQ ID NO: 7.
2. The method of claim 1 , wherein the alopecia is alopecia areata or is related to male pattern baldness or polycystic ovarian syndrome.
3. The method of claim 1 , wherein the composition is administered locally.
4. The method of claim 3 , wherein the composition is administered topically.
5. The method 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 or wherein the collagen-binding polypeptide segment and the therapeutic agent are chemically cross-linked to each other or are polypeptide portions of a fusion protein.
6. The method of claim 1 , wherein the subject is a human.
7. The method of claim 1 , wherein the composition is administered in aqueous solution at pH below about 5.0 or above about 6.0.
8. The method of claim 1 , wherein the bacterial collagen-binding polypeptide segment comprises one of SEQ ID NOs: 13-34, residues 34-158 of SEQ ID NO: 1, or a peptide that is at least 90% identical to residues 34-158 of SEQ ID NO: 1 or SEQ ID NOs: 13-34.
9. The method of claim 1 , wherein the PTH/PTHrP receptor agonist comprises residues 1-33 of SEQ ID NO: 1, PTH (SEQ ID NO: 7), residues 1-14 of SEQ ID NO: 1, residues 1-34 of SEQ ID NO: 7.
10. The method of claim 1 , wherein the bacterial collagen-binding polypeptide segment linked to the PTH/PTHrP receptor agonist is a fusion protein comprising SEQ ID NO: 1.
11. The method of claim 1 , wherein the bacterial collagen-binding polypeptide segment linked to the PTH/PTHrP receptor agonist is a fusion protein comprising SEQ ID NO: 2.
12. The method of claim 1 , wherein the collagen-binding polypeptide segment further comprises residues 807-900 of SEQ ID NO: 6.