Polypeptides derived from calcitonin receptors and methods of use
View Patent ↗The present invention is based, in part, on our discovery of compositions and methods that can be used to treat a patient who has a compromised bone (due, for example, to a disease such as osteoporosis or an injury such as a bone fracture). The compositions can also be administered prophylactically. For example, they can be administered to help maintain bone health as a patient ages. More specifically, the compositions include polypeptides that constitute (or that include) a fragment of a calcitonin receptor (CR) and polypeptides that constitute (or include) biologically active variants of those fragments. Sequence-specific formulas are provided herein, and polypeptides conforming to those formulas, as well as nucleic acids encoding them, expression vectors, host cells, pharmaceutical formulations, and methods of their preparation and use are within the scope of the present invention.
1. A method of treating a patient who is at risk for, or who has been diagnosed as having, a compromised bone, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a substantially pure polypeptide comprising a fragment of a calcitonin receptor, wherein the polypeptide comprises an amino acid sequence conforming to:
(SEQ ID NO:4);
Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp
(SEQ ID NO:5);
Trp-Val-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp
(SEQ ID NO:6);
Trp-Thr-Gln-Phe-Lys-Ile-Gln-Trp-Ser-Gln-Arg-Trp
or
(SEQ ID NO:7),
Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Ser-His-Arg-Trp
and wherein the polypeptide is 12-18 amino acids in length and is amidated at the C-terminus.
2. The method of claim 1 , wherein the compromised bone comprises cancerous cells.
3. The method of claim 1 , wherein the compromised bone is associated with a bone disorder.
4. The method of claim 3 , wherein the bone disorder is osteoporosis, osteopenia, osteomalacia or rickets.
5. The method of claim 1 , wherein the compromised bone is a fractured bone.
6. The method of claim 1 , wherein the patient is a human patient.
7. The method of claim 6 , wherein the human patient is more than about 50 years old.
8. The method of claim 1 , wherein the polypeptide comprises Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp (SEQ ID NO:4).
9. The method of claim 1 , wherein the polypeptide comprises Trp-Val-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp (SEQ ID NO:5).
10. The method of claim 1 , wherein the polypeptide comprises Trp-Thr-Gln-Phe-Lys-Ile-Gln-Trp-Ser-Gln-Arg-Trp (SEQ ID NO:6).
11. The method of claim 1 , wherein the polypeptide comprises Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Ser-His-Arg-Trp (SEQ ID NO:7).
12. The method of claim 6 , wherein the polypeptide further comprises, at the amino terminus of the polypeptide: a glutamate (Glu) residue; a pyroglutamate (pGlu) residue; or the amino acid sequence Lys-Arg-Gln.
13. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence conforming to:
(SEQ ID NO:8);
Glu/pG1u-Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-
Arg-Trp
(SEQ ID NO:9);
Glu/pG1u-Trp-Val-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-
Arg-Trp
(SEQ ID NO:10);
Glu/pG1u-Trp-Thr-Gln-Phe-Lys-Ile-Gln-Trp-Ser-Gln-
Arg-Trp
or
(SEQ ID NO:11)
Glu/pG1u-Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Ser-His-
Arg-Trp.
14. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence conforming to:
Lys-Arg-Gln-Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp (SEQ ID NO:12);
Lys-Arg-Gln-Trp-Val-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp (SEQ ID NO:13);
Lys-Arg-Gln-Trp-Thr-Gln-Phe-Lys-Ile-Gln-Trp-Ser-Gln-Arg-Trp (SEQ ID NO:14); or
Lys-Arg-Gln-Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Ser-His-Arg-Trp (SEQ ID NO:15).
15. The method of claim 1 , wherein the polypeptide consists of an amino acid sequence conforming to:
(SEQ ID NO: 4)
Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp;
(SEQ ID NO: 5)
Trp-Val-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp;
(SEQ ID NO: 6)
Trp-Thr-Gln-Phe-Lys-Ile-Gln-Trp-Ser-Gln-Arg-Trp;
(SEQ ID NO: 7)
Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Ser-His-Arg-Trp;
(SEQ ID NO: 8)
Gln/pGln-Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp;
(SEQ ID NO: 9)
Gln/pGln-Trp-Val-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp;
(SEQ ID NO: 10)
Gln/pGln-Trp-Thr-Gln-Phe-Lys-Ile-Gln-Trp-Ser-Gln-Arg-Trp;
(SEQ ID NO: 11)
Gln/pGln-Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Ser-His-Arg-Trp;
(SEQ ID NO: 12)
Lys-Arg-Gln/pGln-Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp;
(SEQ ID NO: 13)
Lys-Arg-Gln/pGln-Trp-Val-Gln-Phe-Lys-Ile-Gln-Trp-Asn-Gln-Arg-Trp;
(SEQ ID NO: 14)
Lys-Arg-Gln/pGln-Trp-Thr-Gln-Phe-Lys-Ile-Gln-Trp-Ser-Gln-Arg-Trp;
(SEQ ID NO: 15)
Lys-Arg-Gln/pGln-Trp-Ala-Gln-Phe-Lys-Ile-Gln-Trp-Ser-His-Arg-Trp.
16. The method of claim 1 , wherein the pharmaceutical composition is formulated for parenteral administration.
17. The method of claim 16 , wherein the parenteral administration is intravenous administration.