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- Nachgewiesen in: USPTO Patent Applications
- Sprachen: English
- Document Number: 20200131257
- Publication Date: April 30, 2020
- Appl. No: 16/624895
- Application Filed: July 05, 2018
- Claim: 1. A non-natural soluble construct that prevents or minimizes the binding of at least one selected from the group consisting of FGF receptor (FGFR), FGF19, and FGF21 to β-Klotho.
- Claim: 2. The construct of claim 1, wherein the β-Klotho is on the surface of a mammal's cell.
- Claim: 3. The construct of claim 1, which is at least one selected from the group consisting of an antibody, nanobody, recombinant protein, and small molecule.
- Claim: 4. (canceled)
- Claim: 5. The construct of claim 1, wherein the antibody is at least one selected from the group consisting of a polyclonal antibody, monoclonal antibody, humanized antibody, synthetic antibody, heavy chain antibody, human antibody, biologically active fragment of an antibody, and any combinations thereof.
- Claim: 6. The construct of claim 1, which recognizes and binds to at least one amino acid residue of FGF19 or FGF21 that binds to β-Klotho, thus preventing FGF19 or FGF21 binding to β-Klotho.
- Claim: 7. The construct of claim 6, which recognizes and binds to: (a) at least one amino acid within the amino acid residues 169-209 in FGF21 (SEQ ID NO:3); (b) at least one amino acid within the amino acid residues 186-209 in SEQ ID NO:3, or (c) at least one amino acid within the amino acid residues 170-216 in FGF19CT (SEQ ID NO:2).
- Claim: 8. (canceled)
- Claim: 9. (canceled)
- Claim: 10. The construct of claim 1, which recognizes or binds to at least one amino acid residue of β-Klotho that binds to FGF19 or FGF21, thus preventing β-Klotho binding to FGF19 or FGF21.
- Claim: 11. The construct of claim 10, which recognizes or binds to one or more amino acids within the amino acid residues 379-942 in β-Klotho (SEQ ID NO:1).
- Claim: 12. The construct of claim 11, which recognizes or binds to one or more amino acids within amino acids 379-380, 392-394, 419-422, 431, 434-435, 438, 532, 643-647, 692-694, 696-697, 743, 745, 764, 768, 824, 826, 829, 832, 845, 847-851, 853, 862, 889, 931-932, 939-940, and 942 in SEQ ID NO:1.
- Claim: 13. The construct of claim 1, which recognizes and binds to at least one amino acid residue of β-Klotho that binds to a FGFR, thus preventing β-Klotho binding to the FGFR.
- Claim: 14. The construct of claim 13, which recognizes or binds to one or more amino acids within the extracellular region of human β-Klotho (amino acid residues 53-983 of SEQ ID NO:1), or a fragment thereof.
- Claim: 15. The construct of claim 14, which recognizes or binds to one or more amino acids within the fragment of the extracellular region of human β-Klotho comprising amino acid residues 533-575 of SEQ ID NO:1.
- Claim: 16. The construct of claim 1, comprising a FGF19 or FGF21 polypeptide that is capable of binding to and sequestering β-Klotho on the surface of a mammal's cell.
- Claim: 17. The construct of claim 16, which comprises amino acid residues 169-209 of SEQ ID NO:3 (FGF21CT) or amino acid residues 170-216 of SEQ ID NO:2 (FGF19CT).
- Claim: 18. (canceled)
- Claim: 19. The construct of claim 1, comprising a β-Klotho polypeptide that is capable of binding to and sequestering FGF19 or FGF21.
- Claim: 20. The construct of claim 19, wherein the β-Klotho polypeptide comprises the extracellular region of human β-Klotho (amino acids 53-983 of SEQ ID NO:1), or a fragment thereof.
- Claim: 21. The construct of claim 20, wherein the β-Klotho polypeptide comprises the fragment of the extracellular region of human β-Klotho comprising amino acids 379-942 of SEQ ID NO:1.
- Claim: 22. The construct of claim 1, comprising a β-Klotho polypeptide that is capable of binding to a FGFR.
- Claim: 23. The construct of claim 22, which comprises the extracellular region of human β-Klotho (amino acid residues 53-983 of SEQ ID NO:1), or a fragment thereof.
- Claim: 24. The construct of claim 23, which comprises amino acid residues 533-575 of SEQ ID NO:1.
- Claim: 25. The construct of claim 1, which is fused to a stability enhancing domain.
- Claim: 26. The construct of claim 25, wherein the stability enhancing domain comprises at least one selected from the group consisting of albumin, thioredoxin, glutathione S-transferase, and a Fc region of an antibody.
- Claim: 27. The construct of claim 25, wherein the polypeptide and the stability enhancing domain are linked through a polypeptide comprising about 1-18 amino acids.
- Claim: 28. A soluble construct comprising a FGF19 or FGF21 polypeptide that binds to β-Klotho more tightly than wild-type FGF19 or FGF21.
- Claim: 29. The construct of claim 28, wherein the FGF19 or FGF21 polypeptide has at least one mutation in its C-terminal domain.
- Claim: 30. The construct of claim 29, wherein the FGF21 polypeptide has a mutation in: at least one residue selected from the group consisting of V188, R203, and L194; or at least one mutation selected from the group consisting of R203W and L194F.
- Claim: 31. (canceled)
- Claim: 32. The construct of claim 28, which is fused to a stability enhancing domain.
- Claim: 33. The construct of claim 32, wherein the stability enhancing domain comprises at least one selected from the group consisting of albumin, thioredoxin, glutathione S-transferase, and a Fc region of an antibody.
- Claim: 34. The construct of claim 32, wherein the polypeptide and the stability enhancing domain are linked through a polypeptide comprising about 1-18 amino acids.
- Claim: 35. A construct that simultaneously binds to an exposed epitope on FGF21CT and an exposed epitope on β-Klotho in a FGF21CT-β-Klotho complex, thus stabilizing the FGF21CT-β-Klotho complex.
- Claim: 36. The construct of claim 35, which is at least one selected from the group consisting of an antibody, nanobody, recombinant protein, and small molecule.
- Claim: 37. (canceled)
- Claim: 38. The construct of claim 36, wherein the antibody is at least one selected from the group consisting of a polyclonal antibody, monoclonal antibody, humanized antibody, synthetic antibody, heavy chain antibody, human antibody, biologically active fragment of an antibody, and any combinations thereof.
- Claim: 39. A construct comprising a β-Klotho binder fused to at least one selected from the group consisting of a FGF19 polypeptide and FGF21 polypeptide, wherein the construct has at least one selected from the group consisting of FGF19 stimulatory activities and FGF 21 stimulatory activities.
- Claim: 40. A method of treating endocrine FGF-related diseases or disorders in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a construct that modulates interaction of at least one selected from the group consisting of FGF19 and FGF21 with β-Klotho on the surface of a cell of the mammal.
- Claim: 41. The method of claim 40, wherein the construct prevents or minimizes binding of at least one selected from the group consisting of FGF19 and FGF21 to β-Klotho on the surface of the mammal's cell.
- Claim: 42. The method of claim 41, wherein the disease or disorder comprises at least one selected from the group consisting of liver cancer and colon cancer.
- Claim: 43. The method of claim 40, wherein the construct binds more tightly than wild-type FGF19 or FGF21 to β-Klotho on the surface of the mammal's cell.
- Claim: 44. The method of claim 43, wherein the disease or disorder comprises at least one selected from the group consisting of obesity, diabetes, pancreatitis, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).
- Claim: 45. The method of claim 40, wherein the mammal is human.
- Claim: 46. The method of claim 40, wherein the construct is administered by at least one route selected from the group consisting of inhalational, oral, rectal, vaginal, parenteral, intracranial, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, and intravenous.
- Claim: 47. The method of claim 40, wherein the mammal is further administered at least one additional drug that treats or prevents the disease and/or disorder.
- Claim: 48-49. (canceled)
- Current International Class: 07; 07; 12; 07; 61
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