Claims for Patent: 8,992,925

Summary for Patent: 8,992,925

Title:	RANKL antibody-PTH/PTHrP chimeric molecules
Abstract:	Chimeric molecules comprising receptor activator of NF-.kappa.B ligand (RANKL) antibodies and parathyroid hormone/parathyroid hormone-related protein (PTH/PTHrP) peptides are described. Compositions and methods for the treatment of bone diseases are also described.
Inventor(s):	Kostenuik; Paul (Newbury Park, CA), Shen; Wenyan (Palo Alto, CA), Boone; Thomas C. (Newbury Park, CA)
Assignee:	Amgen Inc. (Thousand Oaks, CA)
Application Number:	11/599,629
Patent Claims:	1. A receptor activator of NF-.kappa.B ligand (RANKL) antibody-parathyroid hormone/parathyroid hormone related protein (PTH/PTHrP) chimeric molecule, comprising: (a) an antibody that binds to RANKL; and (b) a PTH/PTHrP peptide comprising a PTH/PTHrP modulating domain; wherein the PTH/PTHrP peptide is operably linked to the antibody. 2. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1, wherein the PTH/PTHrP peptide is operably linked to a heavy chain. 3. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1, wherein the PTH/PTHrP peptide is operably linked to a light chain. 4. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 2, wherein the PTH/PTHrP peptide is operably linked to the N-terminus of the heavy chain. 5. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 3, wherein the PTH/PTHrP peptide is operably linked to the N-terminus of the light chain. 6. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 4, wherein the PTH/PTHrP peptide is fused to the N-terminus of the heavy chain. 7. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 5, wherein the PTH/PTHrP peptide is fused to the N-terminus of the light chain. 8. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1 wherein the antibody comprises a heavy chain comprising CDR1, CDR2, and CDR3 as set forth in SEQ ID NO:11. 9. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1 wherein the antibody comprises a light chain comprising CDR1, CDR2, and CDR3 as set forth in SEQ ID NO:12. 10. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1 wherein the antibody comprises a heavy chain and a light chain, and wherein the heavy chain comprises CDR1, CDR2, and CDR3 as set forth in SEQ ID NO:11, and the light chain comprises CDR1, CDR2, and CDR3 as set forth in SEQ ID NO:12. 11. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1, wherein the antibody is selected from a single-chain Fv antibody (scFv), a Fab antibody, a Fab' antibody, a (Fab')2 antibody, a domain antibody, a nanobody, a minibody, a maxibody, and a diabody. 12. A RANKL antibody-PTH/PTHrP chimeric molecule, comprising: (a) an antibody comprising a heavy chain and a light chain, wherein the antibody binds to RANKL; (b) a first PTH/PTHrP peptide comprising a PTH/PTHrP modulating domain; and (c) a second PTH/PTHrP peptide; wherein the first PTH/PTHrP peptide is operably linked to the light chain and the second PTH/PTHrP peptide is operably linked to the heavy chain, and wherein the first and second PTH/PTHrP peptides are the same or different. 13. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 12, wherein the first PTH/PTHrP peptide is operably linked to the N-terminus of the light chain and the second PTH/PTHrP peptide is operably linked to the N-terminus of the heavy chain. 14. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 12, wherein the first PTH/PTHrP peptide is fused to the N-terminus of the light chain and the second PTH/PTHrP peptide is fused to the N-terminus of the heavy chain. 15. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1, wherein: (a) the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a first variable region comprising the amino acid sequence as set forth in SEQ ID NO: 11, and wherein the light chain comprises a second variable region comprising the amino acid sequence as set forth in SEQ ID NO: 12; and (b) wherein the PTH/PTHrP peptide is operably linked to the heavy chain or the light chain. 16. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 15, wherein the PTH/PTHrP peptide is operably linked to the heavy chain. 17. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 15, wherein the PTH/PTHrP peptide is operably linked to the light chain. 18. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 16, wherein the PTH/PTHrP peptide is operably linked to the N-terminus of the heavy chain. 19. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 17, wherein the PTH/PTHrP peptide is operably linked to the N-terminus of the light chain. 20. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 18, wherein the PTH/PTHrP peptide is fused to the N-terminus of the heavy chain. 21. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 19, wherein the PTH/PTHrP peptide is fused to the N-terminus of the light chain. 22. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 15, wherein the heavy chain and the light chain are connected by a flexible linker to form a single-chain antibody. 23. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 22, wherein the single-chain antibody is a single-chain Fv antibody. 24. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 15, wherein the antibody is a Fab antibody. 25. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 15, wherein the antibody is a Fab' antibody. 26. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 15, wherein the antibody is a (Fab')2 antibody. 27. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 15, wherein the antibody is fully human. 28. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 15, wherein the RANKL antibody-PTH/PTHrP chimeric molecule inhibits binding of RANKL to a receptor activator of NF-.kappa.B (RANK). 29. A RANKL antibody-PTH/PTHrP chimeric molecule, comprising: (a) an antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises a first variable region comprising CDR1, CDR2, and CDR3 as set forth in SEQ ID NO: 11, and wherein the light chain comprises a variable region comprising CDR1, CDR2, and CDR3 as set forth in SEQ ID NO: 12, and wherein the antibody binds to RANKL; (b) a first PTH/PTHrP comprising a PTH/PTHrP modulating domain; and (c) a second PTH/PTHrP peptide; wherein the first PTH/PTHrP peptide is operably linked to the light chain and the second PTH/PTHrP peptide is operably linked to the heavy chain, and wherein the first and second PTH/PTHrP peptides are the same or different. 30. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 29, wherein the first PTH/PTHrP peptide is operably linked to the N-terminus of the light chain and the second PTH/PTHrP peptide is operably linked to the N-terminus of the heavy chain. 31. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 30, wherein the first PTH/PTHrP peptide is fused to the N-terminus of the light chain and the second PTH/PTHrP peptide is fused to the N-terminus of the heavy chain. 32. A RANKL antibody-PTH/PTHrP chimeric molecule, comprising (a) an antibody comprising a heavy chain and a light chain, wherein: (i) the heavy chain comprises a first variable region, wherein the first variable region comprises a sequence that has at least 92% identity to the amino acid sequence set forth in SEQ ID NO: 11, and (ii) the light chain comprises a second variable region, wherein the second variable region comprises a sequence that has at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 12, wherein the antibody binds to RANKL; and (b) a PTH/PTHrP comprising a PTH/PTHrP modulating domain; wherein the PTH/PTHrP peptide is operably linked to the heavy chain or the light chain. 33. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 32, wherein the first variable region comprises a sequence that has at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 11, and wherein the second variable region comprises a sequence that has at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 12. 34. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 32, wherein the first variable region comprises a sequence that has at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 11, and wherein the second variable region comprises a sequence that has at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 12. 35. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1, wherein the PTH/PTHrP peptide comprises a PTH/PTHrP modulating domain comprising the amino acid sequence selected from at least one of SEQ ID NOs: 16 to 67. 36. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 35, wherein the PTH/PTHrP modulating domain comprises the amino acid sequence of SEQ ID NO: 22. 37. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1, wherein the PTH/PTHrP peptide comprises the amino acid sequence of SEQ ID NO: 6 from residue 32 to residue 70. 38. A RANKL antibody-PTH/PTHrP chimeric molecule selected from: (a) a RANKL antibody-PTH/PTHrP chimeric molecule comprising a first polypeptide having the amino acid sequence of SEQ ID NO: 2 from residue 20 to residue 467 and a second polypeptide having the amino acid sequence of SEQ ID NO: 8 from residue 32 to residue 285; (b) a RANKL antibody-PTH/PTHrP chimeric molecule comprising a first polypeptide having the amino acid sequence of SEQ ID NO: 10 from residue 32 to residue 518 and a second polypeptide having the amino acid sequence of SEQ ID NO: 4 from residue 21 to residue 235; and (c) a RANKL antibody-PTH/PTHrP chimeric molecule comprising a first polypeptide having the amino acid sequence of SEQ ID NO: 10 from residue 32 to residue 518 and a second polypeptide having the amino acid sequence of SEQ ID NO: 8 from residue 32 to residue 285. 39. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1, wherein the PTH/PTHrP peptide comprises a PTH/PTHrP modulating domain comprising the amino acid sequence of at least one of SEQ ID NOs: 68 to 89. 40. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1, wherein the PTH/PTHrP peptide comprises a PTH/PTHrP modulating domain comprising the amino acid sequence of at least one of SEQ ID NOs: 90 to 107 except that one or more residues at position 14 through the C-terminus of the PTH/PTHrP modulating domain is substituted with a cysteine residue. 41. A method of treating bone loss in a patient, comprising administering the RANKL antibody-PTH/PTHrP chimeric molecule of any one of claims 1, 12, 15, 29, 32, and 38. 42. A method of treating bone loss in a patient, comprising administering the RANKL antibody-PTH/PTHrP chimeric molecule of any one of claims 1, 12, 15, 29, 32, and 38 and at least one agent selected from a bone anti-resorptive agent, a bone anabolic agent, an anti-inflammatory agent, an immune suppressing agent, and a cancer therapy agent. 43. The method of claim 41 further comprising administering at least one therapeutic agent selected from a bone morphogenic factor, transforming growth factor-62 (TGF-.beta.), an interleukin-1 (IL-1) inhibitor, IL-1ra, anakinra, a TNF.alpha. inhibitor, a soluble TNF.alpha. receptor, etanercept, an anti-TNF.alpha. antibody, infliximab, adalimumab, a prostaglandin, a bisphosphonate, alendronate, fluoride, calcium, a non-steroidal anti-inflammatory drug (NSAID), a COX-2 inhibitor, celecoxib, rofecoxib, an immunosuppressant, methotrexate, leflunomide, a serine protease inhibitor, a secretory leukocyte protease inhibitor (SLPI), an IL-6 inhibitor, an IL-6 antibody, an IL-8 inhibitor, an IL-8 antibody, an IL-18 inhibitor, an IL-18 binding protein, an IL-18 antibody, an Interleukin-1 converting enzyme (ICE) modulator, a fibroblast growth factor (FGF), an FGF modulator, a PAF antagonist, a keratinocyte growth factor (KGF), a KGF-related molecule, a KGF modulator; a matrix metalloproteinase (MMP) modulator, a nitric oxide synthase (NOS) modulator, a modulator of glucocorticoid receptor, a modulator of glutamate receptor, a modulator of lipopolysaccharide (LPS) levels, a noradrenaline, a noradrenaline mimetic, and a noradrenaline modulator. 44. A method of treating bone loss associated with an inflammatory condition in a patient, comprising administering the RANKL antibody-PTH/PTHrP chimeric molecule of any one of claims 1, 12, 15, 29, 32, and 38. 45. A method of treating bone loss associated with an autoimmune condition in a patient, comprising administering the RANKL antibody-PTH/PTHrP chimeric molecule of any one of claims 1, 12, 15, 29, 32, and 38. 46. A method of treating bone loss associated with rheumatoid arthritis in a patient, comprising administering the RANKL antibody-PTH/PTHrP chimeric molecule of any one of claims 1, 12, 15, 29, 32, and 38. 47. A method of treating bone loss associated with cancer comprising administering the RANKL antibody-PTH/PTHrP chimeric molecule of any one of claims 1, 12, 15, 29, 32, and 38. 48. A method of treating bone loss associated with cancer comprising administering the RANKL antibody-PTH/PTHrP chimeric molecule of any one of claims 1, 12, 15, 29, 32, and 38 and at least one therapeutic agent selected from an epidermal growth factor receptor (EGFR) inhibitor, a HER2 inhibitor, a vegF inhibitor, a vegF receptor inhibitor, a hepatocyte growth factor (HGF)/scatter factor (SF) inhibitor, a c-Met inhibitor, an angiopoietin inhibitor, a Tie2 inhibitor, a platelet derived growth factor receptor (PDGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a mucin-like glycoprotein inhibitor, a CDC20 inhibitor, and a CDC33 inhibitor. 49. A method of treating bone loss associated with cancer comprising administering the RANKL antibody-PTH/PTHrP chimeric molecule of any one of claims 1, 12, 15, 29, 32, and 38 and at least one antibody selected from a Her2 antibody, a CDC20 antibody, an EGFR antibody, a vegF antibody, a vegF receptor antibody, a hepatocyte growth factor (HGF)/scatter factor (SF) antibody, an insulin-like growth factor receptor (IFGR) antibody, and a CDC33 antibody. 50. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1, wherein the antibody comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 11. 51. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1, wherein the antibody comprises a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 12. 52. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1 wherein the antibody comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 2 from residue 20 to residue 467. 53. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1 wherein the antibody comprises a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 4 from residue 21 to residue 235. 54. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 1 wherein the antibody comprises a heavy chain and a light chain, and wherein the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 2 from residue 20 to residue 467 and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 4 from residue 21 to residue 235. 55. A RANKL antibody-PTH/PTHrP chimeric molecule, comprising: (a) an antibody that binds to RANKL; and (b) a PTH/PTHrP peptide comprising a PTH/PTHrP modulating domain, wherein the PTH/PTHrP modulating domain comprises the amino acid sequence of SEQ ID NO: 22; and wherein the PTH/PTHrP peptide is operably linked to the N-terminus of a heavy chain of the antibody. 56. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 55 wherein the antibody comprises a heavy chain comprising CDR1, CDR2 and CDR3 as set forth in SEQ ID NO: 11. 57. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 55 wherein the antibody comprises a light chain comprising CDR1, CDR2 and CDR3 as set forth in SEQ ID NO: 12. 58. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 55 wherein the antibody comprises a heavy chain comprising CDR1, CDR2 and CDR3 as set forth in SEQ ID NO: 11 and a light chain comprising CDR1, CDR2 and CDR3 as set forth in SEQ ID NO: 12. 59. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 55 wherein the antibody comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 11. 60. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 55 wherein the antibody comprises a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 12. 61. The RANKL antibody-PTH/PTHrP chimeric molecule of claim 55 wherein the antibody comprises a heavy chain comprising a first variable region comprising the amino acid sequence as set forth in SEQ ID NO: 11 and a light chain comprising a second variable region comprising the amino acid sequence as set forth in SEQ ID NO: 12. 62. A pharmaceutical composition comprising the RANKL antibody-PTH/PTHrP chimeric molecule of any one of claims 1, 12, 15, 29, 32, 38 and 55.

Details for Patent 8,992,925

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2025-11-14
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2025-11-14
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2025-11-14
Immunex Corporation	ENBREL	etanercept	Injection	103795	09/27/2004		2025-11-14