Treatment of bone disorders

• US 20060263355A1
• Filed: 02/28/2006
• Published: 11/23/2006
• Est. Priority Date: 02/28/2005
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Sewell, K. Lea, Quan, Joanne
• Application Number:
  US11/363,091
• Publication Number:
  US 20060263355A1
• Time in Patent Office: Days
• US Class Current: 424/141.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/716 Glucans
• CPC Class Codes: A61K 35/32 Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
• CPC Class Codes: A61K 38/19 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 38/2026 IL-4
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

Methods of treatment of various bone indications, such as osteoporosis, in a mammal are provided wherein an effective amount of an antagonist that binds to a B-cell surface marker, such as a CD20 antibody, is administered, optionally also with another medicament such as an agent that treats such disorders in an effective amount. Articles of manufacture are also provided. Further, a method of inhibiting osteolysis in a mammal is provided comprising introducing into said mammal an isolated odontoprogenitor or osteoprogenitor cell comprising a nucleic acid encoding an antibody that binds to a B-cell surface marker.

Claims

1. A method for treating a bone disorder in a mammal comprising administering to the mammal an effective amount of a CD20 antibody.

2. The method of claim 1 wherein the antibody is a chimeric, human, or humanized antibody.

3. The method of claim 1 wherein the antibody comprises rituximab.

4. The method of claim 1 wherein the antibody is a humanized 2H7 comprising the variable domain sequences in SEQ ID Nos. 2 and 8.

5. The method of claim 1 wherein the antibody is a humanized 2H7 comprising a variable heavy-chain domain with alteration(s) N100A or D56A,N100A in SEQ ID NO:

8 and a variable light-chain domain with alteration(s) M32L, S92A, or M32L,S92A in SEQ ID NO;

2.

6. The method of claim 1 wherein the antibody is a humanized 2H7 comprising the light-chain variable region (V_L) sequence of SEQ ID NO:

30 and the heavy-chain variable region (V_H) sequence of SEQ ID NO;

8, wherein the antibody further contains an amino acid substitution of D56A in VH-CDR2, and N 100 in VII-CDR3 is substituted with Y or W.

7. The method of claim 6 wherein the antibody comprises the v511 light-chain sequence of SEQ ID NO:

31 and the v511 heavy-chain sequence of SEQ ID NO;

32.

8. The method of claim 1 wherein the antibody is a naked antibody.

9. The method of claim 1 wherein the antibody is conjugated with another molecule.

10. The method of claim 9 wherein the antibody is covalently linked to a bone-targeting agent.

11. The method of claim 1 wherein the antibody induces a major clinical response upon administration to the mammal.

12. The method of claim 1 wherein the antibody is administered in a dose of about 400 mg to 1.3 grams at a frequency of about one to four doses within a period of about one month.

13. The method of claim 12 wherein each dose is about 500 mg to 1.2 grams.

14. The method of claim 12 wherein each dose is about 750 mg to 1.1 grams.

15. The method of claim 12 wherein the antibody is administered in two to four doses.

16. The method of claim 12 wherein the antibody is administered in two to three doses.

17. The method of claim 12 wherein the antibody is administered within a period of about 2 to 3 weeks.

18. The method of claim 17 wherein the period is about two weeks.

19. The method of claim 1 wherein the mammal is human.

20. The method of claim 1 wherein the antibody is locally administered at a joint.

21. The method of claim 1 wherein the antibody is locally administered at a site of a bony defect.

22. The method of claim 21 wherein the bony defect is a fracture, bone graft site, implant site, or periodontal pocket.

23. The method of claim 1 wherein the antibody is administered systemically.

24. The method of claim 1 wherein the antibody is administered intravenously.

25. The method of claim 1 wherein the antibody is administered subcutaneously.

26. The method of claim 1 wherein a second medicament is administered in an effective amount, wherein the CD20 antibody is a first medicament.

27. The method of claim 26 wherein the second medicament is more than one medicament.

28. The method of claim 26 wherein the second medicament is an agent that treats osteoclast-associated disorders, an immunosuppressive agent a disease-modifying anti-rheumatic drug (DMARD), a cytotoxic agent, an integrin antagonist, a non-steroidal anti-inflammatory drug (NSAID), a hormone, or a combination thereof.

29. The method of claim 28 wherein the second medicament is an agent that treats osteoclast-associated disorders or an immunosuppressive agent, or both.

30. The method of claim 29 wherein the second medicament is an immunosuppressive agent.

31. The method of claim 30 wherein the immunosuppressive agent is cyclophosphamide, chlorambucil, leflunomide, azathioprine, or methotrexate.

32. The method of claim 31 wherein the immunosuppressive agent is cyclophosphamide or methotrexate.

33. The method of claim 29 wherein the second medicament is an agent that treats osteoclast-associated disorders.

34. The method of claim 33 wherein the agent is an osteoprotegerin, an interleukin, a MMP inhibitor, a beta glucan, an integrin antagonist, calcitonin, a proton pump inhibitor, a protease inhibitor, a bisphosphonate, insulin-like growth factor-1, platelet-derived growth factor, epidermal growth factor, an inhibitor of transforming growth factor-alpha, transforming growth factor-beta, a bone morphogenetic protein, parathyroid hormone, a fibroblast growth factor, Vitamin D, calcium, fluoride, magnesium, boron, vitronectin, plasminogen-activator inhibitor, or a protease inhibitor.

35. The method of claim 34 wherein the agent is a cytokine or bisphosphonate.

36. The method of claim 33 wherein the agent is administered in lower amounts than are used if the CD20 antibody is not administered to a mammal treated with the agent.

37. The method of claim 1 wherein the mammal has never been previously treated with a CD20 antibody.

38. The method of claim 1 wherein the bone disorder is osteoporosis, an osteoporotic fracture, focal bone loss, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, alveolar bone loss, bone loss associated with periodontitis, bone loss associated with an autoimmune disease, or bone disease in multiple myeloma, macroglulinemia or monoclonal gammopathy.

39. The method of claim 38 wherein the bone disorder is focal bone loss, bone disease in multiple myeloma, macroglulinemia or monoclonal gammopathy, bone loss associated with an autoimmune disease, rheumatoid arthritis, or osteoporosis.

40. The method of claim 39 wherein the bone disorder is bone loss associated with rheumatoid arthritis or secondary osteoporosis.

41. The method of claim 39 wherein the bone disorder is focal bone loss.

42. The method of claim 1 wherein the amount of the CD20 antibody is effective to prevent erosive bone disease in inflammatory arthritides.

43. The method of claim 42 wherein the inflammatory arthritides is rheumatoid arthritis.

44. The method of claim 1 wherein the bone disorder is not associated with rheumatoid arthritis or a risk of developing rheumatoid arthritis.

45. The method of claim 1 wherein the antibody is administered in a delivery vehicle.

46. The method of claim 45 wherein the delivery vehicle is powdered bone, tricalcium phosphate, hydroxyapatite, polymethacrylate, a biodegradable polyester, an aqueous polymeric gel, or a fibrin sealant.

47. A method for treating a bone disorder in a mammal comprising administering to the mammal an effective amount of an antibody that binds to a B-cell surface marker.

48. A method for treating a bone disorder in a mammal comprising administering to the mammal an effective amount of an antagonist that binds to a B-cell surface marker.

49. An article of manufacture comprising:

i. a container comprising a CD20 antibody; and

ii. a package insert with instructions for treating a bone disorder in a mammal, wherein the instructions indicate that an effective amount of the CD20 antibody is administered to the mammal.

50. The article of claim 49 further comprising a container comprising a second medicament, wherein the CD20 antibody is a first medicament, further comprising instructions on the package insert for treating the mammal with the second medicament.

51. The article of claim 50 wherein the second medicament is an agent that treats osteoclast-associated disorders, an immunosuppressive agent, a cytotoxic agent, an integrin antagonist, or a hormone.

52. The article of claim 50 wherein the second medicament is an agent that treats osteoclast-associated disorders or an immunosuppressive agent, or both.

53. A method of inhibiting osteolysis in a mammal, comprising introducing into said mammal an isolated odontoprogenitor or osteoprogenitor cell comprising a nucleic acid encoding an antibody that binds to a B-cell surface marker.

54. The method of claim 53 wherein said cell is an odontoprogenitor cell.

55. The method of claim 54 wherein said mammal is suffering from or at risk of developing periodontitis.

56. The method of claim 54 wherein said mammal is suffering from or at risk of developing alveolar bone loss due to periodontal disease.

57. The method of claim 54 wherein said cell is administered to the periodontal ligament in the mandibular section of the jaw.

58. The method of claim 53 wherein said cell is an osteoprogenitor cell.

59. The method of claim 58 wherein said cell is implanted into an articulating joint of said mammal.

60. The method of claim 58 wherein said cell is administered intratibially.

61. The method of claim 58 wherein said cell is administered intrafemorally.

62. The method of claim 53 wherein expression of said antibody is regulated by an antibiotic compound.

63. The method of claim 62 wherein said antibiotic compound is tetracycline or a tetracycline analogue.

64. The method of claim 63 further comprising administering minocycline to said mammal.

65. The method of claim 62 wherein said antibiotic compound is administered systemically.

66. The method of claim 53 further comprising administering an agent that treats an osteoclast-associated disorder.

67. The method of claim 66 wherein the agent is interleukin-4 or an inhibitor of tumor necrosis factor-alpha.

68. The method of claim 53 wherein said mammal is suffering from or at risk of developing rheumatoid arthritis.

69. The method of claim 53 wherein said mammal is not suffering from or at risk of developing rheumatoid arthritis.

70. The method of claim 53 wherein said mammal is suffering from or at risk of developing periapical or endochondral bone loss, artificial joint particle-induced osteolysis, or osteolytic bone metastases.

71. The method of claim 53 wherein the antibody is a CD20 antibody.