Antibodies to OPGL

• US 20120087923A1
• Filed: 11/14/2011
• Published: 04/12/2012
• Est. Priority Date: 06/26/2001
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Fremont Inc. (Amgen Inc.), Amgen Inc.
• Inventors: Boyle, William J., Martin, Francis H., Corvalan, Jose R., Davis, C. Geoffrey
• Granted Patent: US 8,409,578 B2
• Time in Patent Office: Days
• US Class Current: 424/135.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate 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 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 19/04 for non-specific disorders of the connective tissue
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/08 Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 16/2875 : against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/51 : Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 : Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/54 : F(ab')2
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Antibodies that interact with osteoprotegerin ligand (OPGL) are described. Methods of treating osteopenic disorders by administering a pharmaceutically effective amount of antibodies to OPGL are described. Methods of detecting the amount of OPGL in a sample using antibodies to OPGL are described.

Claims

1-29. -29. (canceled)

30. A method of treating bone loss in a patient, comprising administering an antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO:

13 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO;

14, wherein the heavy chain and light chain form an antibody that interacts with a human osteoprotegerin ligand (OPGL) and inhibits binding of human OPGL to an osteoclast differentiation and activation receptor (ODAR).

52. The method of any one of claims 30, 33, 45, 48, 49, 50, and 51, wherein the bone loss is associated with at least one condition selected from an osteopenic disorder, an inflammatory condition, an autoimmune condition, rheumatoid arthritis, and cancer.

53. The method of claim 52, wherein the bone loss is associated with an osteopenic disorder, and wherein the method further comprises administering at least one additional therapeutic agent selected from a bone morphogenic factor, a transforming growth factor-β

(TGF-β

), a parathyroid hormone, an analog of a parathyroid hormone, a parathyroid hormone related protein, an analog of a parathyroid hormone related protein, a prostaglandin, a bisphosphonate, an alendronate, fluoride, calcium, a fibroblast growth factor (FGF), and an FGF modulator.

54. The method of claim 52, wherein the bone loss is associated with an inflammatory condition, and wherein the method further comprises administering at least one additional therapeutic agent selected from an interleukin-1 (IL-1) inhibitor, IL-1ra, Kineret™

, anakinra, a TNFα

inhibitor, a soluble TNFα

receptor, Enbrel™

, etanercept, an anti-TNFα

antibody, Remicade™

, infliximab, a D2E7 antibody, a non-steroidal anti-inflammatory drug (NSAID), a COX-2 inhibitor, Celebrex™

, celecoxib, Vioxx™

, rofecoxib, and leflunomide.

55. The method of claim 52, wherein the bone loss is associated with an autoimmune condition, and wherein the method further comprises administering at least one additional therapeutic agent selected from an interleukin-1 (IL-1) inhibitor, IL-1ra, Kineret™

, anakinra, a TNFα

inhibitor, a soluble TNFα

receptor, Enbrel™

, etanercept, an anti-TNFα

antibody, Remicade™

, infliximab, a D2E7 antibody, methotrexate, a soluble form of CTLA4, and a modulator of glucocorticoid receptor.

56. The method of claim 52, wherein the bone loss is associated with rheumatoid arthritis, and wherein the method further comprises administering at least one additional therapeutic agent selected from an interleukin-1 (IL-1) inhibitor, IL-1ra, Kineret™

, anakinra, a TNFα

inhibitor, a soluble TNFα

receptor, Enbrel™

, etanercept, an anti-TNFα

antibody, Remicade™

, infliximab, a D2E7 antibody, a non-steroidal anti-inflammatory drug (NSAID), a COX-2 inhibitor, Celebrex™

, celecoxib, Vioxx™

, rofecoxib, leflunomide, methotrexate, a soluble form of CTLA4, and a modulator of glucocorticoid receptor.

57. The method of claim 52, wherein the bone loss is associated with cancer, and wherein the method further comprises administering at least one additional therapeutic agent selected from a keratinocyte growth factor (KGF), a KGF-related molecule, a KGF modulator, an anti-Her2 antibody, an anti-CDC20 antibody, and an anti-EGFR antibody, and a PAF antagonist.

58. The method of claim 52, wherein the bone loss is associated with cancer, and wherein the method further comprises administering at least one of radiation therapy and chemotherapy.

59. The method of claim 52, wherein the bone loss is associated with cancer selected from at least one of breast cancer, prostate cancer, thyroid cancer, kidney cancer, lung cancer, esophogeal cancer, rectal cancer, bladder cancer, cervical cancer, ovarian cancer, and liver cancer, and gastrointestional tract cancer.

60. The method of any one of claims 30, 33, 45, 48, 49, 50, and 51, wherein the bone loss is associated with a solid tumor.

61. The method of any one of claims 30, 33, 45, 48, 49, 50, and 51, wherein the bone loss is associated with a metastatic tumor.

62. The method of any one of claims 30, 33, 45, 48, 49, 50, and 51, wherein the bone loss is associated with at least one condition selected from osteoporosis, Paget'"'"'s disease, osteomyelitis, hypercalcemia, osteopenia, and osteonecrosis.

63. The method of any one of claims 30, 33, 45, 48, 49, 50, and 51, wherein the antibody is a fully human antibody.

64. The method of any one of claims 30, 33, 45, 48, 49, 50, and 51, wherein the antibody is selected from a Fab antibody, a Fab′

antibody, a F(ab′

)₂ antibody, and a single-chain scFv antibody.

31. A method of treating bone loss in a patient, comprising administering an antibody comprising a heavy chain and a light chain, wherein:

a) the heavy chain comprises an amino acid sequence having at least 95% identity to SEQ ID NO;

13; and

b) the light chain comprises an amino acid sequence having at least 95% identity to SEQ ID NO;

14;

wherein the heavy chain and light chain form an antibody that interacts with a human osteoprotegerin ligand (OPGL) and inhibits binding of human OPGL to an osteoclast differentiation and activation receptor (ODAR).

32. The method of claim 31, wherein the heavy chain comprises an amino acid sequence having at least 99% identity to SEQ ID NO:

13 and the light chain comprises an amino acid sequence having at least 99% identity to SEQ ID NO;

14.

33. A method of treating bone loss in a patient, comprising administering an antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO:

13, wherein an antibody comprising the heavy chain and the light chain interacts with a human osteoprotegerin ligand (OPGL) and inhibits binding of human OPGL to an osteoclast differentiation and activation receptor (ODAR).

34. The method of claim 33, wherein the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO:

2 from residue 20 to residue 467.

35. The method of claim 33, wherein the heavy chain consists of the amino acid sequence as set forth in SEQ ID NO:

2 from residue 20 to residue 467.

36. The method of claim 33, wherein the light chain comprises the amino acid sequence as set forth in SEQ ID NO:

14.

37. The method of claim 34, wherein the light chain comprises the amino acid sequence as set forth in SEQ ID NO:

14.

38. The method of claim 35, wherein the light chain comprises the amino acid sequence as set forth in SEQ ID NO:

14.

39. The method of claim 33, wherein the light chain comprises the amino acid sequence as set forth in SEQ ID NO:

4 from residue 21 to residue 235.

40. The method of claim 35, wherein the light chain comprises the amino acid sequence as set forth in SEQ ID NO:

4 from residue 21 to residue 235.

41. The method of claim 33, wherein the light chain consists of the amino acid sequence as set forth in SEQ ID NO:

4 from residue 21 to residue 235.

42. The method of claim 34, wherein the light chain consists of the amino acid sequence as set forth in SEQ ID NO:

4 from residue 21 to residue 235.

43. The method of claim 33, 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.

44. The method of claim 33, wherein the heavy chain consists of the amino acid sequence as set forth in SEQ ID NO:

2 from residue 20 to residue 467, and the light chain consists of the amino acid sequence as set forth in SEQ ID NO;

4 from residue 21 to residue 235.

45. A method of treating bone loss in a patient, comprising administering an antibody comprising a heavy chain and a light chain, wherein the light chain comprises the amino acid sequence as set forth in SEQ ID NO:

14, wherein an antibody comprising the heavy chain and the light chain interacts with a human osteoprotegerin ligand (OPGL) and inhibits binding of human OPGL to an osteoclast differentiation and activation receptor (ODAR).

46. The method of claim 45, wherein the light chain comprises the amino acid sequence as set forth in SEQ ID NO:

4 from residue 21 to residue 235.

47. The method of claim 45, wherein the light chain consists of the amino acid sequence as set forth in SEQ ID NO:

4 from residue 21 to residue 235.

48. A method of treating bone loss in a patient, comprising administering an antibody produced by a method comprising expressing a first polynucleotide and a second polynucleotide in an isolated host cell, wherein the first polynucleotide encodes a heavy chain comprising CDR1, CDR2, and CDR3 of SEQ ID NO:

13 and the second polynucleotide encodes a light chain comprising CDR1, CDR2, and CDR3 of SEQ ID NO;

14, and wherein the antibody comprising the heavy chain and the light chain interacts with a human osteoprotegerin ligand (OPGL) and inhibits binding of human OPGL to an osteoclast differentiation and activation receptor (ODAR).

49. A method of treating bone loss in a patient, comprising administering an antibody produced by a method comprising expressing a first polynucleotide and a second polynucleotide in an isolated host cell, wherein the first polynucleotide encodes a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:

13 and the second polynucleotide encodes a light chain, and wherein the antibody comprising the heavy chain and the light chain interacts with a human osteoprotegerin ligand (OPGL) and inhibits binding of human OPGL to an osteoclast differentiation and activation receptor (ODAR).

50. A method of treating bone loss in a patient, comprising administering an antibody produced by a method comprising expressing a first polynucleotide and a second polynucleotide in an isolated host cell, wherein the first polynucleotide encodes a heavy chain and the second polynucleotide encodes a light chain comprising the amino acid sequence of SEQ ID NO:

14, and wherein the antibody comprising the heavy chain and the light chain interacts with a human osteoprotegerin ligand (OPGL) and inhibits binding of human OPGL to an osteoclast differentiation and activation receptor (ODAR).

51. A method of treating bone loss in a patient, comprising administering an antibody produced by a method comprising expressing a first polynucleotide and a second polynucleotide in an isolated host cell, wherein the first polynucleotide encodes a heavy chain comprising the amino acid sequence of SEQ ID NO:

2 and the second polynucleotide encodes a light chain comprising the amino acid sequence of SEQ ID NO;

4, and wherein the antibody comprising the heavy chain and the light chain interacts with a human osteoprotegerin ligand (OPGL) and inhibits binding of human OPGL to an osteoclast differentiation and activation receptor (ODAR).