Uses Of Antibody To M-Csf

• US 20080233118A1
• Filed: 07/27/2006
• Published: 09/25/2008
• Est. Priority Date: 07/28/2005
• Status: Abandoned Application

• Current Assignee: Xoma Technology Ltd. (Xoma Corp.)
• Original Assignee: Novartis Ag, Xoma Technology Ltd. (Xoma Corp.)
• Inventors: Kavanaugh, William M.
• Application Number:
  US11/996,909
• Publication Number:
  US 20080233118A1
• Time in Patent Office: Days
• US Class Current: 424/135.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/243 Colony Stimulating Factors
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• 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

Methods of using M-CSF antibodies to treat macrophage-associated diseases including atherosclerosis and HIV are provided.

Claims

1. A method of treating a macrophage-associated disease comprising administering to a subject having a macrophage-associated disease a non-murine antibody that competes with monoclonal antibody RX1 for binding to M-CSF by more than 75%, wherein said monoclonal antibody RX1 comprises the heavy chain and light chain amino acid sequences set forth in SEQ ID NOs:

2 and 4, respectively.

2. The method of claim 1 wherein the non-murine antibody specifically binds to the same epitope of M-CSF as said monoclonal antibody RX1.

3. The method of claim 1 or 2 wherein said macrophage-associated disease is an atherosclerotic disease.

4. The method of claim 1 or 2 wherein said macrophage-associated disease is a condition associated with HIV infection.

5. The method of claim 2 wherein the non-murine antibody binds an epitope of M-CSF that comprises at least 4 contiguous residues of SEQ ID NO:

120 or 121.

6. The method of any of claims 1-5 wherein the non-murine antibody is a monoclonal antibody.

7. The method of any of claims 1-5 wherein the non-murine antibody is a chimeric antibody, a humanized antibody, a human engineered antibody, a human antibody, or a single chain antibody.

8. The method of any of claims 1-7 wherein the non-murine antibody is an IgG antibody.

9. The method of any of claims 1-8 wherein the non-murine antibody retains an affinity K_d (dissociation equilibrium constant) with respect to M-CSF of SEQ ID NO:

9 of at least 10<sup>−

7</sup> M or higher.

10. The method of claim 9 wherein the non-murine antibody retains an affinity Kd with respect to M-CSF of SEQ ID NO:

9 of at least 10<sup>−

8</sup> M or higher.

11. The method of claim 10 wherein the non-murine antibody retains an affinity Kd with respect to M-CSF of SEQ ID NO:

9 of at least 10<sup>−

9</sup> M or higher.

12. The method of any of claims 1-11 wherein the non-murine antibody comprises an amino acid sequence 90% identical to SEQ ID NO:

24.

13. The method of claim 11 wherein the non-murine antibody comprises SEQ ID NO:

24.

14. The method of any of claims 1-13 wherein the non-murine antibody comprises at least 1 sequence selected from:

(a) the group consisting of SEQ ID NOs;

18, 21, 24, 29, 32, and 36;

or

(b) the group consisting of SEQ ID NOs;

, 21, 24, 32, 36 and QASQSIGTSIH (SEQ ID NO;

______).

15. The method of any of claims 1-13 wherein the non-murine antibody comprises at least 2 sequences selected from:

(a) the group consisting of SEQ ID NOs;

18, 21, 24, 29, 32, and 36;

or

(b) the group consisting of SEQ ID NOs;

, 21, 24, 32, 36 and QASQSIGTSIH (SEQ ID NO;

______).

16. The method of any of claims 1-13 wherein the non-murine antibody comprises at least 3 sequences selected from:

(a) the group consisting of SEQ ID NOs;

18, 21, 24, 29, 32, and 36;

or

(b) the group consisting of SEQ ID NOs;

, 21, 24, 32, 36 and QASQSIGTSIH (SEQ ID NO;

______).

17. The method of any of claims 1-13 wherein the non-murine antibody comprises at least 4 sequences selected from:

(a) the group consisting of SEQ ID NOs;

18, 21, 24, 29, 32, and 36;

or

(b) the group consisting of SEQ ID NOs;

, 21, 24, 32, 36 and QASQSIGTSIH (SEQ ID NO;

______).

18. The method of any of claims 1-13 wherein the non-murine antibody comprises at least 5 sequences selected from:

(a) the group consisting of SEQ ID NOs;

18, 21, 24, 29, 32, and 36;

or

(b) the group consisting of SEQ ID NOs;

, 21, 24, 32, 36 and QASQSIGTSIH (SEQ ID NO;

______).

19. The method of any of claims 1-13 wherein the non-murine antibody comprises all of:

(a) SEQ ID NOs;

18, 21, 24, 29, 32, and 36;

or

(b) SEQ ID NOs;

18, 21, 24, 32, 36 and QASQSIGTSIH (SEQ ID NO;

______).

20. The method of any of claims 11-18 wherein the non-murine antibody further comprises one or more of SEQ ID NOs:

16, 19, 22, 27, 30, and 34.

21. The method of any of claims 11-18 wherein the non-murine antibody further comprises one or more of SEQ ID NOs:

17, 20, 23, 28, 31, and 35.

22. The method of any of claims 11-18 wherein the non-murine antibody further comprises one or more of SEQ ID NOs:

18, 21, 25, 29, 32, and 37.

23. The method of any of claims 11-18 wherein the non-murine antibody further comprises one or more consensus CDRs set forth in SEQ ID NOs:

18, 21, 26, 29, 33, and 38.

24. The method of any of claims 11-23 wherein the non-murine antibody comprises a CDR in which at least one amino acid within a CDR is substituted by a corresponding residue of a corresponding CDR of another anti-M-CSF antibody.

25. The method of any of claims 11-24 wherein the non-murine antibody comprises a variable light chain amino acid sequence which is at least 65% homologous to the amino acid sequence set forth in SEQ ID NO:

4.

26. The method of any of claims 11-25 wherein the non-murine antibody comprises a variable heavy chain amino acid sequence which is at least 65% homologous to the amino acid sequence set forth in SEQ ID NO:

2.

27. The method of any of claims 1-26 wherein the non-murine antibody comprises a constant region of a human antibody sequence and one or more heavy and light chain variable framework regions of a human antibody sequence.

28. The method of claim 27 wherein the human antibody sequence is an individual human sequence, a human consensus sequence, an individual human germline sequence, or a human consensus germline sequence.

29. The method of claim 27 wherein the non-murine antibody comprises a fragment of an IgG1 constant region.

30. The method of claim 29 wherein the non-murine antibody comprises a mutation in the IgG1 constant region that reduces antibody-dependent cellular cytotoxicity or complement dependent cytotoxicity activity.

31. The method of claim 27 wherein the non-murine antibody comprises a fragment of an IgG4 constant region.

32. The method of claim 31 wherein the non-murine antibody comprises a mutation in the IgG4 constant region that reduces formation of half-antibodies.

33. The method of any of claims 1-32, wherein the non-murine antibody comprises a heavy chain variable region that comprises the amino acid sequence XVXLXEXGXXXXXXXXXLXLXCXVXDYSITSDYAWNWIXQXXXXXLXWMGYISY SGSTSXNXXLXXXIXIXRXXXXXXFXLXLXXVXXXDXAXYYCASFDYAHAMDYW GXGTXVXVXX, wherein X is any amino acid.

34. The method of any of claims 1-32, wherein the non-murine antibody comprises a heavy chain variable region that comprises the amino acid sequence DVXLXEXGPXXVXPXXXLXLXCXVTDYSITSDYAWNWIRQXPXXKLEWMGYISYS GSTSYNPSLKXRIXIXRXTXXNXFXLXLXXVXXXDXATYYCASFDYAHAMDYWGX GTXVXVXX, wherein X is any amino acid.

35. The method of any of claims 1-32, wherein the non-murine antibody comprises a heavy chain variable region that comprises the amino acid sequence XVQLQESGPGLVKPSQXLSLTCTVXDYSITSDYAWNWIRQFPGXXLEWMGYISYSGS TSYNPSLKSRIXIXRDTSKNQFXLQLNSVTXXDTAXYYCASFDYAHAMDYWGQGTX VTVSS, wherein X is any amino acid.

36. The method of any of claims 1-32, wherein the non-murine antibody comprises a heavy chain variable region that comprises the amino acid sequence DVQLQESGPGLVKPSQXLSLTCTVTDYSITSDYAWNWIRQFPGXKLEWMGYISYSGS TSYNPSLKSRIXIXRDTSKNQFXLQLNSVTXXDTATYYCASFDYAHAMDYWGQGTX VTVSS, wherein X is any amino acid.

37. The method of any of claims 1-32, wherein the non-murine antibody comprises a heavy chain variable region that comprises the amino acid sequence DVQLQESGPGLVKPSQTLSLTCTVTDYSITSDYAWNWIRQFPGKKLEWMGYISYSGS TSYNPSLKSRITISRDTSKNQFSLQLNSVTAADTATYYCASFDYAHAMDYWGQGTTV TV SS.

38. The method of any of claims 1-32, wherein the non-murine antibody comprises a heavy chain variable region that comprises the amino acid sequence QVQLQESGPGLVKPSQTLSLTCTVSDYSITSDYAWNWIRQFPGKGLEWMGYISYSGS TSYNPSLKSRITISRDTSKNQFSLQLNSVTAADTAVYYCASFDYAHAMDYWGQGTT VTV SS.

39. The method of any of claims 1-32, wherein the non-murine antibody comprises a light chain variable region that comprises the amino acid sequence XIXLXQXXXXXXVXXXXXVXFXCXAXQSIGTSIHWYXQXXXXXPXLLIKYASEXX XXIXXXFXGXGXGXXFXLXIXXVXXXDXADYYCQQINSWPTTFGXGTXLXXXXX, wherein X is any amino acid.

40. The method of any of claims 1-32, wherein the non-murine antibody comprises a light chain variable region that comprises the amino acid sequence XIXLXQXPXXLXVXPXXXVXFXCXASQSIGTSIHWYQQXTXXSPRLLIKYASEXISXI PXRFXGXGXGXXFXLXIXXVXXXDXADYYCQQINSWPTTFGXGTXLXXXXX, wherein X is any amino acid.

41. The method of any of claims 1-32, wherein the non-murine antibody comprises a light chain variable region that comprises the amino acid sequence XIXLTQSPXXLSVSPGERVXFSCRASQSIGTSIHWYQQXTXXXPRLLIKYASEXXXGIP XRFSGSGSGTDFTLXIXXVESEDXADYYCQQINSWPTTFGXGTKLEIKRX, wherein X is any amino acid.

42. The method of any of claims 1-32, wherein the non-murine antibody comprises a light chain variable region that comprises the amino acid sequence XIXLTQSPXXLSVSPGERVXFSCRASQSIGTSIHWYQQXTXXSPRLLIKYASEXISGIPX RFSGSGSGTDFTLXIXXVESEDXADYYCQQINSWPTTFGXGTKLEIKRX, wherein X is any amino acid.

43. The method of any of claims 1-32, wherein the non-murine antibody comprises a light chain variable region that comprises the amino acid sequence XIXLTQSPXXLSVSPGERVXFSCRASQSIGTSIHWYQQXTXXXPRLLIKYASESISGIPX RFSGSGSGTDFTLXIXXVESEDXADYYCQQINSWPTTFGXGTKLEIKRX, wherein X is any amino acid.

44. The method of any of claims 1-32, wherein the non-murine antibody comprises a light chain variable region that comprises the amino acid sequence EIVLTQSPGTLSVSPGERVTFSCRASQSIGTSIHWYQQKTGQAPRLLIKYASESISGIPD RFSGSGSGTDFTLTISRVESEDFADYYCQQINSWPTTFGQGTKLEIKRT.

45. The method of any of claims 1-32, wherein the non-murine antibody comprises a light chain variable region that comprises the amino acid sequence EIVLTQSPGTLSVSPGERVTFSCRASQSIGTSIHWYQQKTGQAPRLLIKYASERATGIP DRFSGSGSGTDFFLTISRVESEDFADYYCQQINSWPTTFGQGTKLEIKRT.

46. The method of any of claims 1-32, wherein the non-murine antibody comprises a light chain variable region that comprises the amino acid sequence EIVLTQSPGTLSVSPGERVTFSCRASQSIGTSIHWYQQKTGQSPRLLIKYASERISGIPD RFSGSGSGTDFTLTISRVESEDFADYYCQQINSWPTTFGQGTKLEIKRT.

47. The method of any of claims 33-46 wherein at least one X is the same as an amino acid at the same corresponding position in SEQ ID NOs:

2 or 4 using Kabat numbering.

48. The method of any of claims 33-46, wherein at least one X is a conservative substitution of an amino acid at the same corresponding position in SEQ ID NOs:

2 or 4 using Kabat numbering.

49. The method of any of claims 33-46, wherein at least one X is a non-conservative substitution of an amino acid at the same corresponding position in SEQ ID NOs:

2 or 4 using Kabat numbering.

50. The method of any of claims 33-46, wherein at least one X is an amino acid at the same corresponding position within a human antibody sequence, using Kabat numbering.

51. The method of any of claims 33-46, wherein at least one X is an amino acid at the same corresponding position within a human consensus antibody sequence, using Kabat numbering.

52. The method of claim 50 wherein the human antibody sequence is a human consensus sequence, human germline sequence, human consensus germline sequence, or any one of the human antibody sequences in Kabat.

53. The method of any of claims 1-32 wherein the non-murine antibody comprises any one of the heavy chain sequences set forth in SEQ ID NOS:

114, 116, or 119.

54. The method of any of claims 1-32 wherein the non-murine antibody comprises any one of the heavy chain variable region sequences set forth in SEQ ID NOS:

41 or 43.

55. The method of any of claims 1-32 wherein the non-murine antibody comprises any one of the light chain sequences set forth in SEQ ID NOS:

45, 47, 48, 51, 53 or 136.

56. The method of claim 1 wherein the non-murine antibody comprises the heavy chain sequence set forth in SEQ ID NO:

114 and the light chain sequence set forth in SEQ ID NO;

47.

57. The method of claim 1 wherein the non-murine antibody comprises the heavy chain sequence set forth in SEQ ID NO:

116 and the light chain sequence set forth in SEQ ID NO;

47.

58. The method of claim 1 wherein the non-murine antibody comprises the heavy chain sequence set forth in SEQ ID NO:

119 and the light chain sequence set forth in SEQ ID NO;

47.

59. The method of any of claims 33-46 wherein the non-murine antibody comprises a variable heavy chain amino acid sequence which is at least 65% identical to the variable heavy chain amino acid sequence set forth in SEQ ID NOs:

41 or 43.

60. The method of claim 59 wherein the non-murine antibody comprises a variable heavy chain amino acid sequence which is at least 80% identical to the variable heavy chain amino acid sequence set forth in SEQ ID NOs:

41 or 43.

61. The method of any of claims 33-46 wherein the non-murine antibody comprises a variable light chain amino acid sequence which is at least 65% identical to the variable light chain amino acid sequence set forth in SEQ ID NOs:

45, 47, 48, 51, or 53.

62. The method of claim 61 wherein the non-murine antibody comprises a variable light chain amino acid sequence which is at least 80% identical to the variable light chain amino acid sequence set forth in SEQ ID NOs:

45, 47, 48, 51, or 53.

63. An method wherein the non-murine antibody comprises a heavy chain as set forth in any one of claims 33-38, 53 or 59-60 and a light chain as set forth in any one of claims 39-46, 54 or 61-62.

64. The method of any of claims 12-63 wherein the non-murine antibody has an affinity Kd of at least 10⁻

7.

65. The method of claim 64 wherein the non-murine antibody has an affinity Kd of at least 10⁻

9.

66. The method of any of claims 12-65 further comprising administering a second therapeutic agent.

67. A kit comprising a therapeutically effective amount of the antibody of any one of claims 1 through 65, packaged in a container, such as a vial or bottle or prefilled syringe, and further comprising a label attached to or packaged with the container, the label describing the contents of the container and providing indications and/or instructions regarding use of the contents of the container to treat a macrophage-associated disease.