M-CSF-Specific Monoclonal Antibody and Uses Thereof

• US 20100092464A1
• Filed: 07/27/2006
• Published: 04/15/2010
• Est. Priority Date: 07/28/2005
• Status: Active Grant

• Current Assignee: Novartis Vaccines And Diagnostics Incorporated (Novartis Ag)
• Original Assignee: Novartis Ag, Xoma Technology Ltd. (Xoma Corp.)
• Inventors: Auckerman, Lea, Sung, Victoria, Kavanaugh, William M.
• Granted Patent: US 8,652,469 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/243 Colony Stimulating Factors
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Abstract

M-CSF-specific RX1-based or RX-I derived antibodies are provided, along with pharmaceutical compositions containing such antibody, kits containing a pharmaceutical composition, and methods of preventing and treating bone loss in or remodeling in a subject afflicted with an osteoblastic or osteolytic disease.

Claims

1. A method of treating a subject suffering from a disease associated with periprosthetic bone loss or increased osteoclastic activity and increased osteoblastic activity comprising administering to the subject 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, said epitope comprising at least 4 contiguous residues of SEQ ID NO:

120 or 121.

3. The method of claim 1 wherein the non-murine antibody is a monoclonal antibody.

4. The method of claim 1 wherein the non-murine antibody is a chimeric antibody, a humanized antibody, a human engineered antibody, a human antibody, or a single chain antibody.

5. The method of claim 1 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.

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

24.

7. The method of claim 1 wherein the non-murine antibody comprises SEQ ID NO:

24.

8. The method of claim 1 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;

     138).

9. The method of claim 1 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;

     138).

10. The method of claim 8 wherein the non-murine antibody further comprises one or more CDRs selected from the group consisting of:

SEQ ID NOs;

16, 19, 22, 27, 30, 34, 17, 20, 23, 28, 31, 35, 18, 21, 25, 29, 32, 37, 18, 21, 26, 29, 33, or 38.

11. The method of claim 10 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-MCSF antibody.

12. The method of claim 8 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.

13. The method of claim 12 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.

14. The method of claim 8 wherein the non-murine antibody comprises a fragment of an IgG1 constant region.

15. The method of claim 14 wherein the non-murine antibody comprises a mutation in the IgG1 constant region that reduces antibody-dependent cellular cytotoxicity or complement dependent cytotoxicity activity.

16. The method of claim 8 wherein the non-murine antibody comprises a fragment of an IgG4 constant region.

17. The method of claim 16 wherein the non-murine antibody comprises a mutation in the IgG4 constant region that reduces formation of half-antibodies.

18. The method of claim 1, wherein the non-murine antibody comprises a heavy chain variable region that comprises the amino acid sequence XVXLXEXGXXXXXXXXXLXLXCXVXDYSITSDYAWNWIXQXXXXXLXWMGYISY SGSTSXNXXLXXXIXIXLXLXXVXXXDXAXYYCASFDYAHAMDYW GXGTXVXVXX, wherein X is any amino acid.

19. The method of claim 1, 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.

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

41 or 43.

21. The method of claim 1 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.

22. The method of claim 8 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.

23. The method of claim 8 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.

24. The method of claim 1 further comprising administering a second therapeutic agent.

25. The method of claim 1 wherein the antibody is administered at a dose between about 0.1 mg/kg to 30 mg/kg body weight.

26. A kit comprising a therapeutically effective amount of the antibody of claim 1 or 8 or 22, packaged in a container, such as a vial or bottle, 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 subject suffering from disease associated with increased osteoclastic activity and increased osteoblastic activity.