Antibodies that immunospecifically bind to B lymphocyte stimulator protein

• US 20060062789A1
• Filed: 11/04/2005
• Published: 03/23/2006
• Est. Priority Date: 06/16/2000
• Status: Active Grant

• Current Assignee: Cambridge Antibody Technology Ltd (Astrazeneca PLC), Human Genome Sciences Incorporated (GSK plc)
• Original Assignee: Cambridge Antibody Technology Ltd (Astrazeneca PLC), Human Genome Sciences Incorporated (GSK plc)
• Inventors: Vaughan, Tristan, Choi, Gil H., Hilbert, David, Ruben, Steven M., Barash, Steven C.
• Granted Patent: US 7,605,236 B2
• Time in Patent Office: Days
• US Class Current: 424/145.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 31/18 for HIV
• 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 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 14/52 Cytokines; Lymphokines; Interferons
• CPC Class Codes: C07K 14/70575 NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154 NGF C07K14/48, TNF C07K14/525
• 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 2317/622 Single chain antibody (scFv)
• CPC Class Codes: G01N 33/564 for pre-existing immune complex or autoimmune disease , i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9

Abstract

The present invention relates to antibodies and related molecules that immunospecifically bind to B Lymphocyte Stimulator. The present invention also relates to methods and compositions for detecting or diagnosing a disease or disorder associated with aberrant B Lymphocyte Stimulator expression or inappropriate function of B Lymphocyte Stimulator comprising antibodies or fragments or variants thereof or related molecules that immunospecifically bind to B Lymphocyte Stimulator. The present invention further relates to methods and compositions for preventing, treating or ameliorating a disease or disorder associated with aberrant B Lymphocyte Stimulator expression or inappropriate B Lymphocyte Stimulator function comprising administering to an animal an effective amount of one or more antibodies or fragments or variants thereof or related molecules that immunospecifically bind to B Lymphocyte Stimulator.

Claims

1. An antibody that immunospecifically binds to B Lymphocyte Stimulator protein comprising:

(a) an amino acid sequence that is at least 85% identical to the VH domain of any one of the scFvs of SEQ ID NOS;

1 through 2128;

(b) an amino acid sequence that is at least 85% identical to the VL domain of any one of the scFvs of SEQ ID NOS;

1 through 2128;

or

(c) an amino acid sequence that is at least 85% identical to the VH domain of any one of the scFvs of SEQ ID NOS;

1 through 2128 and an amino acid sequence that is at least 85% identical to the VL domain of any one of the scFvs of SEQ ID NOS;

1 through 2128.

2. The antibody of claim 1 which comprises:

(a) an amino acid sequence that is at least 95% identical to the VH domain of any one of the scFvs of SEQ ID NOS;

1 through 2128;

(b) an amino acid sequence that is at least 95% identical to the VL domain of any one of the scFvs of SEQ ID NOS;

1 through 2128;

or

(c) an amino acid sequence that is at least 95% identical to the VH domain of any one of the scFvs of SEQ ID NOS;

1 through 2128 and an amino acid sequence that is at least 95% identical to the VL domain of any one of the scFvs of SEQ ID NOS;

1 through 2128.

3. The antibody of claim 1 which comprises:

(a) the amino acid sequence of the VH domain of any one of the scFvs of SEQ ID NOS;

1 through 2128;

(b) the amino acid sequence of the VL domain of any one of the scFvs of SEQ ID NOS;

1 through 2128;

or

(c) the amino acid sequence of the VH domain of any one of the scFvs of SEQ ID NOS;

1 through 2128 and the amino acid sequence of the VL domain of any one of the scFvs of SEQ ID NOS;

1 through 2128.

4. The antibody of claim 1c, wherein the VH and VL domains are from the same scFv.

5. The antibody of claim 3c, wherein the VH and VL domains are from the same scFv.

6. The antibody of claim 1, wherein the B Lymphocyte Stimulator is selected from the group consisting of:

(a) a protein whose amino acid sequence consists of amino acid residues 1-285 of SEQ ID NO;

3228;

(b) a protein whose amino acid sequence consists of amino acid residues 134-285 of SEQ ID NO;

3228; and

(c) a trimer of the protein of (b).

7. The antibody of claim 1 wherein the antibody is selected from the group consisting of a whole immunoglobulin molecule, an scFv, a Fab fragment, an Fab′

fragment, an F(ab′

)2, an Fv, and a disulfide linked Fv.

8. The antibody of claim 1 wherein the antibody is monoclonal.

9. The antibody of claim 1 wherein the antibody has a dissociation constant (K_D) of less than or equal to 10⁻

9M

10. The antibody of claim 1, wherein the antibody is labeled.

11. The antibody of claim 10 which is labeled with a radiolabel, an enzyme, a fluorescent label, a luminescent label, or a bioluminescent label or biotin.

12. The antibody of claim 1 that diminishes or abolishes the ability of B Lymphocyte Stimulator protein or a fragment thereof to bind to a B Lymphocyte Stimulator protein receptor.

13. The antibody of claim 1 that diminishes or abolishes the ability of B Lymphocyte Stimulator protein or a fragment thereof to stimulate B cell proliferation, differentiation, or survival.

14. An isolated nucleic acid molecule encoding the antibody of claim 1.

15. An isolated cell line that express the antibody of claim 1.

16. The cell line of claim 15 which is the cell line deposited under any one of ATCC Accession Nos. PTA-3238, PTA-3239, PTA-3240, PTA-3241, PTA-3242 or PTA-3243.

17. A method for detecting expression of B Lymphocyte Stimulator protein, comprising:

(a) contacting a biological sample with the antibody of claim 1;

and

(b) detecting said B Lymphocyte Stimulator protein.

18. A method for diagnosing an autoimmune disease or a B cell cancer comprising:

(a) contacting a first biological sample with the antibody of claim 1;

(b) assaying the level of B Lymphocyte Stimulator protein the first biological sample;

(c) comparing the level of B Lymphocyte Stimulator protein assayed in the first biological sample with a standard level of B Lymphocyte Stimulator protein or the level of B Lymphocyte Stimulator in a second, normal biological sample;

whereby an increase in the level of B Lymphocyte Stimulator protein in the first biological sample compared to the standard level of B Lymphocyte Stimulator protein or the level of B Lymphocyte Stimulator in the second, normal biological sample indicates that the subject has an autoimmune disease or a B cell cancer.

19. A method of treating, preventing or ameliorating an autoimmune disease or a B cell cancer comprising administering to an animal in need thereof, an antibody of claim 1 in an amount effective to treat, prevent or ameliorate the autoimmune disease or a B cell cancer.

20. The method of claim 19, wherein autoimmune disease is selected from the group consisting of:

(a) Systemic Lupus Erythematosus; and

(b) Rheumatoid Arthritis.