Antibodies that immunospecifically bind BLyS
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.
1. An isolated antibody that immunospecifically binds B Lymphocyte Stimulator protein wherein said antibody comprises a first amino acid sequence at least 85% identical to amino acid residues 1–123 of SEQ ID NO:327 and a second amino acid sequence at least 85% identical to amino acid residues 141–249 of SEQ ID NO:327 and wherein said B Lymphocyte Stimulator protein 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).
2. The antibody of claim 1 wherein the first amino acid sequence is at least 95% identical to amino acid residues 1–123 of SEQ ID NO:327 and the second amino acid sequence is at least 95% identical to amino acid residues 141–249 of SEQ ID NO:327.
3. The antibody of claim 1 wherein the amino acid differences between the first amino acid sequence and amino acid residues 1–123 of SEQ ID NO:327 are in one or more of the CDR regions located at amino acid residues 26–35, 50–66 and 99–112 of SEQ ID NO: 327 and wherein the amino acid differences between the second amino acid sequence and amino acid residues 141–249 of SEQ ID NO: 327 are in one or more of the CDR regions located at amino acid residues 163–173, 189–195 and 228–238 of SEQ ID NO: 327.
4. An isolated antibody that immunospecifically binds B Lymphocyte Stimulator protein wherein said antibody comprises amino acid residues 1–123 of SEQ ID NO: 327 and amino acid residues 141–249 of SEQ ID NO: 327 and wherein said B Lymphocyte Stimulator protein 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).
5. The antibody of claim 1 wherein the antibody is selected from the group consisting of:
(a) a whole immunoglobulin molecule;
(b) an scFv;
(c) a chimeric antibody;
(d) a Fab fragment;
(e) an Fab′ fragment; and
(f) an F(ab′)2.
6. The antibody of claim 1 wherein the antibody is a monoclonal antibody.
7. The antibody of claim 1 wherein the antibody is a human antibody.
8. The antibody of claim 1 which comprises a heavy chain immunoglobulin constant domain selected from the group consisting of:
(a) a human IgM constant domain;
(b) a human IgG1 constant domain;
(c) a human IgG2 constant domain;
(d) a human IgG3 constant domain;
(e) a human IgG4 constant domain; and
(f) a human IgA constant domain.
9. The antibody of claim 1 which comprises a light chain immunoglobulin constant domain selected from the group consisting of:
(a) a human kappa constant domain; and
(b) a human lambda constant domain.
10. The antibody of claim 1 wherein the antibody has a dissociation constant (K D ) less than or equal to 10 −9 M.
11. The antibody of claim 1 wherein the antibody is coupled to a detectable label.
12. The antibody of claim 11 wherein the detectable label is a radioisotope, an enzyme, a fluorescent label, a luminescent label, bioluminescent label or biotin.
13. The antibody of claim 12 wherein the radioisotope is 125 I, 131 I, 111 In, 90 Y, 99m Tc, 177 Lu, 166 Ho, or 153 Sm.
14. The antibody of claim 1 wherein the antibody neutralizes said protein.
15. The antibody of claim 14 wherein the antibody diminishes the ability of said protein to bind to a receptor of said protein.
16. The antibody of claim 15 wherein the receptor is TACI.
17. The antibody of claim 15 wherein the receptor is BCMA.
18. The antibody of claim 14 wherein the antibody diminishes the ability of said protein to stimulate B cell proliferation.
19. The antibody of claim 14 wherein the antibody diminishes the ability of said protein to stimulate immunoglobulin secretion by B cells.
20. The antibody of claim 4 wherein the antibody is selected from the group consisting of:
(a) a whole immunoglobulin molecule;
(b) an scFv;
(c) a chimeric antibody;
(d) a Fab fragment;
(e) an Fab′ fragment; and
(f) an F(ab′)2.
21. The antibody of claim 4 wherein the antibody is a monoclonal antibody.
22. The antibody of claim 4 wherein the antibody is a human antibody.
23. The antibody of claim 4 which comprises a heavy chain immunoglobulin constant domain selected from the group consisting of:
(a) a human IgM constant domain;
(b) a human IgG1 constant domain;
(c) a human IgG2 constant domain;
(d) a human IgG3 constant domain;
(e) a human IgG4 constant domain; and
(f) a human IgA constant domain.
24. The antibody of claim 4 which comprises a light chain immunoglobulin constant domain selected from the group consisting of:
(a) a human kappa constant domain; and
(b) a human lambda constant domain.
25. The antibody of claim 4 wherein the antibody is coupled to a detectable label.
26. The antibody of claim 25 wherein the detectable label is a radioisotope, an enzyme, a fluorescent label, a luminescent label, bioluminescent label or biotin.
27. The antibody of claim 26 wherein the radioisotope is 125 I, 131 I, 111 In, 90 Y, 99m Tc, 177 Lu, 166 Ho, or 153 Sm.
28. An antibody purified from the cell line contained in American Type Culture Collection Deposit Number PTA-3239.
29. An antibody purified from the cell line contained in American Type Culture Collection Deposit Number PTA-3240.
30. The antibody of claim 4 which comprises a human IgG1 heavy chain immunoglobulin constant domain and a human lambda light chain immunoglobulin constant domain.
31. The antibody of claim 4 wherein the antibody neutralizes said protein.
32. The antibody of claim 31 wherein the antibody diminishes the ability of said protein to bind to a receptor of said protein.
33. The antibody of claim 32 wherein the receptor is TACI.
34. The antibody of claim 32 wherein the receptor is BCMA.
35. The antibody of claim 31 wherein the antibody diminishes the ability of said protein to stimulate B cell proliferation.
36. The antibody of claim 31 wherein the antibody diminishes the ability of said protein to stimulate immunoglobulin secretion by B cells.
37. An isolated antibody that immunospecifically binds B Lymphocyte Stimulator protein wherein said antibody comprises amino acid residues 1–123 of SEQ ID NO:2 and amino acid residues 141–249 of SEQ ID NO:2 and wherein said B Lymphocyte Stimulator protein 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).