Antibodies against CD38 for treatment of multiple myeloma
View Patent ↗Isolated human monoclonal antibodies which bind to human CD38, and related antibody-based compositions and molecules, are disclosed. Also disclosed are pharmaceutical compositions comprising the human antibodies, and therapeutic and diagnostic methods for using the human antibodies.
1. An isolated monoclonal antibody which binds to human CD38 (SEQ ID No:31), which does not bind to a mutant human CD38, wherein in the mutant human CD38, the serine residue in position 274 has been substituted with a phenylalanine residue (SEQ ID No:34), and wherein the antibody inhibits the synthesis of cGDPR by at least 25% after 90 minutes at a concentration of 3 μg/ml.
2. An isolated monoclonal antibody which specifically binds to the region SKRNIQFSCKNIYR (SEQ ID NO: 35) and the region EKVQTLEAWVIHGG (SEQ ID NO: 36) of human CD38 (SEQ ID No:31) and inhibits the synthesis of cGDPR by at least 25% after 90 minutes at a concentration of 3 μg/ml.
3. The antibody according to claim 1 or claim 2 , wherein the antibody binds to a mutant human CD38 to the same degree that it binds to human CD38 (SEQ ID No:31), wherein the threonine residue in position 237 of the mutant human CD38 has been substituted with an alanine residue (SEQ ID No:32).
4. The antibody of claim 1 , wherein the antibody further possesses the following binding characteristics: (i) does not bind to a mutant human CD38, wherein the glutamine residue in position 272 has been substituted with an arginine residue (SEQ ID No:33), to the same degree that it binds to human CD38 (SEQ ID No:31), and (ii) binds to a mutant human CD38, wherein the threonine residue in position 237 has been substituted with an alanine residue (SEQ ID No:32), to the same degree that it binds to human CD38 (SEQ ID No:31).
5. The antibody according to claim 1 or claim 2 , wherein the antibody is a full length IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody.
6. An immunoconjugate comprising the antibody according to claim 1 or claim 2 linked to a cytotoxic agent, a radioisotope, or a drug.
7. A pharmaceutical composition comprising the antibody according to claim 1 or claim 2 and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition according to claim 7 comprising one or more further therapeutic agents.
9. The antibody of claim 1 that specifically binds to the region SKRNIQFSCKNIYR (SEQ ID NO: 35) and the region EKVQTLEAWVIHGG (SEQ ID NO: 36) of human CD38 (SEQ ID No:31).
10. The antibody of claim 1 or 2 , wherein the antibody possesses one or more of the following characteristics:
(i) acts as an antagonist of CD38;
(ii) does not induce significant proliferation of peripheral blood mononuclear cells;
(iii) does not induce release of significant IL-6 by human monocytes or peripheral blood mononuclear cells;
(iv) does not induce release of detectable IFN-.gamma. by human T cells or peripheral blood mononuclear cells;
(v) is internalized by CD38 expressing cells;
(vi) induces ADCC;
(vii) induces CDC in the presence of complement;
(viii) inhibits the synthesis of cADPR; and
(ix) binds to human CD38 with an affinity (K D ) of below 10 −8 M.
11. The antibody according to claim 10 , which inhibits the synthesis of cADPR by at least 25% after 90 minutes at a concentration of 3 μg/ml.
12. The antibody according to claim 1 or 2 , wherein the antibody is glycosylated in a eukaryotic cell.
13. The antibody according to claim 1 or 2 , which is an antibody fragment or a single chain antibody.
14. The antibody according to claim 1 or 2 , further comprising a chelator linker for attaching a radioisotope.
15. A bispecific or multispecific molecule comprising the antibody according to claim 1 or 2 and a binding specificity for a human effector cell.
16. A kit for detecting the presence of CD38 antigen, or a cell expressing CD38, in a sample comprising the antibody according to claim 1 or claim 2 .
17. The antibody according to claim 1 or 2 , wherein the antibody is produced in a recombinant host cell.
18. The antibody according to claim 2 , wherein the antibody does not bind to a mutant human CD38, wherein in the mutant human CD38, the serine residue in position 274 has been substituted with a phenylalanine residue (SEQ ID No:34).
19. The pharmaceutical composition of claim 7 , further comprising a preservative.