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 full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:7 or encoded by the nucleotide sequence set forth in SEQ ID NO:6.
2. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:17 or encoded by the nucleotide sequence set forth in SEQ ID NO:16.
3. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:27 or encoded by the nucleotide sequence set forth in SEQ ID NO:26.
4. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:2 or encoded by the nucleotide sequence set forth in SEQ ID NO: 1.
5. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 or encoded by the nucleotide sequence set forth in SEQ ID NO: 11.
6. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:22 or encoded by the nucleotide sequence set forth in SEQ ID NO:21.
7. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises heavy and light chain variable region amino acid sequences as set forth in (a) SEQ ID NOs:7 and 2, respectively; (b) SEQ ID NOs: 17 and 12, respectively; or (c) SEQ ID NOs: 27 and 22, respectively.
8. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises heavy and light chain variable regions encoded by the nucleotide sequence as set forth in (a) SEQ ID NOs:6 and 1, respectively; (b) SEQ ID NOs: 16 and 11, respectively; or (c) SEQ ID NOs: 26 and 21, respectively.
9. An isolated full-length antibody which binds an epitope on human CD38 recognized by the antibody of claim 7 .
10. The antibody of claim 9 , wherein the antibody binds to the region SKRNIQFSCKNIYR (SEQ ID NO: 35) and the region EKVQTLEAWVIHGG (SEQ ID NO: 36) of human CD38 (SEQ ID No: 31).
11. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 8, 9, and 10, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 3, 4, and 5, respectively.
12. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 18, 19, and 20, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 13, 14, and 15, respectively.
13. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 28, 29, and 30, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 23, 24, and 25, respectively.
14. The antibody of any one of claims 9 , 11 , 12 , or 13 , 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 cGDPR; (ix) inhibits the synthesis of cADPR;
(x) binds to human CD38 with an affinity (K D ) of below 10 −8 M;
(xi) binds to a mutant human CD38 with an EC 50 that is less than 50% compared to the EC 50 of the binding of the antibody to human CD38 (SEQ ID No: 31), wherein the serine residue in position 274 of the mutant human CD38 has been substituted with a phenylalanine residue (SEQ ID No: 34);
(xii) binds to a mutant human CD38 with an EC 50 that is less than 50% compared to the EC 50 of the binding of the antibody to human CD38 (SEQ ID No: 31), wherein the glutamine residue in position 272 of the mutant human CD38 has been substituted with an arginine residue (SEQ ID No: 33); or
(xiii) binds to a mutant human CD38 with an EC 50 that is 75%-125% of the EC 50 of the binding of the antibody 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).
15. The antibody of any one of claims 9 , 11 , 12 , or 13 , which is a human monoclonal antibody.
16. The antibody of any one of claims 9 , 11 , 12 , or 13 , wherein the antibody is a full-length IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody.
17. The antibody of any one of claims 9 , 11 , 12 , or 13 , wherein the antibody is glycosylated in a eukaryotic cell.
18. The antibody of any one of claims 9 , 11 , 12 , or 13 , which is an antibody fragment or a single chain antibody.
19. The antibody of any one of claims 9 , 11 , 12 , or 13 , further comprising a chelator linker for attaching a radioisotope.
20. A hybridoma which produces the antibody of claim 7 .
21. A hybridoma which produces the antibody of claim 8 .
22. An immunoconjugate comprising the antibody of any one of claims 9 , 11 , 12 , or 13 .
23. A bispecific or multispecific molecule comprising the antibody of any one of claims 9 , 11 , 12 , or 13 .
24. The bispecific or multispecific molecule of claim 23 , which comprises a binding specificity for CD3, CD4, CD 138, IL-15R, membrane bound TNFα, receptor bound TNFα, a human Fc receptor, membrane bound IL-15, or receptor bound IL-15.
25. A pharmaceutical composition comprising the antibody of any one of claims 9 , 11 , 12 , or 13 and a pharmaceutically acceptable carrier.
26. The pharmaceutical composition according to claim 25 comprising one or more further therapeutic agents.
27. A method of inhibiting growth and/or proliferation of a cell expressing CD38, comprising administration of the antibody of any one of claims 9 , 11 , 12 , or 13 , such that the growth and/or proliferation of the cell is inhibited.
28. A kit comprising the antibody of any one of claims 9 , 11 , 12 , or 13 for detecting the presence of CD38 antigen, or a cell expressing CD38 antigen, in a sample.
29. An anti-idiotypic antibody which binds to the antibody of any one of claims 9 , 11 , 12 , or 13 .