Treatment of leukemias and chronic myeloproliferative diseases with antibodies to EphA3
View Patent ↗The invention provides methods and compositions comprising anti-EphA3 antibodies for the treatment of myeloproliferative disorders.
1. A method of killing myeloproliferative disorder cells that express EphA3 on the cell surface, the method comprising contacting the cells with an anti-EphA3 antibody, wherein the anti-EphA3 antibody (i) activates EphA3 and (ii) induces antibody-dependent cell-mediated cytotoxicity (ADCC).
2. A method of treating a patient that has a myeloproliferative disorder and has myeloproliferative disorder cells that express EphA3 on the cell surface, the method comprising administering a therapeutically effective amount of an anti-EphA3 antibody to the patient, wherein the anti-EphA3 antibody (i) activates EphA3 and (ii) induces ADCC.
3. The method of claim 1 , wherein the myeloproliferative disorder cells are chronic myeloproliferative disorder (CMPD) cells.
4. The method of claim 3 , wherein the CMPD cells are BCR-ABL negative CMPD cells.
5. The method of claim 3 , wherein the CMPD cells are CML cells.
6. The method of claim 1 , wherein the anti-EphA3 antibody comprises a human heavy chain gamma-1 or gamma-3 constant region.
7. The method of claim 1 , wherein the anti-EphA3 antibody is hypofucosylated.
8. The method of claim 1 , wherein the anti-EphA3 antibody competes with an antibody that comprises a V H region CDR1 having a sequence SYWIN (SEQ ID NO:2), a V H region CDR2 having a sequence DIYPGSGNTNYDEKFKR (SEQ ID NO:3), a V H region CDR3 having a sequence SGYYEDFDS (SEQ ID N0:4), a V L region CDR1 having a sequence RASQEISGYLG (SEQ ID NO:9), a V L region CDR2 having a sequence AASTLDS (SEQ ID NO:10), and a V L region CDR3 having a sequence VQYANYPYT (SEQ ID NO:11) for binding to EphA3.
9. The method of claim 1 , wherein the anti-EphA3 antibody is a recombinant or chimeric antibody.
10. The method of claim 1 , wherein the anti-EphA3 antibody is a human antibody.
11. The method of claim 1 , wherein the anti-EphA3 antibody is a monoclonal antibody.
12. The method of claim 1 , wherein the anti-EphA3 antibody comprises a V H region CDR1 having a sequence SYWIN (SEQ ID NO:2), a V H region CDR2 having a sequence DIYPGSGNTNYDEKFKR (SEQ ID NO:3), a V H region CDR3 having a sequence SGYYEDFDS (SEQ ID NO:4), a V L region CDR1 having a sequence RASQEISGYLG (SEQ ID NO:9), a V L region CDR2 having a sequence AASTLDS (SEQ ID NO:10), and a V L region CDR3 having a sequence VQYANYPYT (SEQ ID NO:11).
13. A method of killing myeloproliferative disorder cells that express EphA3 on the surface, the method comprising contacting the cells with an anti-EphA3 antibody that activates EphA3 or induces ADCC, wherein the myeloproliferative disorder cells are acute myeloid leukemia (AML) cells or myelodysplastic syndrome (MDS) cells.
14. A method of treating a patient that has a myeloproliferative disorder and has myeloproliferative disorder cells that express EphA3 on the cell surface, the method comprising administering a therapeutically effective amount of an anti-EphA3 antibody to the patient, wherein the anti-EphA3 antibody activates EphA3 or induces ADCC, wherein the myeloproliferative disorder is AML or MDS.
15. The method of claim 13 , wherein the myeloproliferative disorder cells are AML cells.
16. The method of claim 13 , wherein the anti-EphA3 antibody activates EphA3.
17. The method of claim 13 , wherein the anti-EphA antibody comprises a human heavy chain constant region.
18. The method of claim 13 , wherein the anti-EphA3 antibody competes for EphA3 binding with an antibody that comprises a V H region CDR1 having a sequence SYWIN (SEQ ID NO:2), a V H region CDR2 having a sequence DIYPGSGNTNYDEKFKR (SEQ ID NO:3), a V H region CDR3 having a sequence SGYYEDFDS (SEQ ID NO:4), a V L region CDR1 having a sequence RASQEISGYLG (SEQ ID NO:9), a V L region CDR2 having a sequence AASTLDS (SEQ ID NO:10), and a V L region CDR3 having a sequence VQYANYPYT (SEQ ID NO:11).
19. The method of claim 13 , wherein the anti-EphA3 antibody is a (Fab′) 2 .
20. The method of claim 13 , wherein the anti-EphA3 antibody is a recombinant or chimeric antibody.
21. The method of claim 13 , wherein the anti-EphA3 antibody is a human antibody.
22. The method of claim 13 , wherein the anti-EphA3 antibody is a monoclonal antibody.
23. The method of claim 13 , wherein the anti-EphA3 antibody is a multivalent antibody that comprises a Fab, a Fab′, or an Fv.
24. The method of claim 13 , wherein the anti-EphA3 antibody comprises a V H region CDR1 having a sequence SYWIN (SEQ ID NO:2), a V H region CDR2 having a sequence DIYPGSGNTNYDEKFKR (SEQ ID NO:3), a V H region CDR3 having a sequence SGYYEDFDS (SEQ ID NO:4), a V L region CDR1 having a sequence RASQEISGYLG (SEQ ID NO:9), a V L region CDR2 having a sequence AASTLDS (SEQ ID NO:10), and a V L region CDR3 having a sequence VQYANYPYT (SEQ ID NO:11).
25. The method of claim 13 , wherein the anti-EphA3 antibody induces ADCC.
26. The method of claim 13 , wherein the anti-EphA3 antibody blocks binding of ephrinA5 ligand to EphA3.
27. The method of claim 13 , wherein the anti-EphA3 antibody is hypofucosylated.
28. The method of claim 25 , wherein the anti-EphA3 antibody has a human gamma-1 or gamma-3 constant region.
29. The method of claim 25 , wherein the anti-EphA3 antibody blocks binding of ephrinA5 ligand to EphA3.
30. The method of claim 13 , wherein the anti-EphA3 antibody has a human heavy chain gamma-2 or gamma-4 constant region.