Treatment of Leukemias and Chronic Myeloproliferative Diseases with Antibodies to EphA3
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), wherein the myeloproliferative disorder cells are chronic myeloid proliferative disorder cells; or myeloid leukemia cells.
2 . The method of claim 1 , wherein the myeloproliferative disorder cells are PV, ET, MDS, or IM chronic myeloproliferative disorder cells.
3 . The method of claim 2 , wherein the myeloproliferative disorder cells are IM cells.
4 . The method of claim 1 , wherein the myeloproliferative disorder cells are CMML or JMML myeloid leukemia cells.
5 . The method of claim 1 , wherein the meyloproliferative disorder cells are AML myeloid leukemia cells.
6 . The method of claim 1 , further comprising administering at least one additional therapeutic agent, wherein the at least one additional therapeutic agent is a chemotherapeutic agent.
7 . The method of claim 1 , wherein the anti-EphA3 antibody comprises a human heavy chain gamma-1 or gamma-3 constant region.
8 . The method of claim 1 , wherein the anti-EphA3 antibody is hypofucosylated.
9 . 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 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) for binding to EphA3.
10 . The method of claim 1 , wherein the anti-EphA3 antibody is a recombinant or chimeric antibody.
11 . The method of claim 1 , wherein the anti-EphA3 antibody is a human antibody.
12 . The method of claim 1 , wherein the anti-EphA3 antibody is a monoclonal antibody.
13 . 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).
14 . A method of treating a patient that has a chronic myeloproliferative disorder or a myeloid leukemia 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 antibody-dependent cell-mediated cytotoxicity (ADCC).
15 . The method of claim 14 , wherein the myeloproliferative disorder is PV, ET, MDS, or IM.
16 . The method of claim 15 , wherein the myeloproliferative disorder is IM.
17 . The method of claim 14 , wherein the myeloproliferative disorder is CMML or JMML.
18 . The method of claim 14 , wherein the myeloproliferative disorder is AML.
19 . The method of claim 14 , further comprising administering at least one additional therapeutic agent, wherein the at least one additional therapeutic agent is a chemotherapeutic agent.
20 . The method of claim 14 , wherein the anti-EphA3 antibody comprises a human heavy chain gamma-1 or gamma-3 constant region.
21 . The method of claim 14 , wherein the anti-EphA3 antibody is hypofucosylated.
22 . The method of claim 14 , 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 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) for binding to EphA3.
23 . The method of claim 14 , wherein the anti-EphA3 antibody is a recombinant or chimeric antibody.
24 . The method of claim 14 , wherein the anti-EphA3 antibody is a human antibody.
25 . The method of claim 14 , wherein the anti-EphA3 antibody is a monoclonal antibody.
26 . The method of claim 14 , 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).
27 . A method of monitoring the efficacy of treatment of a patient having a myeloproliferative disorder with EphA3 + myeloproliferative cells, wherein the myeloproliferative disorder is AML or MDS, the method comprising:
obtaining a sample comprising myeloproliferative disorder stem cells and/or blast cells from the patient following a therapeutic treatment for the myeloproliferative disorder; and
detecting expression of EphA3 on the myeloproliferative disorder stem cells and/or blast cells.