Treatment of leukemias and chronic myeloproliferative diseases with antibodies to epha3

Abstract

The invention provides methods and compositions comprising anti-EphA3 antibodies for the treatment of myeloproliferative disorders.

What is claimed is: 
     
         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.