Methods of Treating Hematological Proliferative Disorders by Targeting EphA3 Expressed on Aberrant Vasculature in Bone Marrow

Abstract

The invention provides diagnostic and therapeutic methods for the treatment of hematological proliferative disorders.

What is claimed is: 
     
         1 . A method of treating a patient that has a hematological proliferative disorder where the hematological proliferative disorder cells are substantially EphA3 −  and aberrant vasculature in bone marrow is EphA3 + , the method comprising administering a therapeutically effective amount of an anti-EphA3 antibody to the patient, wherein 20% or fewer of the hematological disorder cells express EphA3. 
     
     
         2 . The method of  claim 1 , wherein 10% or fewer of the hematological proliferative disorder cells express EphA3. 
     
     
         3 . The method of  claim 1 , wherein the hematological proliferative disorder cells are myelodysplastic syndrome (MDS) cells. 
     
     
         4 . The method of  claim 1 , wherein the hematological proliferative disorder cells are myelofibrosis cells. 
     
     
         5 . The method of  claim 1 , wherein the anti-EphA3 antibody comprises a human heavy chain gamma-1 or gamma-3 constant region. 
     
     
         6 . The method of  claim 5 , wherein the anti-EphA3 antibody is provided in a hypofucosylated or afucosylated antibody preparation. 
     
     
         7 . The method of  claim 1 , wherein the anti-EphA3 antibody is a monoclonal antibody. 
     
     
         8 . The method of  claim 1 , wherein the anti-EphA3 antibody induces ADCC. 
     
     
         9 . The method of  claim 1 , wherein:
 (a) the myeloid proliferative disorder cells are myelofibrosis cells or MDS cells; and   (b) the anti-EphA3 is a monoclonal antibody that
 (i) activates EphA3 
 (ii) induces ADCC; 
 (iii) binds to an epitope on EphA3 to which an antibody having 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) binds; 
 (iv) has framework regions from a human immune system; 
 (v) comprises a human heavy chain gamma-1 constant region; and 
 (vi) is provided in a hypofucosylated or afucosylated antibody preparation. 
   
     
     
         10 . The method of  claim 1 , wherein the antibody is a conjugate. 
     
     
         11 . 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. 
     
     
         12 . A method of determining that a patient having a hematological proliferative disorder is a candidate for treatment with an anti-EphA3 antibody, the method comprising:
 providing a bone marrow sample from the patient; and   detecting expression of EphA3 on aberrant vasculature present in the bone marrow.   
     
     
         13 . The method of  claim 12 , wherein EphA3 expression is detected in the endothelial layer of the aberrant vasculature. 
     
     
         14 . The method of  claim 12 , wherein EphA3 expression is detected in the tunica media or tunica externa of the aberrant vasculature. 
     
     
         15 . The method of  claim 12 , wherein the step of detecting expression of EphA3 comprises contacting an anti-EphA3 antibody with the sample. 
     
     
         16 . The method of  claim 15 , wherein the anti-EphA3 antibody is produced by a hybridoma deposited with the American Type Culture Collection (ATCC) having the Patent Deposit Designation PTA-12227; or produced by a hybridoma deposited with the ATCC having the Patent Deposit Designation PTA-12228. 
     
     
         17 . The method of  claim 12 , wherein the patient has AML, CML, CMML, JMML, MDS, PV, ET, IM, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, chronic neutrophilic leukemia, chronic eosinophilic leukemia, or mast cell disease. 
     
     
         18 . A hybridoma deposited with the American Type Culture Collection having the Patent Deposit Designation PTA-12227 or having the Patent Deposit Designation PTA-12228. 
     
     
         19 . A monoclonal antibody produced by the hybridoma of  claim 18 . 
     
     
         20 . A kit containing at least one reagent for detecting EphA3 expression, wherein the at least one reagent is a monoclonal antibody of  claim 19 .