Methods of Treating Hematological Proliferative Disorders by Targeting EphA3 Expressed on Aberrant Vasculature in Bone Marrow
The invention provides diagnostic and therapeutic methods for the treatment of hematological proliferative disorders.
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 .