Methods of treating hematological proliferative disorders by targeting EphA3 expressed on aberrant vasculature in bone marrow
Inventors
Yarranton, Geoffrey T. • Palath, Varghese • Bebbington, Christopher R. • Baer, Mark
Assignees
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Publication Number
US-9109032-B2
Publication Date
2015-08-18
Expiration Date
Abstract
The invention provides diagnostic and therapeutic methods for the treatment of hematological proliferative disorders.
Core Innovation
The invention addresses hematological proliferative disorders in which aberrant bone-marrow vasculature is EphA3+ and where the hematological proliferative disorder cells express little EphA3, including cases in which less than 20% of the disorder cells express EphA3. It identifies EphA3-selective expression on the aberrant bone-marrow vasculature despite EphA3− neoplastic hematological cells or low EphA3 expression.
The invention provides treatment concepts using an anti-EphA3 antibody. The antibody is used to activate EphA3 and/or induce ADCC, including embodiments where the antibody dimerizes and/or cross-links EphA3 and uses active IgG isotypes. The invention also includes embodiments in which the antibody does not block ephrin-A5 binding and can compete with or share epitopes with mAb IIIA4.
The invention includes target and monitoring concepts based on detecting EphA3+ vasculature and re-detecting EphA3 on vasculature to monitor efficacy. Diagnostic and detection antibodies are described, including SL-2 and SL-7, and the invention reports that SL antibodies bind EphA3, and that EphA3 is detectable on AML tumor neovasculature but not normal bone marrow by IHC.
Claims Coverage
The independent claim covers a treatment method grounded on patient selection by EphA3 expression in hematological proliferative disorders and EphA3+ aberrant bone-marrow vasculature. The claim includes two inventive functional aspects for the anti-EphA3 antibody: activation of EphA3 and/or induction of ADCC.
Treating a patient with low EphA3-expressing hematological proliferative disorder and EphA3+ bone marrow vasculature
A method of treating a patient with a hematological proliferative disorder where less than 20% of the disorder cells express EphA3, and where aberrant vasculature in bone marrow is EphA3+, comprising administering a therapeutically effective amount of an anti-EphA3 antibody to the patient.
Activating EphA3 and/or inducing ADCC with an anti-EphA3 antibody
The method further requires that the administered anti-EphA3 antibody activates EphA3 and/or induces ADCC.
Treatment is directed to patients with low EphA3 expression on hematological proliferative disorder cells together with EphA3+ aberrant bone-marrow vasculature, using an anti-EphA3 antibody configured to activate EphA3 and/or induce ADCC. Dependent claims refine EphA3-expression thresholds and specify additional antibody formats, properties, and functional interaction features.
Stated Advantages
Selectively targets patients with EphA3+ aberrant bone-marrow vasculature in hematological proliferative disorders despite low or EphA3− expression on hematological proliferative disorder cells.
Uses anti-EphA3 antibody functionality that can activate EphA3 and/or induce ADCC.
Documented Applications
Treatment of patients having a hematological proliferative disorder with less than 20% EphA3-expressing disorder cells and EphA3+ aberrant bone-marrow vasculature.
Application to specific hematological proliferative disorders, including AML.
Detection/diagnostic use of SL-2 and SL-7 antibodies for EphA3 binding and for EphA3 detectability on AML tumor neovasculature versus absence on normal bone marrow by IHC.
Monitoring efficacy by re-detecting EphA3 on vasculature.
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