A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias

L Dubrovsky, D Pankov, EJ Brea, T Dao… - Blood, The Journal …, 2014 - ashpublications.org
L Dubrovsky, D Pankov, EJ Brea, T Dao, A Scott, S Yan, RJ O'Reilly, C Liu, DA Scheinberg
Blood, The Journal of the American Society of Hematology, 2014ashpublications.org
Acute and chronic leukemias, including CD34+ CML cells, demonstrate increased
expression of the Wilms tumor gene 1 product (WT1), making WT1 an attractive therapeutic
target. However, WT1 is a currently undruggable, intracellular protein. ESKM is a human
IgG1 T-cell receptor mimic monoclonal antibody directed to a 9–amino acid sequence of
WT1 in the context of cell surface HLA-A* 02. ESKM was therapeutically effective, alone and
in combination with tyrosine kinase inhibitors (TKIs), against Philadelphia chromosome …
Abstract
Acute and chronic leukemias, including CD34+ CML cells, demonstrate increased expression of the Wilms tumor gene 1 product (WT1), making WT1 an attractive therapeutic target. However, WT1 is a currently undruggable, intracellular protein. ESKM is a human IgG1 T-cell receptor mimic monoclonal antibody directed to a 9–amino acid sequence of WT1 in the context of cell surface HLA-A*02. ESKM was therapeutically effective, alone and in combination with tyrosine kinase inhibitors (TKIs), against Philadelphia chromosome–positive acute leukemia in murine models, including a leukemia with the most common, pan-TKI, gatekeeper resistance mutation, T315I. ESKM was superior to the first-generation TKI, imatinib. Combination therapy with ESKM and TKIs was superior to either drug alone, capable of curing mice. ESKM showed no toxicity to human HLA-A*02:01+ stem cells under the conditions of this murine model. These features of ESKM make it a promising nontoxic therapeutic agent for sensitive and resistant Ph+ leukemias.
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