A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias
Menée à l'aide d'un modèle murin de leucémie aiguë Ph+ résistante aux inhibiteurs de tyrosine kinase, cette étude évalue l'activité antitumorale d'un anticorps monoclonal appelé ESKM, seul ou en combinaison avec l'imatinib
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 un-druggable, 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, gate keeper 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 non-toxic therapeutic agent for sensitive and resistant Ph+ leukemias.
Blood 2014