ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

 

Leukemias, including acute myeloblastic leukemias, acute lymphoblastic lekemias (ALL), chronic myelogenous leukemia (CML), demonstrate significantly increased expression of Wilms tumor gene 1 protein (WT1), a zinc finger transcription factor. However, this potential therapeutic target is undruggable. Dubrovsky et al. developed an antibody, ESKM, which is therapeutically effective on acute and chronic leukemias in murine models. The article was published on Blood.

 

WT1 is an intracellular transcription factor, therefore, it is hard to be directly inhibited by small-molecule drugs or antibody therapies. Researchers established a human IgG1 T-cell receptor mimic (TCRm) monoclonal antibody called ESKM, which targets a 9-amino acid sequence of WT1, expressed in the context of cell surface HLA-A*02. They found ESKM is effective and not affected by gatekeeper resistance T315I. T315I is a mutation that inactivates  tyrosine kinase inhibitors (TKIs), which is a common uncurative therapy of Philadelphia chromosome-positive (Ph⁺) ALL. However, TKIs combined with ESKM is capable to cure mice Ph+ ALL. In addition, ESKM is specific to the leukemia cells, so it perform minimal effects to other cells. The findings suggested ESKM a promising nontoxic drug for PH⁺ leukemias.

 

Reference:
Blood. 2014 May 22;123(21):3296-304.

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