Research ArticleCancer

Targeting the Intracellular WT1 Oncogene Product with a Therapeutic Human Antibody

Science Translational Medicine  13 Mar 2013:
Vol. 5, Issue 176, pp. 176ra33
DOI: 10.1126/scitranslmed.3005661

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Destroying from Within

Anticancer antibody-based drugs have largely targeted proteins on the surface of cancer cells. But, arguably the most important, tumor-specific proteins are on the inside—safely tucked away within the cell. Wilms tumor 1 (WT1) is one of these intracellular oncoproteins. Despite its insider status, degraded WT1 fragments are presented on the surface of leukemia cells and many other cancer tissues, including ovarian. To kill leukemia, Dao and colleagues hypothesized that intracellular WT1 was the perfect target.

Dao et al. engineered a monoclonal antibody, named “ESK1,” that recognizes a peptide fragment of WT1, called RMF, complexed with human leukocyte antigen (HLA)–A0201. After demonstrating that ESK1 bound to several WT1+ cell lines in vitro and leukemia patient cells ex vivo, the authors tested their new antibody in two mouse models of human acute lymphoblastic leukemia. They delivered ESK1 alone or along with human “effector” cells (peripheral blood natural killer cells) and saw that the combination therapy killed nearly all leukemia in comparison to control groups, allowing all of the treated mice to have prolonged or even leukemia-free survival. Treating animals with cancers that lacked either HLA-A0201 or WT1 had no effect.

With a defined mechanism and no toxicity in mice, this ESK1 antibody is poised for testing in human trials. The authors point out that more than 1 million patients in the world may have a WT1+ cancer, with many of these being HLA-A02+. In this case, ESK1—with its ability to target a cancer protein inside the cell—could help treat many patients that have not responded to antibody-based therapies focused on the cell surface.