Targeting the intracellular WT1 oncogene product with a therapeutic human antibody

T Dao, S Yan, N Veomett, D Pankov, L Zhou… - Science translational …, 2013 - science.org
T Dao, S Yan, N Veomett, D Pankov, L Zhou, T Korontsvit, A Scott, J Whitten, P Maslak…
Science translational medicine, 2013science.org
The Wilms tumor 1 (WT1) oncoprotein is an intracellular, oncogenic transcription factor that
is overexpressed in a wide range of leukemias and solid cancers. RMFPNAPYL (RMF), a
WT1-derived CD8+ T cell human leukocyte antigen (HLA)–A0201 epitope, is a validated
target for T cell–based immunotherapy. Using phage display technology, we discovered a
fully human “T cell receptor–like” monoclonal antibody (mAb), ESK1, specific for the WT1
RMF peptide/HLA-A0201 complex. ESK1 bound to several leukemia and solid tumor cell …
The Wilms tumor 1 (WT1) oncoprotein is an intracellular, oncogenic transcription factor that is overexpressed in a wide range of leukemias and solid cancers. RMFPNAPYL (RMF), a WT1-derived CD8+ T cell human leukocyte antigen (HLA)–A0201 epitope, is a validated target for T cell–based immunotherapy. Using phage display technology, we discovered a fully human “T cell receptor–like” monoclonal antibody (mAb), ESK1, specific for the WT1 RMF peptide/HLA-A0201 complex. ESK1 bound to several leukemia and solid tumor cell lines and primary leukemia cells, in a WT1- and HLA-A0201–restricted manner, with high avidity [dissociation constant (Kd) = 0.1 nM]. ESK1 mediated antibody-dependent human effector cell cytotoxicity in vitro. Low doses of naked ESK1 antibody cleared established, disseminated, human acute lymphocytic leukemia and Philadelphia chromosome–positive leukemia in nonobese diabetic/severe combined immunodeficient γc−/− (NSG) mouse models. At therapeutic doses, no toxicity was seen in HLA-A0201 transgenic mice. ESK1 is a potential therapeutic agent for a wide range of cancers overexpressing the WT1 oncoprotein. This finding also provides preclinical validation for the strategy of developing therapeutic mAbs targeting intracellular oncogenic proteins.
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