Targeting the intracellular WT1 oncogene product with a therapeutic human antibody.

Abstract

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.

• Authors: Tao Dao, Su Yan, Nicholas Veomett, Dmitry Pankov, Liang Zhou, Tatyana Korontsvit, Andrew Scott, Joseph Whitten, Peter Maslak, Emily Casey, Taochao Tan, Hong Liu, Victoria Zakhaleva, Michael Curcio, Ekaterina Doubrovina, Richard J O'Reilly, Cheng Liu, David A Scheinberg
• Journal: Science translational medicine (Sci Transl Med) Vol. 5 Issue 176 Pg. 176ra33 (Mar 13 2013) ISSN: 1946-6242 [Electronic] United States
• PMID: 23486779 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Epitopes
• Oncogene Proteins

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Epitopes (immunology)
• Humans
• Leukemia (immunology, therapy)
• Male
• Mice
• Mice, Inbred NOD
• Oncogene Proteins (genetics, metabolism)
• T-Lymphocytes, Cytotoxic (immunology)
• Wilms Tumor (immunology, therapy)