Targeting the intracellular WT1 oncogene product with a therapeutic human antibody Academic Article uri icon

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

  • Dao, T
  • Yan, S
  • Veomett, N
  • Pankov, D
  • Zhou, L
  • Korontsvit, T
  • Scott, A
  • Whitten, J
  • Maslak, P
  • Casey, E
  • Tan, T
  • Liu, H
  • Zakhaleva, V
  • Curcio, M
  • Doubrovina, E
  • O'Reilly, RJ
  • Liu, C
  • Scheinberg, DA

publication date

  • 2013