title: 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.affiliation: Molecular Pharmacology and Chemistry Program, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Dao
authors.forename: Su
authors.initials: S
authors.lastname: Yan
authors.forename: Nicholas
authors.initials: N
authors.lastname: Veomett
authors.forename: Dmitry
authors.initials: D
authors.lastname: Pankov
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.forename: Tatyana
authors.initials: T
authors.lastname: Korontsvit
authors.forename: Andrew
authors.initials: A
authors.lastname: Scott
authors.forename: Joseph
authors.initials: J
authors.lastname: Whitten
authors.forename: Peter
authors.initials: P
authors.lastname: Maslak
authors.forename: Emily
authors.initials: E
authors.lastname: Casey
authors.forename: Taochao
authors.initials: T
authors.lastname: Tan
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Victoria
authors.initials: V
authors.lastname: Zakhaleva
authors.forename: Michael
authors.initials: M
authors.lastname: Curcio
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Doubrovina
authors.forename: Richard J
authors.initials: RJ
authors.lastname: O'Reilly
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D009396:Wilms Tumor / Q000276:immunology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D015513:Oncogene Proteins