title: Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1.
abstract: Intracellular tumor antigens presented on the cell surface in the context of human leukocyte antigen (HLA) molecules have been targeted by T cell-based therapies, but there has been little progress in developing small-molecule drugs or antibodies directed to these antigens. Here we describe a bispecific T-cell engager (BiTE) antibody derived from a T-cell receptor (TCR)-mimic monoclonal antibody (mAb) ESK1, which binds a peptide derived from the intracellular oncoprotein WT1 presented on HLA-A*02:01. Despite the very low density of the complexes at the cell surface, ESK1-BiTE selectively activated and induced proliferation of cytolytic human T cells that killed cells from multiple leukemias and solid tumors in vitro and in mice. We also discovered that in an autologous in vitro setting, ESK1-BiTE induced a robust secondary CD8 T-cell response specific for tumor-associated antigens other than WT1. Our study provides an approach that targets tumor-specific intracellular antigens without using cell therapy and suggests that epitope spreading could contribute to the therapeutic efficacy of this BiTE.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Dao
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Pankov
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Weill Cornell Medical College, New York, New York, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Scott
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Korontsvit
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Victoriya
authors.initials: V
authors.lastname: Zakhaleva
authors.affiliation: Eureka Therapeutics, Emeryville, California, USA.
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Eureka Therapeutics, Emeryville, California, USA.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Eureka Therapeutics, Emeryville, California, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Yan
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Manuel Direito
authors.initials: MD
authors.lastname: de Morais Guerreiro
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Weill Cornell Medical College, New York, New York, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Veomett
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Dubrovsky
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Curcio
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Doubrovina
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.affiliation: Eureka Therapeutics, Emeryville, California, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Weill Cornell Medical College, New York, New York, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: O'Reilly
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Weill Cornell Medical College, New York, New York, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy*; D015513:Oncogene Proteins / Q000276:immunology; D012097:Repressor Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome; D025721:WT1 Proteins
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015513:Oncogene Proteins; D012097:Repressor Proteins; D025721:WT1 Proteins; C000602896:WT1 protein, mouse