Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1 Journal Article

Authors: Dao, T.; Pankov, D.; Scott, A.; Korontsvit, T.; Zakhaleva, V.; Xu, Y.; Xiang, J.; Yan, S. ; Direito de Morais Guerreiro, M.; Veomett, N.; Dubrovsky, L.; Curcio, M.; Doubrovina, E.; Ponomarev, V.; Liu, C.; O'Reilly, R. J.; Scheinberg, D. A.
Article 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. © 2015 Nature America, Inc. All rights reserved.
Keywords: cytology; tumor antigen; monoclonal antibodies; antigens; tumors; cell membranes; antibodies; therapeutic efficacy; epitopes; cells; t-cells; molecules; human leukocyte antigen; t-cell receptors; cell based therapies; human t cells; monoclonal antibodies (mab); small-molecule drugs
Journal Title: Nature Biotechnology
Volume: 33
Issue: 10
ISSN: 1087-0156
Publisher: Nature Publishing Group  
Date Published: 2015-10-01
Start Page: 1079
End Page: 1086
Language: English
DOI: 10.1038/nbt.3349
PROVIDER: scopus
PMCID: PMC4600043
PUBMED: 26389576
Notes: Export Date: 2 November 2015 -- Source: Scopus
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