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Nat Biotechnol. 2015 Oct;33(10):1079-86. doi: 10.1038/nbt.3349. Epub 2015 Sep 21.

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

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Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Weill Cornell Medical College, New York, New York, USA.
Eureka Therapeutics, Emeryville, California, USA.


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.

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