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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.

Author information

1
Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2
Weill Cornell Medical College, New York, New York, USA.
3
Eureka Therapeutics, Emeryville, California, USA.

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.

Comment in

PMID:
26389576
PMCID:
PMC4600043
DOI:
10.1038/nbt.3349
[Indexed for MEDLINE]
Free PMC Article

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