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

T Dao, D Pankov, A Scott, T Korontsvit… - Nature …, 2015 - nature.com
T Dao, D Pankov, A Scott, T Korontsvit, V Zakhaleva, Y Xu, J Xiang, S Yan…
Nature biotechnology, 2015nature.com
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 …
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.
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