Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1. Academic Article uri icon

Overview

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.

publication date

  • September 21, 2015

Research

keywords

  • Antibodies, Monoclonal
  • Neoplasms, Experimental
  • Repressor Proteins
  • T-Lymphocytes

Identity

PubMed Central ID

  • PMC4600043

Scopus Document Identifier

  • 84943591908

Digital Object Identifier (DOI)

  • 10.1038/nbt.3349

PubMed ID

  • 26389576

Additional Document Info

volume

  • 33

issue

  • 10