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

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.

authors

  • Dao, T
  • Pankov, D
  • Scott, A
  • Korontsvit, T
  • Zakhaleva, V
  • Xu, Y
  • Xiang, J
  • Yan, S
  • De Morais Guerreiro, MD
  • Veomett, N
  • Dubrovsky, L
  • Curcio, M
  • Doubrovina, E
  • Ponomarev, V
  • Liu, C
  • O'Reilly, RJ
  • Scheinberg, DA

publication date

  • 2015