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Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1
Tao Dao1,4, Dmitry Pankov1,4, Andrew Scott1,2, Tatyana Korontsvit1, Victoriya Zakhaleva1, Yiyang Xu3, Jingyi Xiang3, Su Yan3, Manuel Direito de Morais Guerreiro1, Nicholas Veomett1,2, Leonid Dubrovsky1, Michael Curcio1, Ekaterina Doubrovina1, Vladimir Ponomarev1, Cheng Liu3, Richard J OReilly1,2 & David A Scheinberg1,2
Intracellular tumor antigens presented on the cell surface in the context of human leukocyte antigen (HLA) molecules have been targeted by T cellbased 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.
npg 201 5 Nature America, Inc. All rights reserved.
Tumor-specific antigens are in most cases intracellular proteins, inaccessible to classical mAb therapy. These intracellular proteins are, however, degraded, processed and presented by major histocompatibility complex (MHC) class I molecules as peptide-MHC complexes that can be recognized by the TCR of cytotoxic T lymphocytes (CTLs). Immunotherapies involving CTLs have been central to cancer immunotherapy1,2. However, given the intrinsic complexity of cell-based therapies, alternative approaches using molecular agents would be desirable. Although TCR-mimic mAbs35 against tumor-specific intracellular antigens have been developed, their potency will be limited by very low epitope density on the cell surface, which reduces efficacy. In contrast, BiTE antibodiesheterodimers of IgG single-chain fragment variable regions (scFv) with dual specificities for a mAb-defined tumor-associated antigen and for CD3 T cells611may
be a more promising approach because of their greater potency by virtue of their recruiting of cytolytic T cells. BiTE molecules have been shown to redirect...