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

   


Authors: Dao, T.; Pankov, D.; Scott, A.; Korontsvit, T.; Zakhaleva, V.; Xu, Y.; Xiang, J.; Yan, S. ; Direito de Morais Guerreiro, M.; Veomett, N.; Dubrovsky, L.; Curcio, M.; Doubrovina, E.; Ponomarev, V.; Liu, C.; O'Reilly, R. J.; Scheinberg, D. A.
Article Title: Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1
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. © 2015 Nature America, Inc. All rights reserved.
Keywords: cytology; tumor antigen; monoclonal antibodies; antigens; tumors; cell membranes; antibodies; therapeutic efficacy; epitopes; cells; t-cells; molecules; human leukocyte antigen; t-cell receptors; cell based therapies; human t cells; monoclonal antibodies (mab); small-molecule drugs
Journal Title: Nature Biotechnology
Volume: 33
Issue: 10
ISSN: 1087-0156
Publisher: Nature Publishing Group  
Date Published: 2015-10-01
Start Page: 1079
End Page: 1086
Language: English
DOI: 10.1038/nbt.3349
PROVIDER: scopus
PMCID: PMC4600043
PUBMED: 26389576
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84943591908&partnerID=40&md5=ac0d1eaf4f61f2b26c2c686af94ac386
Notes: Export Date: 2 November 2015 -- Source: Scopus
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MSK Authors
  1. Vladimir Ponomarev
    115 Ponomarev
  2. Ekaterina Doubrovina
    99 Doubrovina
  3. David Scheinberg
    478 Scheinberg
  4. Tao Dao
    76 Dao
  5. Dmitry D. Pankov
    21 Pankov
  6. Richard O'Reilly
    717 O'Reilly
  7. Leonid Dubrovsky
    11 Dubrovsky
  8. Viktoriya Zakhaleva
    29 Zakhaleva
  9. Tatyana Korontsvit
    51 Korontsvit
  10. Michael J Curcio
    28 Curcio
  11. Nicholas J Veomett
    10 Veomett
  12. Andrew Crosbie Scott
    14 Scott
  13. Manuel Nuno Direito de Morais Guerreiro
    2 Direito de Morais Guerreiro
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