Targeting the intracellular WT1 oncogene product with a therapeutic human antibody Journal Article

   


Authors: Dao, T.; Yan, S. ; Veomett, N.; Pankov, D.; Zhou, L.; Korontsvit, T.; Scott, A.; Whitten, J.; Maslak, P.; Casey, E.; Tan, T.; Liu, H.; Zakhaleva, V.; Curcio, M.; Doubrovina, E.; O'Reilly, R. J.; Liu, C.; Scheinberg, D. A.
Article Title: Targeting the intracellular WT1 oncogene product with a therapeutic human antibody
Abstract: The Wilms tumor 1 (WT1) oncoprotein is an intracellular, oncogenic transcription factor that is overexpressed in a wide range of leukemias and solid cancers. RMFPNAPYL (RMF), a WT1-derived CD8+ T cell human leukocyte antigen (HLA)-A0201 epitope, is a validated target for T cell-based immunotherapy. Using phage display technology, we discovered a fully human "T cell receptor-like" monoclonal antibody (mAb), ESK1, specific for the WT1 RMF peptide/HLA-A0201 complex. ESK1 bound to several leukemia and solid tumor cell lines and primary leukemia cells, in a WT1- and HLA-A0201-restricted manner, with high avidity [dissociation constant (Kd) = 0.1 nM]. ESK1 mediated antibody-dependent human effector cell cytotoxicity in vitro. Low doses of naked ESK1 antibody cleared established, disseminated, human acute lymphocytic leukemia and Philadelphia chromosome-positive leukemia in nonobese diabetic/severe combined immunodeficient γc-/- (NSG) mouse models. At therapeutic doses, no toxicity was seen in HLA-A0201 transgenic mice. ESK1 is a potential therapeutic agent for a wide range of cancers overexpressing the WT1 oncoprotein. This finding also provides preclinical validation for the strategy of developing therapeutic mAbs targeting intracellular oncogenic proteins. Copyright 2013 by the American Association for the Advancement of Science; all rights reserved.
Journal Title: Science Translational Medicine
Volume: 5
Issue: 176
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2013-03-13
Start Page: 176ra33
Language: English
DOI: 10.1126/scitranslmed.3005661
PROVIDER: scopus
PUBMED: 23486779
PMCID: PMC3963696
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84875207852&partnerID=40&md5=7d6af37637ef11bac18d5eb559b47c98
Notes: --- - "Export Date: 1 April 2013" - "Source: Scopus"
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MSK Authors
  1. Ekaterina Doubrovina
    101 Doubrovina
  2. David Scheinberg
    499 Scheinberg
  3. Amie Marie Scott
    45 Scott
  4. Tao Dao
    81 Dao
  5. Peter Maslak
    197 Maslak
  6. Dmitry D. Pankov
    22 Pankov
  7. Richard O'Reilly
    748 O'Reilly
  8. Joseph Anthony Whitten
    3 Whitten
  9. Emily Catherine Casey
    9 Casey
  10. Viktoriya Zakhaleva
    29 Zakhaleva
  11. Tatyana Korontsvit
    53 Korontsvit
  12. Michael J Curcio
    28 Curcio
  13. Nicholas J Veomett
    10 Veomett
  14. Andrew Crosbie Scott
    14 Scott
  15. Adrienne Crystal Scott
    1 Scott
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