PMID- 23486779
OWN - NLM
STAT- MEDLINE
DCOM- 20130904
LR  - 20231120
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 5
IP  - 176
DP  - 2013 Mar 13
TI  - Targeting the intracellular WT1 oncogene product with a therapeutic human 
      antibody.
PG  - 176ra33
LID - 10.1126/scitranslmed.3005661 [doi]
AB  - 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 
      gammac-/- (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.
FAU - Dao, Tao
AU  - Dao T
AD  - Molecular Pharmacology and Chemistry Program, Department of Medicine, Memorial 
      Sloan-Kettering Cancer Center, New York, NY 10021, USA.
FAU - Yan, Su
AU  - Yan S
FAU - Veomett, Nicholas
AU  - Veomett N
FAU - Pankov, Dmitry
AU  - Pankov D
FAU - Zhou, Liang
AU  - Zhou L
FAU - Korontsvit, Tatyana
AU  - Korontsvit T
FAU - Scott, Andrew
AU  - Scott A
FAU - Whitten, Joseph
AU  - Whitten J
FAU - Maslak, Peter
AU  - Maslak P
FAU - Casey, Emily
AU  - Casey E
FAU - Tan, Taochao
AU  - Tan T
FAU - Liu, Hong
AU  - Liu H
FAU - Zakhaleva, Victoria
AU  - Zakhaleva V
FAU - Curcio, Michael
AU  - Curcio M
FAU - Doubrovina, Ekaterina
AU  - Doubrovina E
FAU - O'Reilly, Richard J
AU  - O'Reilly RJ
FAU - Liu, Cheng
AU  - Liu C
FAU - Scheinberg, David A
AU  - Scheinberg DA
LA  - eng
GR  - R01 CA055349/CA/NCI NIH HHS/United States
GR  - T32 CA062948/CA/NCI NIH HHS/United States
GR  - P01 CA023766/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P01 CA23766/CA/NCI NIH HHS/United States
GR  - R01 CA55349/CA/NCI NIH HHS/United States
GR  - UL1 TR000457/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Epitopes)
RN  - 0 (Oncogene Proteins)
SB  - IM
CIN - Nat Rev Drug Discov. 2013 May;12(5):346. PMID: 23598509
MH  - Animals
MH  - Antibodies, Monoclonal/*immunology/*therapeutic use
MH  - CD8-Positive T-Lymphocytes/*immunology/metabolism
MH  - Epitopes/immunology
MH  - Humans
MH  - Leukemia/immunology/therapy
MH  - Male
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Oncogene Proteins/genetics/metabolism
MH  - T-Lymphocytes, Cytotoxic/immunology
MH  - Wilms Tumor/immunology/*therapy
PMC - PMC3963696
MID - NIHMS560692
COIS- Competing interests: Sloan-Kettering and Eureka Inc. have filed for patent 
      protection for the mAb. The authors have no other competing interests.
EDAT- 2013/03/15 06:00
MHDA- 2013/09/05 06:00
PMCR- 2014/03/24
CRDT- 2013/03/15 06:00
PHST- 2013/03/15 06:00 [entrez]
PHST- 2013/03/15 06:00 [pubmed]
PHST- 2013/09/05 06:00 [medline]
PHST- 2014/03/24 00:00 [pmc-release]
AID - 5/176/176ra33 [pii]
AID - 10.1126/scitranslmed.3005661 [doi]
PST - ppublish
SO  - Sci Transl Med. 2013 Mar 13;5(176):176ra33. doi: 10.1126/scitranslmed.3005661.