A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias Journal Article


Authors: Dubrovsky, L.; Pankov, D.; Brea, E. J.; Dao, T.; Scott, A.; Yan, S.; O'Reilly, R. J.; Liu, C.; Scheinberg, D. A.
Article Title: A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias
Abstract: Acute and chronic leukemias, including CD34+ CML cells, demonstrate increased expression of the Wilms tumor gene 1 product (WT1), making WT1 an attractive therapeutic target. However, WT1 is a currently undruggable, intracellular protein. ESKM is a human IgG1 T-cell receptor mimic monoclonal antibody directed to a 9-amino acid sequence of WT1 in the context of cell surface HLA-A*02. ESKM was therapeutically effective, alone and in combination with tyrosine kinase inhibitors (TKIs), against Philadelphia chromosome - positive acute leukemia in murine models, including a leukemia with the mostcommon,pan-TKI, gatekeeper resistance mutation, T315I.ESKMwassuperior to the first-generation TKI, imatinib. Combination therapy with ESKM and TKIs was superior to eitherdrugalone, capable of curing mice.ESKMshowednotoxicity tohumanHLA-A*02:01+ stem cells under the conditions of this murine model. These features of ESKM make it a promising nontoxic therapeutic agent for sensitive and resistant Ph+ leukemias. © 2014 by The American Society of Hematology.
Keywords: controlled study; unclassified drug; gene mutation; human cell; diarrhea; drug dose reduction; monotherapy; nonhuman; mouse; imatinib; cancer immunotherapy; animal experiment; animal model; dasatinib; chronic myeloid leukemia; acute lymphoblastic leukemia; cancer resistance; stem cell; monoclonal antibody; protein tyrosine kinase inhibitor; t lymphocyte receptor; acute leukemia; bcr abl protein; immunoglobulin g1; wt1 protein; drug dose increase; hla a antigen; leukemia relapse; plerixafor; leukemia cell line; leukemia remission; cell surface; antileukemic agent; molecular mimicry; philadelphia chromosome positive cell; ponatinib; human; male; priority journal; article; monoclonal antibody eskm; murine leukemia
Journal Title: Blood
Volume: 123
Issue: 21
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2014-05-22
Start Page: 3296
End Page: 3304
Language: English
DOI: 10.1182/blood-2014-01-549022
PROVIDER: scopus
PMCID: PMC4046427
PUBMED: 24723681
DOI/URL:
Notes: Export Date: 1 August 2014 -- CODEN: BLOOA -- Source: Scopus
Altmetric Score
MSK Authors
  1. Tao Dao
    57 Dao
  2. Dmitry D. Pankov
    18 Pankov
  3. Richard O'Reilly
    476 O'Reilly
  4. Andrew Crosbie Scott
    11 Scott
  5. Elliott Joseph Brea
    13 Brea