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 |
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