Title | A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Dubrovsky L, Pankov D, Brea EJoseph, Dao T, Scott A, Yan S, O'Reilly RJ, Liu C, Scheinberg DA |
Journal | Blood |
Volume | 123 |
Issue | 21 |
Pagination | 3296-304 |
Date Published | 2014 May 22 |
ISSN | 1528-0020 |
Keywords | Animals, Antibodies, Monoclonal, Cell Line, Cell Line, Tumor, Dasatinib, Drug Resistance, Neoplasm, HLA-A2 Antigen, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Male, Mice, Mice, SCID, Protein Kinase Inhibitors, Pyrimidines, Thiazoles, WT1 Proteins |
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 most common, pan-TKI, gatekeeper resistance mutation, T315I. ESKM was superior to the first-generation TKI, imatinib. Combination therapy with ESKM and TKIs was superior to either drug alone, capable of curing mice. ESKM showed no toxicity to human HLA-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. |
DOI | 10.1182/blood-2014-01-549022 |
Alternate Journal | Blood |
PubMed ID | 24723681 |
PubMed Central ID | PMC4046427 |
Grant List | R01 CA055349 / CA / NCI NIH HHS / United States T32 CA062948 / CA / NCI NIH HHS / United States R01CA55349 / CA / NCI NIH HHS / United States P01 CA023766 / CA / NCI NIH HHS / United States GM0773 / GM / NIGMS NIH HHS / United States P01CA23766 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States T32CA62948-18 / CA / NCI NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:09pm