A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias.
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.
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY;
Leonid
http://orcid.org/0000-0003-2799-4765
L
Dubrovsky
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY; Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY;
Dmitry
D
Pankov
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY; Weill Cornell Medical College, New York, NY; and.
Elliott Joseph
EJ
Brea
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY;
Tao
T
Dao
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY;
Andrew
A
Scott
Eureka Therapeutics, Emeryville, CA.
Su
S
Yan
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY; Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY;
Richard J
RJ
O'Reilly
Eureka Therapeutics, Emeryville, CA.
Cheng
C
Liu
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY; Weill Cornell Medical College, New York, NY; and.
David A
DA
Scheinberg
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000276:immunology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D025721:WT1 Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; C524866:HLA-A*02 antigen; D015789:HLA-A2 Antigen; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D025721:WT1 Proteins; C583751:WT1 protein, human; D000069439:Dasatinib