TY - JOUR
T1 - An anti-PR1/HLA-A2 T-cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells
AU - Sergeeva, Anna
AU - Alatrash, Gheath
AU - He, Hong
AU - Ruisaard, Kathryn
AU - Lu, Sijie
AU - Wygant, James
AU - McIntyre, Bradley W.
AU - Ma, Qing
AU - Li, Dan
AU - St John, Lisa
AU - Clise-Dwyer, Karen
AU - Molldrem, Jeffrey J.
PY - 2011/4/21
Y1 - 2011/4/21
N2 - PR1 (VLQELNVTV) is a human leukocyte antigen-A2 (HLA-A2) - restricted leukemia-associated peptide from proteinase 3 (P3) and neutrophil elastase (NE) that is recognized by PR1-specific cytotoxic T lymphocytes that contribute to cytogenetic remission of acute myeloid leukemia (AML).We report a novel T-cell receptor (TCR) - like immunoglobulin G2a (IgG2a) antibody (8F4) with high specific binding affinity (dissociation constant [KD] = 9.9nM) for a combined epitope of the PR1/HLA-A2 complex. Flow cytometry and confocal microscopy of 8F4-labeled cells showed significantly higher PR1/HLA-A2 expression on AML blasts compared with normal leukocytes (P = .046). 8F4 mediated complement-dependent cytolysis of AML blasts and Lin -CD34+CD38- leukemia stem cells (LSCs) but not normal leukocytes (P < .005). Although PR1 expression was similar on LSCs and hematopoietic stem cells, 8F4 inhibited AML progenitor cell growth, but not normal colony-forming units from healthy donors (P < .05). This study shows that 8F4, a novel TCR-like antibody, binds to a conformational epitope of the PR1/HLA-A2 complex on the cell surface and mediates specific lysis of AML, including LSCs. Therefore, this antibody warrants further study as a novel approach to targeting leukemia-initiating cells in patients with AML.
AB - PR1 (VLQELNVTV) is a human leukocyte antigen-A2 (HLA-A2) - restricted leukemia-associated peptide from proteinase 3 (P3) and neutrophil elastase (NE) that is recognized by PR1-specific cytotoxic T lymphocytes that contribute to cytogenetic remission of acute myeloid leukemia (AML).We report a novel T-cell receptor (TCR) - like immunoglobulin G2a (IgG2a) antibody (8F4) with high specific binding affinity (dissociation constant [KD] = 9.9nM) for a combined epitope of the PR1/HLA-A2 complex. Flow cytometry and confocal microscopy of 8F4-labeled cells showed significantly higher PR1/HLA-A2 expression on AML blasts compared with normal leukocytes (P = .046). 8F4 mediated complement-dependent cytolysis of AML blasts and Lin -CD34+CD38- leukemia stem cells (LSCs) but not normal leukocytes (P < .005). Although PR1 expression was similar on LSCs and hematopoietic stem cells, 8F4 inhibited AML progenitor cell growth, but not normal colony-forming units from healthy donors (P < .05). This study shows that 8F4, a novel TCR-like antibody, binds to a conformational epitope of the PR1/HLA-A2 complex on the cell surface and mediates specific lysis of AML, including LSCs. Therefore, this antibody warrants further study as a novel approach to targeting leukemia-initiating cells in patients with AML.
UR - http://www.scopus.com/inward/record.url?scp=79955966609&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955966609&partnerID=8YFLogxK
U2 - 10.1182/blood-2010-07-299248
DO - 10.1182/blood-2010-07-299248
M3 - Article
C2 - 21296998
AN - SCOPUS:79955966609
SN - 0006-4971
VL - 117
SP - 4262
EP - 4272
JO - Blood
JF - Blood
IS - 16
ER -