An anti–PR1/HLA-A2 T-cell receptor–like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells

A Sergeeva, G Alatrash, H He… - Blood, The Journal …, 2011 - ashpublications.org
A Sergeeva, G Alatrash, H He, K Ruisaard, S Lu, J Wygant, BW McIntyre, Q Ma, D Li…
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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]= 9.9 nM)
for a combined epitope of the PR1/HLA-A2 complex. Flow cytometry and confocal …
Abstract
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 LinCD34+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.
ashpublications.org