title: An anti-PR1/HLA-A2 T-cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells.
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 [K(D)] = 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.
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Sergeeva
authors.forename: Gheath
authors.initials: G
authors.lastname: Alatrash
authors.forename: Hong
authors.initials: H
authors.lastname: He
authors.forename: Kathryn
authors.initials: K
authors.lastname: Ruisaard
authors.forename: Sijie
authors.initials: S
authors.lastname: Lu
authors.forename: James
authors.initials: J
authors.lastname: Wygant
authors.forename: Bradley W
authors.initials: BW
authors.lastname: McIntyre
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Lisa
authors.initials: L
authors.lastname: St John
authors.forename: Karen
authors.initials: K
authors.lastname: Clise-Dwyer
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
mesh_terms: D000818:Animals; D002460:Cell Line; D003165:Complement System Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology; D013234:Stem Cells / Q000276:immunology
chemical_list: D000939:Epitopes; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell; D017452:Receptors, IgG; D003165:Complement System Proteins