title: Activity of 8F4, a T-cell receptor-like anti-PR1/HLA-A2 antibody, against primary human AML in vivo.
abstract: The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a high-affinity T-cell receptor-like murine monoclonal antibody, 8F4, that binds to the PR1/HLA-A2 complex, mediates lysis of AML and inhibits leukemia colony formation. Here, we explored whether 8F4 was active in vivo against chemotherapy-resistant AML, including secondary AML. In a screening model, coincubation of AML with 8F4 ex vivo prevented engraftment of all tested AML subtypes in immunodeficient NSG (NOD scid IL-2 receptor γ-chain knockout) mice. In a treatment model of established human AML, administration of 8F4 significantly reduced or eliminated AML xenografts and extended survival compared with isotype antibody-treated mice. Moreover, in secondary transfer experiments, mice inoculated with bone marrow from 8F4-treated mice showed no evidence of AML engraftment, supporting the possible activity of 8F4 against the subset of AML with self-renewing potential. Our data provide evidence that 8F4 antibody is highly active in AML, including chemotherapy-resistant disease, supporting its potential use as a therapeutic agent in patients with AML.
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sergeeva
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: He
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ruisaard
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: St John
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Alatrash
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Clise-Dwyer
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Patenia
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Hong
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Sukhumalchandra
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Molldrem
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D019272:Leukocyte Elastase / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008875:Middle Aged; D053146:Myeloblastin / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D015789:HLA-A2 Antigen; D019272:Leukocyte Elastase; D053146:Myeloblastin