title: The anti-human leukocyte antigen-DR monoclonal antibody 1D09C3 activates the mitochondrial cell death pathway and exerts a potent antitumor activity in lymphoma-bearing nonobese diabetic/severe combined immunodeficient mice.
abstract: The fully human anti-HLA-DR antibody 1D09C3 has been shown to delay lymphoma cell growth in severe combined immunodeficient (SCID) mice. The present study was aimed at (a) investigating the mechanism(s) of 1D09C3-induced cell death and (b) further exploring the therapeutic efficacy of 1D09C3 in nonobese diabetic (NOD)/SCID mice. The chronic lymphocytic leukemia cell line JVM-2 and the mantle cell lymphoma cell line GRANTA-519 were used. Generation of reactive oxygen species (ROS) and mitochondrial membrane depolarization were measured by flow cytometry following cell incubation with dihydroethidium and TMRE, respectively. Western blot analysis was used to detect c-Jun-NH(2)-kinase (JNK) phosphorylation and apoptosis-inducing factor (AIF). NOD/SCID mice were used to investigate the activity of 1D09C3 in early- or advanced-stage tumor xenografts. In vitro, 1D09C3-induced cell death involves a cascade of events, including ROS increase, JNK activation, mitochondrial membrane depolarization, and AIF release from mitochondria. Inhibition of JNK activity significantly reduced 1D09C3-induced apoptosis, indicating that 1D09C3 activity involves activation of the kinase. In vivo, 1D09C3 induces long-term disease-free survival in a significant proportion of tumor-bearing mice treated at an early stage of disease. Treatment of mice bearing advanced-stage lymphoma results in a highly significant prolongation of survival. These data show that 1D09C3 (a) exerts a potent antitumor effect by activating ROS-dependent, JNK-driven cell death, (b) cures the great majority of mice treated at an early-stage of disease, and (c) significantly prolongs survival of mice with advanced-stage disease.
authors.affiliation: Cristina Gandini Medical Oncology Unit, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. carmelo.carlostella@unimi.it
authors.forename: Carmelo
authors.initials: C
authors.lastname: Carlo-Stella
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Nicola
authors.forename: Maria Caterina
authors.initials: MC
authors.lastname: Turco
authors.forename: Loredana
authors.initials: L
authors.lastname: Cleris
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lavazza
authors.forename: Paolo
authors.initials: P
authors.lastname: Longoni
authors.forename: Marco
authors.initials: M
authors.lastname: Milanesi
authors.forename: Michele
authors.initials: M
authors.lastname: Magni
authors.forename: Massimo
authors.initials: M
authors.lastname: Ammirante
authors.forename: Arturo
authors.initials: A
authors.lastname: Leone
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Nagy
authors.forename: Walter R
authors.initials: WR
authors.lastname: Gioffrè
authors.forename: Franca
authors.initials: F
authors.lastname: Formelli
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Gianni
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D006684:HLA-DR Antigens; D017382:Reactive Oxygen Species