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

被引:38
作者
Carlo-Stella, C
Di Nicola, M
Turco, MC
Cleris, L
Lavazza, C
Longoni, P
Milanesi, M
Magni, M
Ammirante, M
Leone, A
Nagy, Z
Gioffrè, WR
Formelli, F
Gianni, AM
机构
[1] Ist Nazl Tumori, Cristina Gandhi Med Oncol Unit, I-20133 Milan, Italy
[2] Ist Nazl Tumori, Dept Expt Oncol, I-20133 Milan, Italy
[3] Univ Milan, I-20133 Milan, Italy
[4] Univ Salerno, Dept Pharmacol, I-84100 Salerno, Italy
[5] GPC Biotech AG, Munich, Germany
[6] Univ Siena, CIRAS, UOC Senol, I-53100 Siena, Italy
关键词
D O I
10.1158/0008-5472.CAN-05-1200
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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-NH2-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 All? 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.
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页码:1799 / 1808
页数:10
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