1DO9C3 Exerts Potent Anti-Tumor Activity Against CLL Cells

[Guest guest]

Cancer Res. 2006 Feb 1;66(3):1799-1808.

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.

Carlo-Stella C, Di Nicola M, Turco MC, Cleris L, Lavazza C, Longoni

P, Milanesi M, Magni M, Ammirante M, Leone A, Nagy Z, Gioffre WR,

Formelli F, Gianni AM.

" Cristina Gandini " Medical Oncology Unit and Department of

Experimental Oncology, Istituto Nazionale Tumori.

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 ( 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, ( cures the great

majority of mice treated at an early-stage of disease, and ©

significantly prolongs survival of mice with advanced-stage disease.

(Cancer Res 2006; 66(3): 1799-808).

PMID: 16452241 [PubMed - as supplied by publisher]