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Experimental Therapeutics, Preclinical Pharmacology |
1 Departments of Medicine and
2 Immunology, Roswell Park Cancer Institute Buffalo, New York
ABSTRACT
Purpose: Rituximab is a chimeric antibody (Ab) directed against the cluster designated (CD) 20 antigen found on normal and malignant B cells. Rituximab activity has been associated with complement-mediated cytotoxicity, Ab-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. Recent studies performed in severe combined immunodeficiency (SCID) mouse models suggest that in vivo rituximab-associated ADCC is mediated via the Fc
RIII receptor on effector cells. Despite low level expression of FcRIII, neutrophils are also known to induce ADCC primarily via FcRI receptor (CD64). The purpose of this work was to study the effect(s) of neutrophils on the in vivo antitumor activity of rituximab.
Experimental Design: To better characterize the biological activity of rituximab, we used a human non-Hodgkin’s lymphoma animal model by injecting Raji cells i.v. into natural killer (NK) cell-depleted SCID mice. Disseminated disease involving liver, lung, and central nervous system developed, with subsequent death occurring approximately 3 weeks after tumor inoculation. Specifically, 6–8-week-old NK cell-depleted SCID mice were inoculated by tail vein injection with 1 x 106 Raji cells on day 0. The animals then were divided into three cohorts: (a) group A received placebo (PBS); (b) group B received rituximab administered via tail vein injection at 10 mg/kg on days 3, 5, 7, and 11; and (c) group C consisted of neutrophil-depleted SCID mice treated with rituximab at 10 mg/kg on the same schedule. Neutrophils were depleted by i.p. administration of 80 µg of rat antimouse Ly-6G (Gr-1) Ab (BD PharMingen, Inc.) on days –1, 4, 9, and 14. The end point of the study was survival. Differences in outcome between treatment groups were analyzed by Kaplan-Meier methodology.
Results: Neutrophil- and NK cell-depleted SCID mice (group C) did not respond to rituximab, and the mean survival time was not significantly different from that of control mice. NK cell-depleted SCID mice with intact neutrophil function (group B) responded to rituximab, and 66% remained alive and appeared healthy after a mean follow-up period of 246 days. Overall, NK cell-depleted SCID mice with intact neutrophil function treated with rituximab had statistically longer mean survival as compared with mice in neutrophil-depleted and control groups (161 days versus 28 days versus 22 days, P = 0.003).
Conclusions: In the absence of neutrophils, rituximab was less effective in controlling lymphoma cell growth or prolonging survival in our B-cell lymphoma SCID mouse model. Neutrophil-induced ADCC appears to contribute to the in vivo antitumor activity of rituximab. Strategies that improve the function of neutrophils, such as granulocyte-macrophage colony-stimulating factor or G-CSF priming, may increase the antitumor effects of rituximab. Additional in vivo animal studies are warranted.
Commentary
Clin. Cancer Res. 2003 9: 5810-5812.
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