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Clin. transl. oncol. (Print) ; 14(5): 376-381, mayo 2012. ilus, tab
Article in English | IBECS | ID: ibc-126912

ABSTRACT

INTRODUCTION: In patients, a transient decrease in peripheral blood lymphocyte counts was observed following intraperitoneal administration of the trifunctional monoclonal antibody catumaxomab (anti-human EpCAM x anti-human CD3). The aim of this study was to clarify the observed effect in a preclinical mouse model and to analyse the related mechanism of action in vitro. MATERIALS AND METHODS: A related antibody, BiLu (antihuman EpCAM x anti-mouse CD3), was administered to mice and blood leukocytes were analysed. In vitro studies measured activation and cytokine secretion from human peripheral blood mononuclear cells (PBMC). For the analysis of T cell adhesion, PBMC were preincubated with catumaxomab and then co-cultured with human endothelial cells (HUVEC); T cell adhesion was assessed in the presence or absence of endothelial cell preactivation by TNFα. Adherent T cells were determined by flow cytometry. RESULTS: Treatment of mice with BiLu resulted in a dosedependent transient decrease in CD3+ T cells (both CD4+ and CD8+) that returned to the normal range within 48 h. Catumaxomab physiologically activated T cells in vitro (increased CD69 expression) and induced cytokine release (TNFα, IFNγ). TNFα increased expression of adhesion molecules CD54 and CD62E on endothelial cells. Furthermore, catumaxomab dose-dependently enhanced adhesion of T cells to endothelial cells. Adhesion was further increased when endothelial cells were preactivated with TNFα. CONCLUSIONS: Catumaxomab increases adhesion of T cells to endothelial cells due to antibody-mediated activation of T cells and production of T cell cytokines that up-regulate endothelial cell adhesion molecules. These results provide a mechanistic rationale for the transient, reversible decrease in lymphocyte counts observed following catumaxomab administration in patients, which is likely to be due to redistribution of lymphocytes (AU)


Subject(s)
Animals , Tumor Necrosis Factor Receptor Superfamily, Member 7/administration & dosage , Tumor Necrosis Factor Receptor Superfamily, Member 7/analysis , Tumor Necrosis Factor Receptor Superfamily, Member 7/blood , Tumor Necrosis Factor Receptor Superfamily, Member 7/chemical synthesis , Tumor Necrosis Factor Receptor Superfamily, Member 7/classification , Tumor Necrosis Factor Receptor Superfamily, Member 7/deficiency , Tumor Necrosis Factor Receptor Superfamily, Member 7 , Tumor Necrosis Factor Receptor Superfamily, Member 7/toxicity
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