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Clinical and Translational Oncology

, Volume 14, Issue 5, pp 376–381 | Cite as

Transient lymphocyte decrease due to adhesion and migration following catumaxomab (anti-EpCAM x anti-CD3) treatment in vivo

  • Kirsten Dettmar
  • Isabell Seitz-Merwald
  • Carsten Lindemann
  • Petra Schroeder
  • Diane Seimetz
  • Judith AtzEmail author
Open Access
Research Articles

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.

Keywords

Catumaxomab Trifunctional antibody T lymphocyte Endothelium Adhesion Redistributi 

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Copyright information

© Feseo 2012

Authors and Affiliations

  • Kirsten Dettmar
    • 1
  • Isabell Seitz-Merwald
    • 1
  • Carsten Lindemann
    • 2
  • Petra Schroeder
    • 2
  • Diane Seimetz
    • 1
  • Judith Atz
    • 1
    Email author
  1. 1.Fresenius Biotech GmbHMunichGermany
  2. 2.EUFETS GmbHIdar-ObersteinGermany

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