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

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 TNF. Adherent T cells were determined by fl ow 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 (TNF, IFN). TNF 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 TNF.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.

TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas’ heart disease

“…Besides that, the chronic infection increased the frequency of naive, central, memory and effector memory T cells, up-regulated the frequency of cell adhesion molecule-bearing cells and increased cytokine (TGF-β) production. Altogether, this process leads to increase of lymphocytes adhesion to endothelium and migration into the extravascular space [60] of inflamed tissues. It could explain the increase of numbers of CD3 + lymphocytes in the heart during the chronic disease.…”

The trifunctional antibody catumaxomab amplifies and shapes tumor-specific immunity when applied to gastric cancer patients in the adjuvant setting

“…We believe that this phenomenon is based on the redistribution of this particular T-cell subtype from the peripheral blood into peripheral tissues, an idea that would be supported by a recent in vitro study indicating that catumaxomab promotes the transendothelial migration of activated T cells. 40 Chemokine receptor CXCR3 is preferentially expressed by effector T cells with a Th1 phenotype 28 and traditionally T cells secreting Th1 cytokines (i.e., IFN-γ, TNF-α) have been considered critically important for the induction of cellular immunity and the generation of a relevant anti-tumor response in vivo. 41 It has also repeatedly been shown that the mobilization of Th1-type effector T cells into the tumor tissue and subsequent antitumor effects are mediated by chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 [42][43][44][45][46][47] and that, consequently, the presence of CXCR3 + T cells within the tumor has a positive influence on the patients' outcome.…”

A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors

“…Regarding the immune response to ertumaxomab, we made following observations: CD3+ T cell counts decreased 24 h post infusion, but normal values were obtained 1 week later. Transient lymphocytopenia was also observed in other clinical studies with trifunctional antibodies [12, 15] and is provoked by their mode of action: The full reversibility and the short recovery period indicate that the phenomenon is attributed to lymphocyte redistribution which could be confirmed in a pre-clinical model [17]. …”