Abstract 2447: Transient lymphocyte decrease due to adhesion & migration following treatment with catumaxomab (anti-EpCAM x anti-CD3) in vivo

Abstract

Abstract Catumaxomab is a trifunctional, bispecific antibody targeting EpCAM and CD3 which redirects T-cells to EpCAM expressing tumor cells and is able to evoke T-cell cytotoxic responses. The hybrid Fc region of catumaxomab provides a third functional binding site, which is able to bind and activate Fcγ receptor (FcγR)-positive accessory cells. In clinical trials a transient decrease in peripheral blood lymphocyte counts was observed following i.p. administration of catumaxomab. Lymphocyte decrease may be a result of either decreased production or increased destruction of lymphocytes, redistribution of lymphocytes or various unknown / multifactorial pathogeneses. We determined whether the observed transient decrease in patients might be due to antibody induced adhesion of lymphocytes to endothelial cells or to migration of lymphocytes into the tissue. Therefore, we investigated the influence of catumaxomab on adhesion of human T cells to endothelial cells in vitro. Catumaxomab physiologically activated T-cells by increasing expression of the activation marker CD69 and induced the release of cytokines, including TNFα and IFNγ. TNFα increased expression of adhesion molecules CD54 and CD62E on endothelial cells. Furthermore, catumaxomab dose-dependently increased adhesion of T cells to endothelial cells, and the adhesion was further increased when the endothelial cells were preactivated with TNFα. Thus, catumaxomab increases adhesion of T-cells to endothelial cells, which is due to antibody mediated upregulation of adhesion molecules on T-cells and production of cytokines that upregulate endothelial cell adhesion molecules. Furthermore, we showed that treatment of BALB/c mice with the related trifunctional antibody BiLu (anti-human EpCAM x anti-mouse CD3), that binds to mouse CD3, also resulted in a dose-dependent transient decrease in CD3+ T-cells (both CD4+ and CD8+) that returned to the normal range within 48 h. These results provide a rationale for the transient and reversible decrease in peripheral lymphocyte counts observed following catumaxomab administration in clinical studies, which is likely to be due to redistribution of lymphocytes and not due to depletion of circulating lymphocytes or stem cells. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2447.