Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell Lines

Abstract

Outcome in high-risk patients with refractory or relapsed germ cell tumours (GCT) remains poor. Novel strategies enhancing therapeutic efficacy whilst limiting therapeutic burden are warranted, yet immunotherapy approaches geared towards activating endogenous antitumor responses have not been successful thus far. Redirection of cytotoxic effector cells by bispecific antibodies represents a promising approach in this setting. We demonstrate that the Epithelial Cell Adhesion Molecule (EpCAM) is broadly expressed in GCT cell lines of different histologic origin including seminoma, choriocarcinoma (CHC), and embryonal carcinoma (EC). In these GCT lines of variable EpCAM surface expression, targeting T cells by the prototypic bispecific EpCAM/CD3-antibody (bAb) Catumaxomab together with natural killer (NK) cell engagement via the Fc domain promotes profound cytotoxicity across a broad range of antibody dilutions. In contrast, tumor cell lysis mediated by either immune cell subset alone is influenced by surface density of the target antigen. In the CHC line JAR, NK cell-dependent cytotoxicity dominates, which may be attributed to differential surface expression of immunomodulatory proteins such as MHC-I, CD24, and Fas receptors on CHC and EC. In view of redirecting T cell therapy mediated by bispecific antibodies, such differences in GCT immunophenotype potentially favoring immune escape are worth further investigation.

Antitumor activities of a defucosylated anti‑EpCAM monoclonal antibody in colorectal carcinoma xenograft models

“…This event promotes the formation of cytotoxic synapse and T-cell-mediated cytotoxicity. Furthermore, catumaxomab recruits natural killer (NK) cells and macrophages through the Fc domain and enhances antibody-dependent cellular cytotoxicity (Adcc) (16,17). catumaxomab has demonstrated promising outcomes in several clinical trials (18)(19)(20), and has been approved by the European Union for the treatment of patients with malignant ascites (21).…”

Development of a Novel Anti-EpCAM Monoclonal Antibody for Various Applications

“…Catumaxomab binds to EpCAM-overexpressed tumors and recruits T cells to tumor cells, which promote cytotoxic synapse formation and tumor cell lysis. Furthermore, through the Fc domain, Catumaxomab also recruits natural killer cells and macrophages and enhances antibody-dependent cellular cytotoxicity (ADCC) [ 8 , 9 ]. Several clinical trials have demonstrated promising outcomes [ 10 , 11 , 12 ], and Catumaxomab has been approved by the European Union for the treatment of patients with malignant ascites in EpCAM-positive carcinomas [ 13 ].…”

A Defucosylated Anti-EpCAM Monoclonal Antibody (EpMab-37-mG2a-f) Exerts Antitumor Activity in Xenograft Model

“…Catumaxomab recognizes EpCAM on tumors, recruits T cells through the anti-CD3 arm, and recruits natural killer (NK) cells and macrophages through the Fc domain. These events enhanced ADCC activity [ 22 ]. Catumaxomab exhibited promising outcomes in several clinical trials [ 23 , 24 , 25 ], and was approved by the European Union for the treatment of patients with malignant ascites in 2009 [ 23 ].…”