[Frontiers in Bioscience 5042-5049, May 1, 2008]

EpCAM-targeted induction of apoptosis

Edwin Bremer, Wijnand Helfrich

Groningen University Institute for Drug Exploration (GUIDE), Department of Pathology and Laboratory Medicine, Section Medical Biology, Laboratory for Tumor Immunology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1 .Tumor cell evasion of immune recognition
3. Retargeting cytotoxic immune effector cells to epcam-positive carcinoma
3.1. Retargeting cytotoxic T-cells to EpCAM-positive carcinoma using bispecific antibodies
3.2. Retargeting cytotoxic T-cells to EpCAM-positive carcinoma using recombinant bispecific single-chain antibodies
3.3. Retargeting of myeloid immune effector cells to EpCAM-positive carcinoma
3.4. Trifunctional bispecific antibodies for EpCAM-positive carcinoma
4. EpCAM-targeted (re-)activation of apoptosis
4.1. Tumor cell evasion of apoptotic elimination
4.2. Target cell-restricted activation of apoptosis by scFv:sTRAIL fusion proteins
5. Summary and perspectives
6. References

1. ABSTRACT

EpCAM is a well-established pancarcinoma-associated target antigen that has been used in a variety of therapeutic approaches. Of particular appeal are those strategies that aim to retarget and locally activate immune effector mechanisms involving apoptosis. Cancer cells typically employ various strategies to evade recognition and elimination by immune effector cells, including low or absent expression of MHCI molecules and active elimination of tumor infiltrating immune cells. In addition, cancer cells show an increased resistance towards endogenous pro-apoptotic stimuli due to aberrancies in their apoptotic machinery. However, compelling evidence indicates that cancer cells are often reliant on these molecular aberrations for continued cell survival. This pivotal role of immune evasion and apoptosis resistance has fueled the quest for therapeutic strategies that can selectively retarget and reactivate immune effector cells or molecules, whereby the balance of cellular fate of cancer cells is selectively tipped towards apoptosis. Here we review and discuss the perspectives for EpCAM-targeted apoptosis induction in cancer by EpCAM-selective bispecific antibodies and TRAIL fusion proteins.