Targeting of cancer stem cell marker EpCAM by bispecific antibody EpCAMxCD3 inhibits pancreatic carcinoma

J Cell Mol Med. 2009 Sep;13(9B):4023-33. doi: 10.1111/j.1582-4934.2009.00723.x.

Abstract

Patients with pancreatic cancer have a poor survival rate, and new therapeutic strategies are needed. Epithelial cell adhesion molecule (EpCAM), suggested as a marker for cancer stem cells, is over-expressed on most pancreatic tumour cells but not on normal cells and may be an ideal therapeutic target. We evaluated the anti-tumour efficiency of bispecific EpCAMxCD3 antibody linking tumour cells and T lymphocytes. In NOD SCID mice, EpCAMxCD3 had a long serum half-life (t(1/2) approximately 7 days). EpCAMxCD3 significantly retarded growth of BxPC-3 pancreatic carcinoma xenografts. For mimicking a pancreatic cancer microenvironment in vitro, we used a three-dimensional tumour reconstruct system, in which lymphocytes were co-cultured with tumour cells and fibroblasts in a collagen matrix. In this in vivo-like system, EpCAMxCD3 potently stimulated production of the effector cytokines IFN-gamma and TNF-alpha by extracorporally pre-activated lymphocytes. Moreover, compared with a bivalent anti-CD3 antibody, EpCAMxCD3 more efficiently activated the production of TNF-alpha and IFN-gamma by non-stimulated peripheral blood mononuclear cells. Most excitingly, we demonstrate for the first time that EpCAMxCD3 induces prolonged contacts between lymphocytes and tumour cells, which may be the main reason for the observed anti-tumour effects. As an important prerequisite for future use in patients, EpCAMxCD3 did not alter lymphocyte migration as measured by time-lapse video microscopy. Our data may open a way to improve the immune response and treatment outcome in patients with pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / therapeutic use*
  • Antigens, Neoplasm / biosynthesis*
  • CD3 Complex / immunology*
  • Carcinoma / immunology*
  • Carcinoma / metabolism
  • Cell Adhesion Molecules / antagonists & inhibitors
  • Cell Adhesion Molecules / biosynthesis*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Coculture Techniques
  • Epithelial Cell Adhesion Molecule
  • Fibroblasts / metabolism
  • Humans
  • Immunotherapy / methods
  • Interferon-gamma / metabolism
  • Lymphocytes / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / metabolism
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antibodies, Bispecific
  • Antigens, Neoplasm
  • CD3 Complex
  • Cell Adhesion Molecules
  • Epithelial Cell Adhesion Molecule
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma