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

Alexei V. Salnikov, Ariane Groth, Anja Apel, Georgios Kallifatidis, Benjamin M. Beckermann, Akmal Khamidjanov, Eduard Ryschich, Markus W. Büchler, Ingrid Herr, Gerhard Moldenhauer

Research output: Contribution to journalArticle

31 Citations (Scopus)

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∼ 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-γ and TNF-α by extracorporally pre-activated lymphocytes. Moreover, compared with a bivalent anti-CD3 antibody, EpCAMxCD3 more efficiently activated the production of TNF-α and IFN-γ 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.

Original languageEnglish (US)
Pages (from-to)4023-4033
Number of pages11
JournalJournal of Cellular and Molecular Medicine
Volume13
Issue number9 B
DOIs
StatePublished - Sep 1 2009
Externally publishedYes

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Bispecific Antibodies
Neoplastic Stem Cells
Pancreatic Neoplasms
Lymphocytes
Neoplasms
Cultured Tumor Cells
Video Microscopy
Inbred NOD Mouse
Tumor Microenvironment
SCID Mice
Heterografts
Half-Life
Pancreatic Carcinoma
Epithelial Cell Adhesion Molecule
Anti-Idiotypic Antibodies
Blood Cells
Collagen
Survival Rate
Fibroblasts
Cytokines

Keywords

  • Bispecific antibody
  • Cancer immunotherapy
  • Cancer stem cells
  • EpCAM
  • Lymphocytes
  • Pancreatic carcinoma
  • Tumour microenvironment

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

Cite this

Targeting of cancer stem cell marker EpCAM by bispecific antibody EpCAMxCD3 inhibits pancreatic carcinoma. / Salnikov, Alexei V.; Groth, Ariane; Apel, Anja; Kallifatidis, Georgios; Beckermann, Benjamin M.; Khamidjanov, Akmal; Ryschich, Eduard; Büchler, Markus W.; Herr, Ingrid; Moldenhauer, Gerhard.

In: Journal of Cellular and Molecular Medicine, Vol. 13, No. 9 B, 01.09.2009, p. 4023-4033.

Research output: Contribution to journalArticle

Salnikov, AV, Groth, A, Apel, A, Kallifatidis, G, Beckermann, BM, Khamidjanov, A, Ryschich, E, Büchler, MW, Herr, I & Moldenhauer, G 2009, 'Targeting of cancer stem cell marker EpCAM by bispecific antibody EpCAMxCD3 inhibits pancreatic carcinoma', Journal of Cellular and Molecular Medicine, vol. 13, no. 9 B, pp. 4023-4033. https://doi.org/10.1111/j.1582-4934.2009.00723.x
Salnikov, Alexei V. ; Groth, Ariane ; Apel, Anja ; Kallifatidis, Georgios ; Beckermann, Benjamin M. ; Khamidjanov, Akmal ; Ryschich, Eduard ; Büchler, Markus W. ; Herr, Ingrid ; Moldenhauer, Gerhard. / Targeting of cancer stem cell marker EpCAM by bispecific antibody EpCAMxCD3 inhibits pancreatic carcinoma. In: Journal of Cellular and Molecular Medicine. 2009 ; Vol. 13, No. 9 B. pp. 4023-4033.
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