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Open Access Highly Accessed Research article

Specific antibody-receptor interactions trigger InlAB-independent uptake of listeria monocytogenes into tumor cell lines

Martin Heisig123*, Alexa Frentzen24, Birgit Bergmann12, Katharina Galmbacher15, Ivaylo Gentschev14, Christian Hotz16, Christoph Schoen27, Jochen Stritzker24, Joachim Fensterle18, Ulf R Rapp19 and Werner Goebel102

Author affiliations

1 Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Versbacher Straße 8, Würzburg, 97078, Deutschland

2 Institut für Mikrobiologie, Universität Würzburg, Biozentrum Am Hubland, Würzburg, 97074, Deutschland

3 Yale University, School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, 300 Cedar Street, New Haven, CT 06520, USA

4 Genelux Corporation, 3030 Bunker Hill St., Ste310, San Diego, CA 92109, USA

5 Interlab GmbH, Bayerstr. 53, München, 80335, Deutschland

6 Abteilung für Klinische Pharmakologie, Klinikum der Universität München, Ziemssenstraße 1, München, 80336, Deutschland

7 Institut für Hygiene und Mikrobiologie, Universität Würzburg, Josef-Schneider-Str. 2, Würzburg, 97070, Deutschland

8 Æterna Zentaris, Weismüllerstrasse 50, Frankfurt/Main, 60314, Deutschland

9 Max Planck Institut für Biochemie, Abteilung für molekulare Biologie, Am Klopferspitz 18, Martinsried, 82152, Deutschland

10 Max-von-Pettenkofer Institut für Hygiene und Medizinische Mikrobiologie, LMU München, Pettenkoferstr. 9a, München, 80336, Deutschland

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Citation and License

BMC Microbiology 2011, 11:163  doi:10.1186/1471-2180-11-163

Published: 11 July 2011

Abstract

Background

Specific cell targeting is an important, yet unsolved problem in bacteria-based therapeutic applications, like tumor or gene therapy. Here, we describe the construction of a novel, internalin A and B (InlAB)-deficient Listeria monocytogenes strain (Lm-spa+), which expresses protein A of Staphylococcus aureus (SPA) and anchors SPA in the correct orientation on the bacterial cell surface.

Results

This listerial strain efficiently binds antibodies allowing specific interaction of the bacterium with the target recognized by the antibody. Binding of Trastuzumab (Herceptin®) or Cetuximab (Erbitux®) to Lm-spa+, two clinically approved monoclonal antibodies directed against HER2/neu and EGFR/HER1, respectively, triggers InlAB-independent internalization into non-phagocytic cancer cell lines overexpressing the respective receptors. Internalization, subsequent escape into the host cell cytosol and intracellular replication of these bacteria are as efficient as of the corresponding InlAB-positive, SPA-negative parental strain. This specific antibody/receptor-mediated internalization of Lm-spa+ is shown in the murine 4T1 tumor cell line, the isogenic 4T1-HER2 cell line as well as the human cancer cell lines SK-BR-3 and SK-OV-3. Importantly, this targeting approach is applicable in a xenograft mouse tumor model after crosslinking the antibody to SPA on the listerial cell surface.

Conclusions

Binding of receptor-specific antibodies to SPA-expressing L. monocytogenes may represent a promising approach to target L. monocytogenes to host cells expressing specific receptors triggering internalization.