title: Specific antibody-receptor interactions trigger InlAB-independent uptake of Listeria monocytogenes into tumor cell lines.
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.
authors: Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Versbacher Strasse 8, Würzburg, 97078, Deutschland. martin.heisig@yale.edu
authors: Martin
authors: M
authors: Heisig
authors: Alexa
authors: A
authors: Frentzen
authors: Birgit
authors: B
authors: Bergmann
authors: Katharina
authors: K
authors: Galmbacher
authors: Ivaylo
authors: I
authors: Gentschev
authors: Christian
authors: C
authors: Hotz
authors: Christoph
authors: C
authors: Schoen
authors: Jochen
authors: J
authors: Stritzker
authors: Joachim
authors: J
authors: Fensterle
authors: Ulf R
authors: UR
authors: Rapp
authors: Werner
authors: W
authors: Goebel
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D004705:Endocytosis; D066246:ErbB Receptors / Q000276:immunology; D005260:Female; D006801:Humans; D008089:Listeria monocytogenes / Q000472:pathogenicity*; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D013205:Staphylococcal Protein A / Q000235:genetics / Q000378:metabolism*
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D066246:ErbB Receptors; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D013205:Staphylococcal Protein A; C095768:inlB protein, Listeria monocytogenes; C069761:internalin protein, Bacteria; C512478:EGFR protein, human; C508053:ERBB2 protein, human