title: ADAM17-overexpressing breast cancer cells selectively targeted by antibody-toxin conjugates.
abstract: A disintegrin and metalloproteinase 17 (ADAM17) is significantly upregulated not only in malignant cells but also in the pro-inflammatory microenvironment of breast cancer. There, ADAM17 is critically involved in the processing of tumor-promoting proteins. Therefore, ADAM17 appears to be an attractive therapeutic target to address not only tumor cells but also the tumor-promoting environment. In a previous study, we generated a monoclonal anti-ADAM17 antibody (A300E). Although showing no complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity, the antibody was rapidly internalized by ADAM17-expressing cells and was able to transport a conjugated toxin into target cells. As a result, doxorubicin-coupled A300E or Pseudomonas exotoxin A-loaded A300E was able to kill ADAM17-expressing cells. This effect was strictly dependent on the presence of ADAM17 on the surface of target cells. As a proof of principle, both immunotoxins killed MDA-MB-231 breast cancer cells in an ADAM17-dependent manner. These data suggest that the use of anti-ADAM17 monoclonal antibodies as a carrier might be a promising new strategy for selective anti-cancer drug delivery.
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098, Kiel, Germany.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Trad
authors.forename: Hinrich P
authors.initials: HP
authors.lastname: Hansen
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shomali
authors.forename: Matthias
authors.initials: M
authors.lastname: Peipp
authors.forename: Katja
authors.initials: K
authors.lastname: Klausz
authors.forename: Nina
authors.initials: N
authors.lastname: Hedemann
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yamamoto
authors.forename: André
authors.initials: A
authors.lastname: Mauermann
authors.forename: Christine
authors.initials: C
authors.lastname: Desel
authors.forename: Inken
authors.initials: I
authors.lastname: Lorenzen
authors.forename: Hilmar
authors.initials: H
authors.lastname: Lemke
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
mesh_terms: D051722:ADAM Proteins / Q000276:immunology* / Q000378:metabolism; D000072198:ADAM17 Protein; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy*; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003165:Complement System Proteins / Q000276:immunology; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D058990:Molecular Targeted Therapy
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D004317:Doxorubicin; D003165:Complement System Proteins; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human