ADAM17-overexpressing breast cancer cells selectively targeted by antibody–toxin conjugates

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2013-03, Vol.62 (3), p.411-421
• Main Authors: Trad, Ahmad, Hansen, Hinrich P., Shomali, Mohammad, Peipp, Matthias, Klausz, Katja, Hedemann, Nina, Yamamoto, Kosuke, Mauermann, André, Desel, Christine, Lorenzen, Inken, Lemke, Hilmar, Rose-John, Stefan, Grötzinger, Joachim
• Format: Article
• Language: English
• Subjects: ADAM protein; ADAM Proteins - immunology; ADAM Proteins - metabolism; ADAM17 Protein; Antibiotics, Antineoplastic - administration & dosage; Antibodies, Monoclonal - therapeutic use; Antibody-Dependent Cell Cytotoxicity; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - therapy; Cancer Research; Cell Membrane - metabolism; Cell Proliferation - drug effects; Complement System Proteins - immunology; Cytotoxicity; Data processing; Doxorubicin - administration & dosage; Drug delivery; Exotoxins; Female; Humans; Immunology; Immunotherapy; Immunotoxins; Immunotoxins - therapeutic use; Inflammation; Medicine; Medicine & Public Health; Microenvironments; Molecular Targeted Therapy; Monoclonal antibodies; Oncology; Original; Original Article; Pseudomonas; Toxins; Tumor cells
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-012-1346-x

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.