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

作者：Trad Ahmad; Hansen Hinrich P; Shomali Mohammad; Peipp Matthias; Klausz Katja; Hedemann Nina; Yamamoto Kosuke; Mauermann Andre; Desel Christine; Lorenzen Inken; Lemke Hilmar; Rose John Stefan; Groetzinger Joachim

来源：Cancer Immunology, Immunotherapy, 2013, 62(3): 411-421.

DOI：10.1007/s00262-012-1346-x

• ADAM17
• Monoclonal antibody
• Doxorubicin
• Pseudomonas exotoxin A

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.

• 出版日期2013-3