Human epithelial cell adhesion molecule (EpCAM) is overexpressed in many cancers. Although anti-EpCAM antibodies have shown promise in preclinical studies, early-phase clinical evaluation of these antibodies has been disappointing.
To determine whether the antitumor activity of anti-EpCAM antibody could be improved, Moldenhauer and colleagues from the German Cancer Research Center in Heidelberg, Germany, constructed a novel conjugate consisting of a chimerized anti-EpCAM monoclonal antibody and α-amanitin, a toxin that inhibits DNA transcription. The conjugate reduced cell proliferation in human pancreatic, colorectal, breast, and bile duct cancer cell lines.
A single dose of the conjugate significantly reduced subcutaneous pancreatic carcinoma xenograft growth in immunocompromised mice compared with the antibody alone. At higher doses of α-amanitin in the conjugate, complete tumor regression was seen in 90% of tumors, with increased apoptosis and reduced cell proliferation observed in all animals.
As stated by the investigators, these findings suggest that “anti-EpCAM antibody conjugates with α-amanitin have the potential to be highly effective therapeutic agents for pancreatic carcinomas and various EpCAM-expressing malignancies.” ■
Moldenhauer G, et al: J Natl Cancer Inst 104:622-634, 2012.