Inhibition Of Breast Cancer Cell Proliferation And Unique Epitope Recognition By Epcam-Specific Human Monoclonal Antibody Adecatumumab

Epithelial cell adhesion molecule (EpCAM; CD326) is frequently and highly expressed on a wide variety of human carcinomas. The emerging role of EpCAM as a signalling receptor and activator of the wnt pathway, and its expression on tumor-initiating cells, further add to its attractiveness as target for immunotherapy of cancer. Thus far, five conventional monoclonal IgG antibodies have been tested in cancer patients for safety and anti-tumor activity. These are murine IgG2a edrecolomab and its murine/human chimeric IgG1 antibody version, and humanized, human-engineered and fully human IgG1 antibodies 3622W94, ING-1, and adecatumumab (MT201), respectively. We have recombinantly produced all antibodies but murine edrecolomab in Chinese hamster ovary cells and investigated all five antibodies for their binding affinity, EpCAM epitope recognition, antibody-dependent cellular (ADCC) and complement-dependent cytotoxicity (CDC), and inhibition of breast cancer cell proliferation. ING-1 and 3622W94 bound to recombinant EpCAM with much higher affinity than adecatumumab and edrecolomab, which was largely determined by slower off-rates. Edrecolomab, ING-1, and 3622W94 all recognized epitopes in the exon 2-encoded, N-terminal domain of EpCAM, while adecatumumab recognized a more membrane proximal epitope encoded by exon 5. All antibodies induced lysis of EpCAM-expressing human cancer cell lines by both ADCC and CDC with potencies that correlated with their binding affinities for recombinant EpCAM. The chimeric version of edrecolomab with a human Fcγ1 domain was much more potent in ADCC with human effector cells than the murine IgG2a version of the antibody. Of the five antibodies, only adecatumumab showed a significant inhibition of MCF7 breast cancer cell proliferation in the absence of complement and immune cells. A moderate binding affinity and recognition of a distinct domain of EpCAM may best explain why adecatumumab showed a larger therapeutic window in cancer patients than the two high-affinity IgG1 antibodies ING-1 and 3622W94, both of which caused acute pancreatitis. Adecatumumab emerges as an anti-EpCAM antibody with unique characteristics and biological activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5339.