Abstract
BackgroundEpithelial cell adhesion molecule (EpCAM) is frequently and highly expressed on 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. 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. Here we compared all anti-EpCAM antibodies in an attempt to explain differences in clinical activity and safety.MethodsWe recombinantly produced all antibodies but murine edrecolomab and investigated them for binding affinity, EpCAM epitope recognition, ADCC and CDC, and inhibition of breast cancer cell proliferation.ResultsING-1 and 3622W94 bound to EpCAM with much higher affinity than adecatumumab and edrecolomab. 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 cancer cell lines by both ADCC and CDC with potencies that correlated with their binding affinities. The chimeric version of edrecolomab with a human Fcγ1 domain was much more potent in ADCC than the murine IgG2a version. Only adecatumumab showed a significant inhibition of MCF-7 breast cancer cell proliferation in the absence of complement and immune cells.ConclusionA 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.
Highlights
Epithelial cell adhesion molecule EpCAM (CD326; 17-1A antigen) was among the first human tumor-associated antigens discovered [1]
Equilibrium dissociations constants (KD values) for binding to recombinant EpCAM coated on Biacore sensor chips were 1.5 and 2.1 μM for edrecolomab and chimeric edrecolomab, respectively, 100 nM for adecatumumab, and 190 and 160 pM for 3622W94 and ING-1, respectively (Table 1)
The two highest affinity monoclonal antibody (mAb), 3622W94 and ING-1 had very slow off-rates translating into a prolonged binding to the EpCAM target
Summary
Epithelial cell adhesion molecule EpCAM (CD326; 17-1A antigen) was among the first human tumor-associated antigens discovered [1]. It was initially identified by the monoclonal antibody (mAb) 17-1A after immunization of mice with human colorectal cancer cells [2]. The first monoclonal antibody ever tested in cancer patients was the EpCAM-specific murine IgG2a antibody 17-1A produced in ascites of mice [24,25]. This antibody was later produced by fermentation and called edrecolomab. We compared all antiEpCAM antibodies in an attempt to explain differences in clinical activity and safety
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