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  3. Medizin - Open Access LMU - Teil 17/22 Podcast
  4. Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies
Background: Epithelial 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. Methods: We 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. Results: ING-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 Fc gamma 1 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. Conclusion: 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.

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„Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies“

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