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Cancer Cell International
Published in: Cancer Cell International 1/2010

Open Access 01-12-2010 | Primary research

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

Authors: Markus Münz, Alexander Murr, Majk Kvesic, Doris Rau, Susanne Mangold, Stefan Pflanz, John Lumsden, Jörg Volkland, Jan Fagerberg, Gert Riethmüller, Dominik Rüttinger, Peter Kufer, Patrick A Baeuerle, Tobias Raum

Published in: Cancer Cell International | Issue 1/2010

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Abstract

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 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.

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.
Appendix
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Metadata
Title
Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies
Authors
Markus Münz
Alexander Murr
Majk Kvesic
Doris Rau
Susanne Mangold
Stefan Pflanz
John Lumsden
Jörg Volkland
Jan Fagerberg
Gert Riethmüller
Dominik Rüttinger
Peter Kufer
Patrick A Baeuerle
Tobias Raum
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2010
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-10-44

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