Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies
<p>Abstract</p> <p>Background</p> <p>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, fur...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-11-01
|
| Series: | Cancer Cell International |
| Online Access: | http://www.cancerci.com/content/10/1/44 |
| _version_ | 1811277589794258944 |
|---|---|
| author | Pflanz Stefan Mangold Susanne Rau Doris Kvesic Majk Murr Alexander Münz Markus Lumsden John Volkland Jörg Fagerberg Jan Riethmüller Gert Rüttinger Dominik Kufer Peter Baeuerle Patrick A Raum Tobias |
| author_facet | Pflanz Stefan Mangold Susanne Rau Doris Kvesic Majk Murr Alexander Münz Markus Lumsden John Volkland Jörg Fagerberg Jan Riethmüller Gert Rüttinger Dominik Kufer Peter Baeuerle Patrick A Raum Tobias |
| author_sort | Pflanz Stefan |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p> |
| first_indexed | 2024-04-13T00:18:21Z |
| format | Article |
| id | doaj.art-d6c0b83823474fd2aa489b9aa23104f7 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-04-13T00:18:21Z |
| publishDate | 2010-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-d6c0b83823474fd2aa489b9aa23104f72022-12-22T03:10:51ZengBMCCancer Cell International1475-28672010-11-011014410.1186/1475-2867-10-44Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodiesPflanz StefanMangold SusanneRau DorisKvesic MajkMurr AlexanderMünz MarkusLumsden JohnVolkland JörgFagerberg JanRiethmüller GertRüttinger DominikKufer PeterBaeuerle Patrick ARaum Tobias<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p>http://www.cancerci.com/content/10/1/44 |
| spellingShingle | Pflanz Stefan Mangold Susanne Rau Doris Kvesic Majk Murr Alexander Münz Markus Lumsden John Volkland Jörg Fagerberg Jan Riethmüller Gert Rüttinger Dominik Kufer Peter Baeuerle Patrick A Raum Tobias Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies Cancer Cell International |
| title | Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies |
| title_full | Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies |
| title_fullStr | Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies |
| title_full_unstemmed | Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies |
| title_short | Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies |
| title_sort | side by side analysis of five clinically tested anti epcam monoclonal antibodies |
| url | http://www.cancerci.com/content/10/1/44 |
| work_keys_str_mv | AT pflanzstefan sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT mangoldsusanne sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT raudoris sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT kvesicmajk sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT murralexander sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT munzmarkus sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT lumsdenjohn sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT volklandjorg sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT fagerbergjan sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT riethmullergert sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT ruttingerdominik sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT kuferpeter sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT baeuerlepatricka sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies AT raumtobias sidebysideanalysisoffiveclinicallytestedantiepcammonoclonalantibodies |