The biology of the 17–1A antigen (Ep-CAM)

Balzar, Maarten; Winter, Manon J.; Boer, Carla J. de; Litvinov, Sergey V.

doi:10.1007/s001099900038

Cited by 490 publications

(471 citation statements)

References 59 publications

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“…Binding studies with truncated Ep-CAM showed that both 323/A3 and edrecolomab do bind the immunodominant EGFlike domain I of Ep-CAM. 10,24 We infer from the competition data that M79 and MT201 also recognized this subdomain, although this conclusion may require further support from binding studies using truncated Ep-CAM versions.…”

Section: Discussionmentioning

confidence: 85%

“…5,6 Murine IgG2a is the functional equivalent of human IgG1, which to some extent can also exhibit ADCC and CDC with human effector cells and human complement, respectively. Edrecolomab was obtained by immunization of mice with human colon cancer cells and recognizes the pan-epithelial differentiation antigen Ep-CAM, [7][8][9][10] which is widely involved in homotypic cell adhesion of epithelial cells. Since then, numerous clinical trials have been undertaken with edrecolomab and other Ep-CAM-specific murine, chimeric and humanized monoclonal antibodies of various affinities.…”

mentioning

confidence: 99%

“…10,14 However, a recent study with transgenic mice expressing human Ep-CAM suggested that Ep-CAM is a valid tumor target based on its differential accessibility to parenterally administered Ep-CAM antibodies. 15 I.v.-injected anti-human Ep-CAM antibody did homogenously stain human Ep-CAM-expressing syngenic tumors in transgenic mice while no significant binding of the antibody to the Ep-CAM present on normal tissue such as colon, pancreas or lung was detected.…”

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confidence: 99%

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In vitro and in vivo activity of MT201, a fully human monoclonal antibody for pancarcinoma treatment

Naundorf

Preithner

Mayer

et al. 2002

Intl Journal of Cancer

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In our study, a novel, fully human, recombinant monoclonal antibody of the IgG1 isotype, called MT201, was characterized for its binding properties, complement-dependent (CDC) and antibody-dependent cellular cytotoxicity (ADCC), as well as for its in vivo antitumor activity in a nude mouse model. MT201 was found to bind its target, the epithelial cell adhesion molecule (Ep-CAM; also called 17-1A antigen, KSA, EGP-2, GA733-2), with low affinity in a range similar to that of the clinically validated, murine monoclonal IgG2a antibody edrecolomab (Panorexா). MT201 exhibited Ep-CAM-specific CDC with a potency similar to that of edrecolomab. However, the efficacy of ADCC of MT201, as mediated by human immune effector cells, was by 2 orders of magnitude higher than that of edrecolomab. Addition of human serum reduced the ADCC of MT201 while it essentially abolished ADCC of edrecolomab within the concentration range tested. In a nude mouse xenograft model, growth of tumors derived from the human colon carcinoma line HT-29 was significantly and comparably suppressed by MT201 and edrecolomab. The fully human nature and the improved ADCC of MT201 with human effector cells will make MT201 a promising candidate for the clinical development of a novel pan-carcinoma antibody that is superior to edrecolomab.

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Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

mentioning

confidence: 99%

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In vitro and in vivo activity of MT201, a fully human monoclonal antibody for pancarcinoma treatment

Naundorf

Preithner

Mayer

et al. 2002

Intl Journal of Cancer

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“…Epithelial cell adhesion molecule (also referred to as 17-1A, KSA, GA733-2 or ESA) is a 40 kDa transmembrane glycoprotein that is expressed at relatively low levels on basolateral cell surfaces of most human simple epithelia (Balzar et al, 1999). Expression of Ep-CAM is highest during embryogenesis and in association with metaplastic or neoplastic changes, and lowest in mature epithelial tissues.…”

mentioning

confidence: 99%

Cellular and complement-dependent cytotoxicity of Ep-CAM-specific monoclonal antibody MT201 against breast cancer cell lines

Prang¹,

Preithner²,

Brischwein³

et al. 2005

Br J Cancer

130

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MT201 is a fully human monoclonal IgG1 antibody with moderate affinity for epithelial cell adhesion molecule (Ep-CAM) being clinically developed for the treatment of carcinomas. Like many other clinically validated IgG1 monoclonal antibodies, MT201 primarily acts by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Here, we analysed ADCC and CDC induced by MT201 and, as reference, trastuzumab against a panel of nine human breast cancer cell lines expressing distinct surface levels of Ep-CAM and human epithelial growth factor receptor type 2 antigen. Maximal cell lysis by ADCC by MT201 and trastuzumab in the presence of peripheral mononuclear cells did not significantly differ when averaged over the nine cell lines, but showed marked differences with respect to individual cell lines. The extent of cell lysis at intermediate surface target density was highly variable, suggesting a dominant influence of other susceptibility factors. Only one breast cancer cell line was eliminated via CDC, but only by MT201. Resistance to CDC appeared to correlate with high expression levels of complement resistance factors. Our present data as well as recent data on the prevalence and prognostic relevance of Ep-CAM expression in metastatic breast cancer suggest that Ep-CAM-specific monoclonal IgG1 antibodies may have a significant therapeutic potential in the treatment of breast cancer.

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“…This antigen is believed to be involved in homotypic calciumindependent cell-cell adhesion, as one of several classes of intercellular adhesion molecules [2]. Additional studies demonstrated Ep-CAM colocalization with the intracellular actin cytoskeleton, and also found that selective mutational analysis of the cytoplasmic domain resulted in lack of adhesion [3].…”

Section: Introductionmentioning

confidence: 96%

Genetic vaccines against Ep‐CAM break tolerance to self in a limited subset of subjects: Initial identification of predictive biomarkers

et al. 2006

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The epithelial cell adhesion molecule, Ep-CAM, has been historically considered a target of passive immunotherapy using monoclonal antibodies, and more recently, of a first Pox-vector-based cancer vaccine Phase I trial in colorectal cancer patients. To shed further light on the use of this antigen, we isolated the mouse and rhesus homologues of human Ep-CAM and explored different genetic vaccination modalities based on the use of adenoviral vectors as well as DNA electroporation (DNA-EP). Immune responses to Ep-CAM were measured by IFN-c ELISPOT and intracellular staining assays using overlapping sets of peptides covering the entire coding regions. We found the most powerful vaccination regimen to be constituted by DNA-EP-prime/Adeno-boost mixedmodality protocols. Vaccination in rhesus macaques resulted in breakage of immunological tolerance in a minority of cases. Similarly, a low frequency of responders was observed with the mouse Ep-CAM vaccine in outbred CD1 mice. When immunized CD1 mice were analyzed for MHC haplotype and TCR expression levels, we observed that immune responders all had the same q/q MHC class I haplotype and showed higher expression levels of the TCRVb4 and TCRVb8 T cell receptors. Our results underscore the current limitations in our capacity to induce efficient cancer vaccines against self antigens like Ep-CAM, but also represent a first effort to identify predictive biomarkers of response.See accompanying commentary: http://dx

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The biology of the 17–1A antigen (Ep-CAM)

Cited by 490 publications

References 59 publications

In vitro and in vivo activity of MT201, a fully human monoclonal antibody for pancarcinoma treatment

In vitro and in vivo activity of MT201, a fully human monoclonal antibody for pancarcinoma treatment

Cellular and complement-dependent cytotoxicity of Ep-CAM-specific monoclonal antibody MT201 against breast cancer cell lines

Genetic vaccines against Ep‐CAM break tolerance to self in a limited subset of subjects: Initial identification of predictive biomarkers

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