Epidermal Growth Factor-Like Repeats Mediate Lateral and Reciprocal Interactions of Ep-CAM Molecules in Homophilic Adhesions

Balzar, Maarten; Bruijn, IH Briaire-De; Rees-Bakker, Ham; Prins, F.; Helfrich, Wijnand; Leij, de Louis; Riethmüller, Gert; Alberti, Saverio; Warnaar, SO; Fleuren, Gj; Litvinov, Sergey V.

doi:10.1128/mcb.21.7.2570-2580.2001

Cited by 160 publications

(167 citation statements)

References 43 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: 86%

“…For 323/A3 and edrecolomab, the subdomain of Ep-CAM was previously determined to be the immunodominant, outer EGF-like domain I. 24 Because both M79 and 323/A3 did compete efficiently with all other antibodies, it appears they recognized epitopes on the same Ep-CAM subdomain that are overlapping with those recognized by MT201 and edrecolomab. Within this Ep-CAM subdomain, MT201 and edrecolomab apparently recognized the most distant epitopes, as was evident from their weakest cross-competition among the 4 anti-Ep-CAM mAbs tested.…”

Section: Epitope Recognition Of Mt201 Relative To Other Anti-ep-cam Mabsmentioning

confidence: 99%

“…20 -22 Conjugates of other Ep-CAM antibodies with toxins also showed significant side effects as is expected for antibodies attacking epithelia. 23 Edrecolomab and 3622W94 were reported to bind the same subdomain of Ep-CAM, 24 suggesting that affinity and not epitope recognition was responsible for the difference in tolerability. A drawback of edrecolomab for human therapy is its murine nature, resulting in a neutralizing immune response, short serum half-life, no option for chronic treatment and reduced compatibility with human immune effector mechanisms.…”

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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: 86%

Section: Epitope Recognition Of Mt201 Relative To Other Anti-ep-cam Mabsmentioning

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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“…The exact function of these domains is still unclear, but they have been reported, e.g. to mediate homophilic and heterophilic protein-protein interactions [19,20]. Recently, a similar domain in a homologous molecule Stabilin-2 has been shown to play a key role in the clearance of aged and apoptotic cells through recognition of the exposed phosphatidyl serine (PS) on the cell surface [21].…”

Section: Discussionmentioning

confidence: 99%

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

et al. 2009

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Clever-1/Stabilin-1 is a scavenger receptor present on lymphatic and sinusoidal endothelium as well as on a subset of type II macrophages. It is also induced on vasculature at sites of inflammation. However, its in vivo function has remained practically unknown and this work addresses those unknown aspects. We demonstrate using in vivo models that Clever-1/Stabilin-1 mediates migration of T and B lymphocytes to the draining lymph nodes in vivo and identify the adhesive epitope of the Clever-1/Stabilin-1 molecule responsible for the interaction between lymphocytes and lymphatic endothelium. Moreover, we demonstrate that Ab blocking of Clever-1/Stabilin-1 efficiently inhibits peritonitis in mice by decreasing the entrance of granulocytes by 50%, while migration of monocytes and lymphocytes into the inflamed peritoneum is prevented almost completely. Despite efficient anti-inflammatory activity the Ab therapy does not dramatically dampen immune responses against the bacterial and foreign protein Ag tested and bacterial clearance. These results indicate that anti-Clever-1/Stabilin-1 treatment can target two different arms of the vasculature -traffic via lymphatics and inflamed blood vessels. IntroductionImmune cell trafficking between blood and lymphoid organs is an essential element in the proper functioning of the immune system. The mechanisms mediating lymphocyte entrance from the blood into the lymphoid organs and leukocyte trafficking to sites of inflammation are well known [1][2][3]. In contrast, mechanisms involved in lymphocyte migration from the periphery via the afferent lymphatics into the draining lymph nodes and their exit from the lymph nodes are poorly known. Besides lymphocytes, many tumors also use lymphatics for dissemination to distant sites of the body [4]. Eur. J. Immunol. 2009. 39: 3477-3487 DOI 10.1002 Innate immunity 3477Clever-1/Stabilin-1, also known as Feel-1, is a multifunctional molecule possessing scavenging ability on a subset of type II macrophages [5,6]. It is also present both on afferent and efferent lymphatic endothelial cells and sinusoidal endothelial cells in the liver and spleen [7][8][9][10]. In man, it is brightly expressed on high endothelial venules (HEV), which are the specific vessels within organized lymphatic tissues mediating lymphocyte entrance into the tissues, and on sinusoidal macrophages. Moreover, at sites of inflammation its expression is induced in flat-walled vessels. On lymphatic vasculature it is able to bind lymphocytes and certain tumor cells and on inflamed blood vessel endothelium it can mediate adhesion of lymphocytes, granulocytes and monocytes [8,11]. In vitro analyses have indicated it to be important in the transmigration step during the leukocyte extravasation process [12].Clever-1/Stabilin-1 is involved in two intracellular trafficking pathways, namely in receptor mediated endocytosis and recycling as well as in shuttling between endosomal compartment and trans-Golgi network. These complex mechanisms require interactions with several molecules ...

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“…Expression of Ep-CAM in human adult tissues is largely restricted to epithelial cells, with a few exceptions such as squamous epithelium and some epithelium-derived cells such as hepatocytes [1]. 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: 99%

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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Epidermal Growth Factor-Like Repeats Mediate Lateral and Reciprocal Interactions of Ep-CAM Molecules in Homophilic Adhesions

Cited by 160 publications

References 43 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

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

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

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