Concentrations of EpCAM ectodomain as found in sera of cancer patients do not significantly impact redirected lysis and T-cell activation by EpCAM/CD3-bispecific BiTE antibody MT110

Petsch, Silke; Gires, Olivier; Rüttinger, Dominik; Denzel, Sabine; Lippold, Sandra; Baeuerle, Patrick A.; Wolf, Andreas

doi:10.4161/mabs.3.1.14193

Cited by 26 publications

(32 citation statements)

References 25 publications

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“…In the physiological state, EpCAM is primarily expressed in the intercellular space of epithelial cells (except squamous epithelia), but is not expressed in other tissues such as connective tissue. However, EpCAM is widely expressed in various adenocarcinomas (Petsch et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Expression of EpCAM and Wnt/ β-catenin in human colon cancer

Zhou¹,

Qi²,

Xu³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aims of this study were to explore the correlation between the expression of EpCAM and the Wnt/β-catenin pathway in human colon cancer and its clinical significance for the evaluation of cancer prognosis. Samples from colon cancer, para-carcinoma, or benign intestinal tissue from individual patients (50) and from normal intestinal mucosal tissues (20) were obtained from the Pathology Department of the Shandong Province Binzhou People's Hospital (Shandong, China). Immunohistochemistry was used to detect the expression levels of EpCAM and β-catenin proteins in these tissues, and the prognoses of the patients from whom the samples were derived were determined on follow-up examination. The corresponding in vitro mechanistic siRNA experiments were subsequently performed in the human colon cancer cell line HCT116 to observe the regulatory effects of silencing EpCAM expression on the Wnt/β-catenin pathway. From these analyses, we determined that the expression levels of EpCAM and β-catenin were higher in cancer tissues compared with other tissues 4486©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 4485-4494 (2015) from the same patient, and that the expression of EpCAM and Wnt/β-catenin in colon cancers were positively correlated. The prognostic analysis showed an inverse correlation between EpCAM and Wnt/β-catenin expression and patient prognosis. A further examination of cellular mechanisms confirmed that the silencing of EpCAM led to decreased expression of Wnt/β-catenin, and thus reduced proliferation and increased the apoptosis ratio in the cells. These results suggest that suppression of EpCAM might be a new approach for treating colon cancer.

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Section: Discussionmentioning

confidence: 99%

Expression of EpCAM and Wnt/ β-catenin in human colon cancer

Zhou¹,

Qi²,

Xu³

et al. 2015

Genet. Mol. Res.

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“…Ten percent of the patients showed increased amounts of EpCAM protein (in the range of 2-78 ng/ml) in the blood. In contrast Petsch et al found detectable EpCAM in 17% of cancer patients, with concentrations one log scale lower than Abe [16].…”

Section: Discussionmentioning

confidence: 76%

“…Considering the large amount of literature on EpCAM, with more than hundred clinical studies published including several immunotherapeutic trials it is rather surprising that so far only three reports have dealt with the issue of circulating EpCAM protein in the serum and none analyzed the different protein isoforms [16][17][18].…”

Section: Discussionmentioning

confidence: 97%

“…Moreover, a splice variant called EpCAM-006 encodes a soluble form of the protein without its transmembrane region. Soluble forms of EpCAM can be detected in human plasma [12][13][14][15][16], which are a mix of shed extracellular EpCAM and the soluble protein encoded by the splice variant. However, relatively little is known about the significance of EpCAM levels in the blood [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Detection of circulating tumor-associated antigen depends on the domains recognized by the monoclonal antibodies used: N-terminal trimmed EpCAM-levels are much higher than untrimmed forms

Schmetzer¹,

Moldenhauer²,

Nicolaou³

et al. 2012

Immunology Letters

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“…Binding of tumor cells and T cells by BiTE antibody constructs results in the formation of a cytolytic synapse between tumor and T cells, which is followed by a release of pore-forming and pro-apoptotic components of cytotoxic T cell granules, mediating cancer cell death (5,7). The activation of T cells occurs only in the presence of a target cell (8). To date, 4 BiTE antibody constructs, blinatumomab, BAY2010112/AMG 212, MT111/AMG 211, and MT110/AMG 110, are or have been tested in clinical trials.…”

mentioning

confidence: 99%

Biodistribution and PET Imaging of Labeled Bispecific T Cell–Engaging Antibody Targeting EpCAM

et al. 2016

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AMG 110, a bispecific T cell engager (BiTE) antibody construct, induces T cell-mediated cancer cell death by cross-linking epithelial cell adhesion molecule (EpCAM) on tumor cells with a cluster of differentiation 3 ε (CD3ε) on T cells. We labeled AMG 110 with 89 Zr or nearinfrared fluorescent dye (IRDye) 800CW to study its tumor targeting and tissue distribution. Methods: Biodistribution and tumor uptake of 89 Zr-AMG 110 was studied up to 6 d after intravenous administration to nude BALB/c mice bearing high EpCAM-expressing HT-29 colorectal cancer xenografts. Tumor uptake of 89 Zr-AMG 110 was compared with uptake in head and neck squamous cell cancer FaDu (intermediate EpCAM) and promyelocytic leukemia HL60 (EpCAM-negative) xenografts. Intratumoral distribution in HT-29 tumors was studied using 800CW-AMG 110. Results: Tumor uptake of 89 Zr-AMG 110 can be clearly visualized using small-animal PET imaging up to 72 h after injection. The highest tumor uptake of 89 Zr-AMG 110 at the 40-μg dose level was observed at 6 and 24 h (respectively, 5.35 ± 0.22 and 5.30 ± 0.20 percentage injected dose per gram; n 5 3 and 4). Tumor uptake of 89 Zr-AMG 110 was EpCAM-specific and correlated with EpCAM expression. 800CW-AMG 110 accumulated at the tumor cell surface in viable EpCAM-expressing tumor tissue. Conclusion: PET and fluorescent imaging provided real-time information about AMG 110 distribution and tumor uptake in vivo. Our data support using 89 Zr and IRDye 800CW to evaluate tumor and tissue uptake kinetics of bispecific T cell engager antibody constructs in preclinical and clinical settings.

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Concentrations of EpCAM ectodomain as found in sera of cancer patients do not significantly impact redirected lysis and T-cell activation by EpCAM/CD3-bispecific BiTE antibody MT110

Cited by 26 publications

References 25 publications

Expression of EpCAM and Wnt/ β-catenin in human colon cancer

Expression of EpCAM and Wnt/ β-catenin in human colon cancer

Detection of circulating tumor-associated antigen depends on the domains recognized by the monoclonal antibodies used: N-terminal trimmed EpCAM-levels are much higher than untrimmed forms

Biodistribution and PET Imaging of Labeled Bispecific T Cell–Engaging Antibody Targeting EpCAM

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