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PubMedDate not supplied

Ex vivo evaluation of anti-EpCAM immunocytokine huKS-IL2 in ovarian cancer.

Despite encouraging responses to treatment, 70% to 80% of women with ovarian cancer will recur due to subclinical residual disease. One experimental agent that merits testing in this setting is the immunocytokine huKS-IL2. Immunocytokines are fusion proteins consisting of a humanized monoclonal antibody linked to IL-2 (or other cytokines). The humanized monoclonal antibody (mAb) huKS, which recognizes the epithelial cell adhesion molecule (EpCAM), has been used to construct the immunocytokine huKS-IL2. To determine the potential therapeutic use of huKS-IL2 in ovarian cancer, the authors evaluated the expression of EpCAM in these cancers and investigated the effects of huKS-IL2 on peritoneal white blood cells and peripheral blood mononuclear cells from women with ovarian cancer. EpCAM expression was determined by immunohistochemistry using both huKS-IL2 and the parent KS1/4 antibody. Ascites fluid was collected and the cellular fraction cultured with or without huKS-IL2 to evaluate the cellular content and potential anti-tumor effects of the peritoneal effector cells (PECs). Peritoneal cells were incubated with FITC-conjugated KS antibody to determine the relative amount of EpCAM-positive cells. Nonadherent cells were analyzed by flow cytometry for hematopoietic origin with CD45 mAb and for CD69 expression as an indication of immune cell activation. EpCAM-positive NIH:OVCAR-3 cells were radiolabeled as targets in a chromium release assay with either PECs or PBMCs as effector cells in the presence or absence of 0.25 mcg/mL huKS-IL2. Differences between treatments were determined by t test. Thirty-two of thirty-three (97%) ovarian cancers were found to express EpCAM via immunohistochemistry. Eleven cases were stained using both KS1/4 and huKS-IL2, and identical patterns of staining were seen. All ascites samples tested had EpCAM-positive cells by flow cytometry. The mean fluorescence intensity of CD69 expression on peritoneal WBCs was increased from 20.7 to 43.9 as a result of culturing with huKS-IL2, indicating effector cell activation. In chromium release assays, KS-IL2 facilitated cell lysis of NIH:OVCAR-3 by PBMCs from both healthy controls and patients with ovarian cancer. PECs from all cases tested showed significant cell lysis induced by huKS-IL2 compared with untreated control cultures. Based on these findings, huKS-IL2 warrants further investigation as a potential immunotherapy for patients with epithelial ovarian cancer, preferably in a minimal disease setting as seen after complete cytoreductive surgery, after a complete clinical response to primary therapy, or when elevated CA-125 levels predict recurrent disease prior to clinical relapse.

Antibodies, Monoclonal↗
PubMed2006

Expression of EpCAM in uveal melanoma.

BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, and nearly 40% of UM will develop metastasis that will ultimately lead to death. The Epithelial Cell Adhesion Molecule (EpCAM) is a type I transmembrane glycoprotein expressed by carcinomas of head and neck, ovary, colon, breast, kidney and lung. Recently, antibodies against EpCAM such as Edrecolomab and Catumaxomab were developed, and clinical trials with these antibodies have been used in several types of neoplasia. We studied the expression of EpCAM in UM. METHODS: 25 enucleated formalin-fixed, paraffin-embedded UM specimens were immunostained for EpCAM. Histopathological analysis of the specimens with regards to prognostic factors such as cell type, largest (linear) tumor dimension, number of mitotic figures, scleral invasion and tumor infiltrating lymphocytes were done. RESULTS: None of them was positive for this EpCAM. CONCLUSION: In our report, UM did not express EpCAM. Therefore, it is not a helpful immunohistochemical marker to predict the behavior of UM. Further studies are needed to verify if EpCAM could also be related with prognosis and treatment of UM.

Journal Article↗
PubMed2001

Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors.

Application of recombinant adenoviral vectors for cancer gene therapy is currently limited due to lack of specificity for tumor cells. For gastric and esophageal adenocarcinoma, we present here that the relative abundant expression of the primary adenovirus receptor, coxsackie/adenovirus receptor (CAR), on normal epithelium compared to carcinoma favors the transduction of the epithelium. As such, to achieve specific transduction of cancer cells, targeting approaches are required that ablate the binding of the virus to CAR and redirect the virus to tumor-specific receptors. By immunohistochemistry and reverse transcriptase polymerase chain reaction assays, we demonstrate a marked difference in expression of the human epithelial cell adhesion molecule (EpCAM) between normal and (pre)malignant lesions of the stomach and esophagus. Based on this, we explored the feasibility of using EpCAM to achieve gastric and esophageal adenocarcinoma selective gene transfer. Adenoviral vectors redirected to EpCAM using bispecific antibodies against the adenovirus fiber-knob protein and EpCAM specifically infected gastric and esophageal cancer cell lines. Using primary human cells, an improved ratio of tumor transduction over normal epithelium transduction was accomplished by the EpCAM-targeted vectors. This study thus indicates that EpCAM-targeted adenoviral vectors may be useful for gastric and esophageal cancer-specific gene therapy in patients.

Adenocarcinoma↗
PubMedDate not supplied

EpCAM overexpression in thyroid carcinomas: a histopathological study of 121 cases.

Epithelial cell adhesion molecule (EpCAM) is expressed by a broad variety of carcinoma cells. It is recognized by the monoclonal antibody 17-1A, which has already been applied for immunotherapy of several carcinoma types in preclinical and small clinical studies. In the present study the immunohistochemical properties of 17-1A were evaluated in 121 cases of thyroid carcinomas of follicular cell origin, comprising of 75 differentiated (DTC; 35 papillary and 40 follicular carcinomas), 24 poorly differentiated (PDTC) and 22 anaplastic thyroid carcinomas. Overexpression of EpCAM, as recently defined, was found with a distinct membranous staining pattern in 81.3% of DTCs and in 66.6% of PDTCs. In contrast, all anaplastic thyroid carcinomas (0%) completely lacked EpCAM expression. Normal thyroid tissue presented with weak and heterogeneous EpCAM staining. This study demonstrates EpCAM overexpression as a common finding in DTCs and PDTCs, and thus these tumors as possible novel targets for EpCAM-directed immunotherapy. Our findings suggest that patients with recurrent or advanced tumor disease and metastatic spread could benefit from this modern therapeutic regime, especially after insufficient radioiodine therapy.

Adenocarcinoma, Follicular↗
PubMed2006

EpCAM and gpA33 are markers of Barrett's metaplasia.

AIMS: To characterise a specific and sensitive marker of Barrett's metaplasia (BM). METHODS: Cases of normal oesophageal squamous mucosa (11 fresh endoscopic biopsies and 10 formalin fixed, paraffin embedded tissue blocks), BM (11 biopsies and 11 tissue blocks), and normal gastric body mucosa (five biopsies and five tissue blocks) were analysed using reverse transcriptase PCR, Western blotting, and immunohistochemistry for EpCAM, and reverse transcriptase PCR for gpA33. RESULTS: Strong EpCAM mRNA expression was detected in all the BM cases, in contrast to weak expression in all the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Strong gpA33 mRNA expression was detected in all the BM cases, in contrast to weak expression in a quarter of the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Western blotting showed EpCAM protein expression in all the BM cases and in none of the normal gastric or oesophageal mucosal samples tested. Immunohistochemistry showed strong EpCAM protein expression in BM and complete absence of expression in normal oesophageal squamous epithelium. Scattered EpCAM expressing cells were found in the gland bases of normal gastric body mucosa. CONCLUSIONS: EpCAM protein and gpA33 mRNA expressions are specific and sensitive markers of BM.

Antigens, Neoplasm↗
PubMedDate not supplied

EpCAM: A new therapeutic target for an old cancer antigen.

The use of monoclonal antibodies as adjuvants to cancer chemotherapy has drawn considerable interest in recent years, due to the success of several novel agents against a broad range of targets. One such target is EpCAM (aka GA733-2, KSA, 17-1A antigen), a human cell surface glycoprotein expressed on some normal and most neoplastic epithelial cells. It is now widely recognized as having an important role in tumor biology, especially in colorectal cancer, and since its original discovery in the early 1980s, the known mechanism by which it functions has steadily evolved. Initial studies of monoclonal antibodies directed against EpCAM demonstrated the presence of anti-idiotype networks involving both B and T cells, antibody-dependent cell cytotoxicity, and complement mediated cell death as mechanisms of tumor growth inhibition. Recently, a novel receptor for EpCAM has been described that is a member of the inhibitory group of immunoglobulin-like receptors and is present on lymphocytes, monocytes, dendritic cells, and NK cells. Neoplastic cells that interact with this receptor, named LAIR-1, may enact an immunologic escape, and thus confer a selective advantage for their growth and spread. This novel mechanism of action may add to our current understanding of how monoclonal antibodies targeted against EpCAM inhibit tumor growth. Passive vaccination with this antibody may induce a tertiary anti-idiotypic network which correlates with clinical outcome, but the mechanism behind this outcome in select patients with minimal residual disease may additionally involve a novel blockade of tumor specific immunosuppression. This review will focus on the initial discoveries of EpCAM's cellular adhesion properties, its role in normal and neoplastic cell function, its distribution and presumed mechanism of action, and clinical studies of EpCAM as a therapeutic target. Clinical trials of edrecolomab, one such monoclonal antibody, in patients with colon cancer will be reviewed and updated. While phase III trials of edrecolomab have not demonstrated improved efficacy as adjuvant therapy for stage III colon cancer, newer agents with improved affinity, less chimerism, and improved delivery may still demonstrate benefit.

Antibodies, Monoclonal↗
PubMed2005

The cell-cell adhesion molecule EpCAM interacts directly with the tight junction protein claudin-7.

We recently described that in the metastasizing rat pancreatic carcinoma line BSp73ASML the cell-cell adhesion molecule EpCAM, CD44 variant isoforms and the tetraspanins D6.1A and CD9 form a complex that is located in glycolipid-enriched membrane microdomains. This complex contains, in addition, an undefined 20 kDa protein. As such complex formation influenced cell-cell adhesion and apoptosis resistance, it became of interest to identify the 20 kDa polypeptide. This 20 kDa protein, which co-precipitated with EpCAM in BSp73ASML lysates, was identified as the tight junction protein claudin-7. Correspondingly, an association between EpCAM and claudin-7 was noted in rat and human tumors and in non-transformed tissues of the gastrointestinal tract. Co-localization of the two molecules was most pronounced at basolateral membranes, but was also observed in tight junctions. Evidence for direct protein-protein interactions between EpCAM and claudin-7 was obtained by co-immunoprecipitation after treatment of tumor cells with a membrane-permeable chemical cross-linker. The complex, which is located in glycolipid-enriched membrane microdomains, is not disrupted by partial cholesterol depletion, but claudin-7 phosphorylation is restricted to the localization in glycolipid-enriched membrane microdomains. This is the first report on an association between EpCAM and claudins in both non-transformed tissues and metastasizing tumor cell lines.

Animals↗
PubMed2004

CD44 variant isoforms associate with tetraspanins and EpCAM.

The metastasizing subline of the rat pancreatic adenocarcinoma BSp73 expresses a set of membrane molecules, the combination of which has not been detected on non-metastasizing tumor lines. Hence, it became of interest whether these molecules function independently or may associate and exert specialized functions as membrane complexes. Separation of CD44v4-v7 containing membrane complexes in mild detergent revealed an association with the alpha3 integrin, annexin I, EpCAM, and the tetraspanins D6.1A and CD9. EpCAM and the tetraspanins associate selectively with CD44 variant (CD44v), but not with the CD44 standard (CD44s) isoform. The complexes are found in glycolipid-enriched membrane (GEM) microdomains, which are dissolved by stringent detergents, but the complexes are not destroyed by methyl-beta-cyclodextrin (MbetaCD) treatment, which implies that complex formation does not depend on a lipid-rich microenvironment. However, a complex-associated impact on cell-matrix and cell-cell adhesion as well as on resistance towards apoptosis essentially depended on the location in GEMs. Thus, CD44v-specific functions may well be brought about by complex formation of CD44v with EpCAM, the tetraspanins, and the alpha3 integrin. Because CD44v4-v7-EpCAM complex-specific functions strictly depended on the GEM localization, linker or signal-transducing molecules associating with the complex are likely located in GEMs.

Adenocarcinoma↗
PubMed2004

Opsonization with a trifunctional bispecific (alphaCD3 x alphaEpCAM) antibody results in efficient lysis in vitro and in vivo of EpCAM positive tumor cells by cytotoxic T lymphocytes.

Removab is a trifunctional bispecific antibody which can bridge CD3+ T cells and epithelial cell adhesion molecule positive (EpCAM+) tumor cells, and binds with its Fc fragment to antigen presenting cells. To explore a new approach for the treatment of patients with carcinoma of the upper aerodigestive tract, we investigated whether Removab can induce specific cellular responses to the EpCAM+ carcinoma cell line BHY. Particular emphasis was put on the opsonization of peripheral blood mononuclear cells (PBMN) with respect to clinical application. Tumor cells and allogeneic PBMN of healthy volunteers were incubated with or without Removab. In a third group, PBMN were opsonized with Removab and washed before incubation with tumor cells. Inverse microscopy, ELISPOT, flow cytometry analysis and cytotoxicity assays on the chorioallantois membrane (CAM) were performed. In comparison with PBMN alone, opsonization with Removab resulted in: a) activation of CD83+ antigen presenting cells, b) secretion of interferon gamma, and c) granzyme B mediated lysis of targeted BHY cells by EpCAM specific CD8+ T cells. The secretion of tumor necrosis factor alpha, interferon gamma and interleukin-2 by opsonized PBMN was significantly reduced after 24 h. Washed opsonized PBMN maintained their lytic activity against tumor cells as tested on the CAM. Removab is an appropriate agent for the therapeutic amplification of T cell responses against EpCAM+ tumor cells by opsonization of PBMN without putting patients at risk for severe adverse events caused by a cytokine storm.

Antibodies, Bispecific↗
PubMed2003

Naturally occurring antibodies to epithelial cell adhesion molecule (EpCAM).

Epithelial cell adhesion molecule (Ep-CAM) is an epithelial tumor-associated antigen that is expressed by a number of normal tissues and has been used as a target in many immunotherapy studies. The purpose of this study was to determine the incidence of serum anti-EpCAM IgG (immunoglobulin G) antibodies in colon cancer and tumor-free patients and to assess the tumor protective value of anti-EpCAM antibodies. One third of both the cancer (16/48) and the control (9/27) patients had detectable antibodies. Although the mean antibody concentration was higher in cancer patients (0.048 +/- 0.120 U) than in controls (0.038 +/- 0.064 U) the difference was not statistically significant. Western blot analysis revealed reactivity to multiple HT29 cell proteins including a 40-kDa protein (presumed to be Ep-CAM). Monoclonal anti-EpCAM 323/A3 antibody did not have a tumor-protective effect in murine Ep-CAM expressing colocarcinoma. We conclude that Ep-CAM is immunogenic not only for cancer patients, but also for tumor-free individuals.

Adenocarcinoma↗
PubMed2005

Adenoviral vector-mediated expression of a gene encoding secreted, EpCAM-targeted carboxylesterase-2 sensitises colon cancer spheroids to CPT-11.

CPT-11 (irinotecan or 7-ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is an anticancer agent in use for the treatment of colon cancer. In order to be fully active, CPT-11 needs to be converted into SN-38 (7-ethyl-10-hydroxycamptothecin) by the enzyme carboxylesterase (CE). In humans, only a minority of CPT-11 is converted to SN-38. To increase the antitumour effect of CPT-11 by gene-directed enzyme prodrug therapy, we constructed a replication-deficient adenoviral vector Ad.C28-sCE2 containing a fusion gene encoding a secreted form of human liver CE2 targeted to the surface antigen epithelial cell adhesion molecule (EpCAM) that is highly expressed on most colon carcinoma cells. By targeting CE2 to EpCAM, the enzyme should accumulate specifically in tumours and leakage into the circulation should be minimised. Ad.C28-sCE2-transduced colon carcinoma cells expressed and secreted active CE that bound specifically to EpCAM-expressing cells. In sections of three-dimensional colon carcinoma spheroids transduced with Ad.C28-sCE2, it was shown that C28-sCE2 was capable of binding untransduced cells. Most importantly, treatment of these spheroids with nontoxic concentrations of CPT-11 resulted in growth inhibition comparable to treatment with SN-38. Therefore, Ad.C28-sCE2 holds promise in gene therapy approaches for the treatment of colon carcinoma.

Adenoviridae↗
PubMed2001

Lysis of prostate carcinoma cells by trifunctional bispecific antibodies (alpha EpCAM x alpha CD3).

Bispecific monoclonal antibodies (bsAbs) are a promising immunotherapeutic option for treatment of cancer, especially in situations of minimal residual disease. The combination of an anti-CD3 and anti-tumor-associated antigen antibody redirects cytotoxic T-lymphocytes towards malignant cells. Using a trifunctional bispecific antibody against EpCAM x CD3, that additionally activates Fc gamma R(+) accessory cells via its Fc region, we investigated the interaction between three EpCAM(+) prostate carcinoma cell lines and peripheral blood mononuclear cells (PBMCs) of healthy donors and patients with prostate carcinoma (PC). Visualization was performed by double immunocytochemical methods and computerized sequential video microscopy. Tumor cells and PBMCs supplemented with alpha EpCAM x alpha CD3 in 16-well chamber slides resulted in lysis of tumor cells within 1--3 days without any differences between patient and healthy donor PBMCs. The characteristic necrotic way of tumor cell killing (rounding, swelling, disrupting) could be observed in computerized sequences of video frames. Simultaneously, we could not reveal any form of apoptotic signal using three different apoptotic markers (TUNEL, M30 cyto death, anti-active caspase 3). Within the first 48 hr we observed typical PBMC cluster formation with increasing cell proliferation. PBMCs surrounding the tumor cells were not dominated by CD4(+), CD8(+), or CD14(+) cells. Lymphocytes with pore-forming perforin proteins concentrated towards the tumor target cells. Our combination of double immunocytochemical and computerized video microscopic techniques may serve as an important improvement of validity of cell-cell interaction experiments using in vitro models. (J Histochem Cytochem 49:911-917, 2001)

Antibodies, Bispecific↗
PubMed2000

A bispecific single-chain antibody directed against EpCAM/CD3 in combination with the cytokines interferon alpha and interleukin-2 efficiently retargets T and CD3+CD56+ natural-killer-like T lymphocytes to EpCAM-expressing tumor cells.

Cytokine-induced killer cells (CIK), generated in vitro from peripheral blood mononuclear cells (PBMC) by addition of interferon gamma (IFNgamma), interleukin-2 (IL-2), IL-1 and a monoclonal antibody (mAb) against CD3, are highly efficient cytotoxic effector cells with the CD3+CD56+ phenotype. In this study, we evaluated whether the cytotoxicity of these natural-killer-like T lymphocytes against the colorectal tumor cell line HT29 can be enhanced by the addition of a bispecific single-chain antibody (bsAb) directed against EpCAM/CD3. For determination of bsAb-redirected cellular cytotoxicity we used a new flow-cytometric assay, which directly counts viable tumor cells and can assess long-term cytotoxicity. We found that this bsAb induced distinct cytotoxicity at a concentration above 100 ng/ml with both PBMC and CIK at an effector-to-target cell ratio as low as 1:1. CIK cells revealed higher bsAb-redirected cytotoxicity than PBMC. Cellular cytotoxicity appeared after 24 h whereas PBMC showed the highest bsAb-redirected cytotoxicity after 72 h. The addition of the cytokines IL-2 and IFNalpha but not granulocyte/macrophage-colony-stimulating factor enhanced bsAb-redirected cytotoxicity of both PBMC and CIK. When the bsAb was combined with the murine mAb BR55-2, which recognizes the Lewis(Y) antigen, bsAb-redirected cytotoxicity was partly augmented, whereas murine mAb 17-1A, which binds to EpCAM as well, slightly suppressed bsAb-redirected cytotoxicity induced by the bsAb. We conclude that CIK generated in vitro or in vivo combined with this new EpCAM/CD3 bsAb and the cytokine IL-2 should be evaluated for the treatment of EpCAM-expressing tumors.

Animals↗
PubMed2006

Exchanging human Fcgamma1 with murine Fcgamma2a highly potentiates anti-tumor activity of anti-EpCAM antibody adecatumumab in a syngeneic mouse lung metastasis model.

An important mode of action shared by human IgG1 antibody therapies is antibody-dependent cellular cytotoxicity (ADCC). ADCC relies on the interaction of the antibody's Fc portion with Fc-gama receptors (FcgammaR) on immune effector cells. The anti-tumor activity of human IgG1 antibodies is frequently assessed in mouse models. Binding of human IgG1 to murine FcgammaRs is however of reduced affinity. We here show that ADCC of adecatumumab (MT201), a fully human IgG1 antibody specific for epithelial cell adhesion molecule (EpCAM/CD326), is drastically lower if human peripheral blood mononuclear cells are replaced by murine splenocytes as effector cells. When the variable domains of adecatumumab were genetically fused to a murine IgG2a backbone (yielding mu-adecatumumab), ADCC with murine effector cells was much improved, but at the same time significantly reduced with human effector cells. The serum half-lives of adecatumumab and mu-adecatumumab were determined in mice and dosing schedules established that gave similar serum trough levels during a 4-week antibody treatment. The anti-tumor activities of adecatumumab and mu-adecatumumab were then compared side-by-side in a lung metastasis mouse model established with a syngeneic B16 melanoma line expressing human EpCAM at physiologically relevant levels. Treatment of mice with mu-adecatumumab led to an almost complete prevention of lung metastases, while the human version of the antibody was much less active. This shows that adecatumumab has high anti-tumor activity when tested in a form that is better compatible with the species' immune system. Moreover, our data suggest to routinely compare in mouse models human IgG1 and murine IgG2a versions of antibodies to properly assess the contribution of ADCC to overall anti-tumor activity.

Animals↗
PubMed2006

Drug evaluation: IGN-101--an anti-EpCAM murine antibody vaccine for cancer.

Igeneon GmbH, a wholly owned subsidiary of Aphton Corp, is developing IGN-101, an anticancer vaccine containing the EpCAM-targeting aluminum-adsorbed munrine monoclonal antibody 17-1A (edrecolomab), for the potential subcutaneous treatment of epithelial cancers such as colorectal and rectal tumors. By February 2004, Igeneon was seeking to outlicense the drug.

Animals↗
PubMed2004

Anti-EpCAM monoclonal antibody (MAb17-1A) based treatment combined with alpha-interferon, 5-fluorouracil and granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal carcinoma.

Monoclonal antibodies (MAbs) have different modes of action and toxicity profile compared to chemotherapeutics, which makes it interesting to combine these drugs. Addition of cytokines to MAb therapy may also augment immune effector functions utilized by MAb. In an effort to improve the therapeutic effect of a MAb-based regimen in colorectal carcinoma (CRC) patients, the effects of a combination of alpha-interferon (alpha-IFN), 5-fluorouracil (5-FU), granulocyte-macrophage colony-stimulating factor (GM-CSF) and mouse MAb17-1A was evaluated in 27 patients with metastatic disease. alpha-IFN was given s.c. once daily for 5 consecutive days and at days 4 and 5, 5-FU was administered as a daily i.v. bolus injection. After 2 days rest, GM-CSF was given s.c. once daily, days 8-14 and on day 10, MAb17-1A was given i.v. The treatment cycle was repeated every 4th week. One patient achieved a partial remission and 13 patients showed a minor response or stable disease >3 months, inducing an overall response rate of 54%. Responding patients survived significantly longer than non-responding patients (p=0.021). Median overall survival time for all patients was 75 weeks and progression-free survival time 15 weeks. Adverse events related to alpha-IFN, GM-CSF and 5-FU were as expected. The frequency of patients with an immediate-type allergic reaction (ITAR) against MAb17-1A at the 1st, 2nd, 3rd and 4th treatment cycles was 11%, 52%, 62% and 64% respectively. The planned MAb17-1A dose had to be reduced by repeated infusions. No patient received full dose of MAb17-1A from the 3rd cycle and onward. Compared to historical control patients treated with MAb17-1A alone, the present combination regimen seemed to improve the response rate (54% vs 15%) as well as progression-free survival (15 vs 7 weeks; p<0.05).

Adult↗