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

Ladwein, Markus; Pape, Ulrich Frank; Schmidt, Daniel; Schnölzer, Martina; Fiedler, Sabine; Langbein, Lutz; Franke, Werner W.; Moldenhauer, Gerhard; Zöller, Margot

doi:10.1016/j.yexcr.2005.06.013

Cited by 142 publications

(149 citation statements)

References 72 publications

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“…The underlying mechanisms have not been fully uncovered. We noted that EpC can associate with cld-7 (14,34). Notably, EpC and cld-7 also display striking colocalization in hepatic progenitor cells with repopulating capacity (40).…”

Section: Discussionmentioning

confidence: 67%

“…Coimmunoprecipitation of EpC and cld-7 is only observed with a membrane-permeable cross-linker (34). The finding suggests that the extracellular domain may not be involved.…”

Section: The Transmembrane Domain Of Epc Is Decisive For Complex Formmentioning

confidence: 88%

“…In the metastatic BSp73ASML subline, EpC is associated with claudin-7 (cld-7), CD44v, several integrins, and the tetraspanin D6.1A (33)(34)(35), where only the EpC-cld-7 association is based on a direct protein-protein interaction (14,34). Tetraspanins are located in glycolipid-enriched membrane microdomains (14,34), called tetraspanin-enriched membrane microdomains (TEM), which serve as a signaling platform (36,37). According to its association with tetraspanins, the EpC-cld-7 complex is supposed to be TEM located.…”

Section: Introductionmentioning

confidence: 99%

“…According to its association with tetraspanins, the EpC-cld-7 complex is supposed to be TEM located. In fact, there is evidence for cooperative activity of the EpC-cld-7-CD44v-tetraspanin complex (14,33,34). Matrix adhesion and cluster formation of tumor cells expressing the complex, but not the individual molecules, is reduced after partial cholesterol depletion, which destroys TEM.…”

Section: Introductionmentioning

confidence: 99%

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Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression

Nübel¹,

Preobraschenski²,

Tuncay³

et al. 2009

Molecular Cancer Research

104

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EpCAM has been described as a therapeutically relevant tumor marker. We noted an interaction between EpCAM and the tight junction protein claudin-7 and here explored the nature of this interaction and its effect on EpCAM-mediated functions. The interaction between EpCAM and claudin-7 was defined in HEK293 cells transfected with rat claudin-7 and EpCAM cDNA. Deletions of the epidermal growth factor -like and the thyroglobin repeat domains of EpCAM or the cytoplasmic domain of EpCAM or claudin-7 did not prevent the EpCAM-claudin-7 association. A chimeric EpCAM molecule with an exchange of the cytoplasmic and transmembrane domains and an EpCAM molecule with point mutations in an AxxxG motif in the transmembrane region do not associate with claudin-7. HEK cells and the rat pancreatic tumor line BSp73AS, transfected with (mutated) EpCAM and claudin-7 cDNA, revealed that the association of both molecules severely alters the functional activity of EpCAM. Claudin-7 -associated

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Section: Discussionmentioning

confidence: 67%

“…Coimmunoprecipitation of EpC and cld-7 is only observed with a membrane-permeable cross-linker (34). The finding suggests that the extracellular domain may not be involved.…”

Section: The Transmembrane Domain Of Epc Is Decisive For Complex Formmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression

Nübel¹,

Preobraschenski²,

Tuncay³

et al. 2009

Molecular Cancer Research

104

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“…1-4 Although EpCAM can be detected on the basolateral membrane of various normal epithelial tissues, including colon, small intestine, and hepatoblasts, 5 , 6 it is believed to be less accessible to traditional antibody constructs due to sequestration within tight cellular junctions. 7 , 8 The univalent EpCAM antibodies edrecolomab and adecatumumab have shown modest single-agent activity in the treatment of colon, prostate, and breast cancer. 9-11 …”

Section: Introductionmentioning

confidence: 99%

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

Kebenko

Goebeler

Wolf³

et al. 2018

OncoImmunology

119

106

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We assessed the tolerability and antitumor activity of solitomab, a bispecific T-cell engager (BiTE®) antibody construct targeting epithelial cell adhesion molecule (EpCAM). Patients with relapsed/refractory solid tumors not amenable to standard therapy received solitomab as continuous IV infusion in a phase 1 dose-escalation study with six different dosing schedules. The primary endpoint was frequency and severity of adverse events (AEs). Secondary endpoints included pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. Sixty-five patients received solitomab at doses between 1 and 96 µg/day for ≥28 days. Fifteen patients had dose-limiting toxicities (DLTs): eight had transient abnormal liver parameters shortly after infusion start or dose escalation (grade 3, n = 4; grade 4, n = 4), and one had supraventricular tachycardia (grade 3); all events resolved with solitomab discontinuation. Six patients had a DLT of diarrhea: four events resolved (grade 3, n = 3; grade 4, n = 1), one (grade 3) was ongoing at the time of treatment-unrelated death, and one (grade 3) progressed to grade 5 after solitomab discontinuation. The maximum tolerated dose was 24 µg/day. Overall, 95% of patients had grade ≥3 treatment-related AEs, primarily diarrhea, elevated liver parameters, and elevated lipase. Solitomab half-life was 4.5 hours; serum levels plateaued within 24 hours. One unconfirmed partial response was observed. In this study of a BiTE® antibody construct targeting solid tumors, treatment of relapsed/refractory EpCAM-positive solid tumors with solitomab was associated with DLTs, including severe diarrhea and increased liver enzymes, which precluded dose escalation to potentially therapeutic levels.

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Antibodies in Phase I/II/III: Cancer Therapy

Deckert¹

2007

Handbook of Therapeutic Antibodies

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

Cited by 142 publications

References 72 publications

Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression

Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

Antibodies in Phase I/II/III: Cancer Therapy

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