Phase-I Clinical Trial of Monoclonal Antibody in Treatment of Gastrointestinal Tumours

Sears, Henry F.; Mattis, Jeffrey A.; Herlyn, Dorothee; Häyry, P; Atkinson, Barbara; Ernst, Carolyn S.; Steplewski, Zenon; Koprowski, Hilary

doi:10.1016/s0140-6736(82)91811-6

Cited by 308 publications

(113 citation statements)

References 11 publications

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“…Moreover, the first monoclonal antibody ever applied for human cancer therapy was murine mAb 17-1A recognising EpCAM (Sears et al, 1982(Sears et al, , 1984. In 1994, mAb17-1A (later named edrecolomab and Panorex s ) was also the first to show clinical efficacy in a human cancer indication in terms of prolonged overall survival (Riethmüller et al, 1994).…”

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confidence: 99%

EpCAM (CD326) finding its role in cancer

Baeuerle¹,

2007

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Although epithelial cell adhesion/activating molecule (EpCAM/CD326) is one of the first tumour-associated antigens identified, it has never received the same level of attention as other target proteins for therapy of cancer. It is also striking that ever since its discovery in the late 1970s the actual contribution of EpCAM to carcinogenesis remained unexplored until very recently. With a First International Symposium on EpCAM Biology and Clinical Application this is now changing. Key topics discussed at the meeting were the frequency and level of EpCAM expression on various cancers and its prognostic potential, the role of EpCAM as an oncogenic signalling molecule for cancer cells, recent progress on EpCAM-directed immunotherapeutic approaches in clinical development and the interaction of EpCAM with other proteins, which may provide a basis for a therapeutic window and repression of its growthpromoting signalling in carcinoma. Future research on EpCAM may benefit from a unified nomenclature and more frequent exchange among those who have been working on this cancer target during the past 30 years and will do so in the future.

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confidence: 99%

EpCAM (CD326) finding its role in cancer

Baeuerle¹,

2007

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“…7A and B). The HEK-EpC-cld-7 and HEK-cld-7 tumor -bearing mice developed a single, solid intraperitoneal Several clinical studies report on convincing therapeutic efficacy of EpC-specific antibodies, particularly with respect to a reduction in ascitic load (35,(39)(40)(41)(42)(43)(44). Hence, we finally asked whether coexpression of cld-7 alters the growth profile of EpC-expressing tumor cells and whether the therapeutic efficacy of EpC-specific antibodies correlates with the EpCcld-7 association.…”

Section: Mol Cancer Res 2009;7(3) March 2009mentioning

confidence: 99%

Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression

Nübel¹,

Preobraschenski²,

Tuncay³

et al. 2009

Molecular Cancer Research

110

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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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“…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.…”

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confidence: 99%

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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Phase-I Clinical Trial of Monoclonal Antibody in Treatment of Gastrointestinal Tumours

Cited by 308 publications

References 11 publications

EpCAM (CD326) finding its role in cancer

EpCAM (CD326) finding its role in cancer

Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression

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

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