Isolation and characterization of 5T4, a tumour‐associated antigen

Hole, Nicholas; Stern, Peter L.

doi:10.1002/ijc.2910450132

Cited by 61 publications

(53 citation statements)

References 40 publications

(43 reference statements)

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“…Primary antibodies were as follows: mouse anti-human E-cadherin (1:100 dilution; Invitrogen); rabbit anti-N-cadherin (1:100 dilution, Santa Cruz Biotechnology), mouse anti-human 5T4 (1 Ag/mL; ref. 41) and incubated for 1 h on ice. Cells were washed once in 900 AL of PBS, resuspended in 100 AL of fluorescence-activated cell sorting buffer containing appropriate phycoerythrin-conjugated secondary antibody (all 1:100 dilution; Santa Cruz Biotechnology), and incubated for 30 min on ice.…”

Section: Methodsmentioning

confidence: 99%

Epithelial-Mesenchymal Transition Events during Human Embryonic Stem Cell Differentiation

et al. 2007

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Epithelial-mesenchymal transition (EMT) occurs during embryonic development and may also be associated with the metastatic spread of epithelial tumors. During EMT, E-cadherin is down-regulated and this correlates with increased motility and invasion of cells. We show that differentiation of human embryonic stem (ES) cells in monolayer culture is associated with an E-to N-cadherin switch, increased vimentin expression, up-regulation of E-cadherin repressor molecules (Snail and Slug proteins), and increased gelatinase (matrix metalloproteinases; MMP-2 and MMP-9) activity and cellular motility, all characteristic EMT events. The 5T4 oncofetal antigen, previously shown to be associated with early human ES cell differentiation, is also part of this process. Abrogation of E-cadherin-mediated cellcell contact in undifferentiated ES cells using neutralizing antibody (nAb) SHE78.7 resulted in increased cellular motility, altered actin cytoskeleton arrangement and a mesenchymal phenotype together with presentation of the 5T4 antigen at the cell surface. nAb-treated ES cells remained in an undifferentiated state, as assessed by OCT-4 protein expression, and did not express EMT-associated transcripts. Removal of nAb from ES cells resulted in the restoration of cell-cell contact, absence of cell surface 5T4, decreased mesenchymal cellular morphology and motility, and enabled the differentiation of the cells to the three germ layers upon their removal from the fibroblast feeder layer. We conclude that E-cadherin functions in human ES cells to stabilize the cortical actin cyoskeletal arrangement and this prevents cell surface localization of the 5T4 antigen. Furthermore, human ES cells represent a useful model system with which to study EMT events relevant to embryonic development and tumor cell metastasis. [Cancer Res 2007;67(23):11254-62]

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Section: Methodsmentioning

confidence: 99%

Epithelial-Mesenchymal Transition Events during Human Embryonic Stem Cell Differentiation

et al. 2007

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“…Expression of 5T4 is observed in a variety of solid carcinomas, whereas expression in normal adult tissues is limited (13,14). Expression of 5T4 is associated with advanced disease and/or worse clinical outcome in NSCLC and gastric, colorectal, and ovarian carcinomas (8,(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Sapra

Damelin

DiJoseph

et al. 2013

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4, an oncofetal antigen expressed on tumorinitiating cells (TIC), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo antitumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after the last dose. Strikingly, animals showed pathologic complete response in each model with doses as low as 3 mg antibody/kg dosed every 4 days. In a non-small cell lung cancer patient-derived xenograft model, in which 5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors, such as TICs. In exploratory safety studies, A1mcMMAF exhibited no overt toxicities when administered to cynomolgus monkeys at doses up to 10 mg antibody/kg/ cycle Â 2 and displayed a half-life of 5 days. The preclinical efficacy and safety data established a promising therapeutic index that supports clinical testing of A1mcMMAF. Mol Cancer Ther; 12(1); 38-47. Ó2012 AACR.

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“…5T4 is expressed by a wide spectrum of cancers but is not detected on most normal adult tissues (19,20). In colorectal, gastric, and ovarian carcinomas, h5T4 expression is associated with poorer clinical outcome (21)(22)(23).…”

Section: Combination Of Vaccination and Chimeric Receptor Expressing mentioning

confidence: 99%

Combination of Vaccination and Chimeric Receptor Expressing T Cells Provides Improved Active Therapy of Tumors

Jiang

Gilham

Mulryan

et al. 2006

The Journal of Immunology

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We have generated murine T cells expressing chimeric immune receptors (CR) against human 5T4 oncofetal Ag (h5T4) and evaluated their tumor therapeutic efficacy alone and in combination with immunization using a replication-defective adenovirus encoding h5T4 (Rad.h5T4) and bone marrow-derived dendritic cells (BMDC). The h5T4-specific engineered T cells demonstrated Ag-specific, non-MHC-restricted cytolysis of h5T4-positive B16 and CT26 tumor cells in vitro by cytotoxicity assay and antitumor activity in vivo using a Winn assay. In the s.c. injected B16h5T4 melanoma model, early local but not systemic i.v. administration of syngeneic h5T4-specific CR T cells significantly increased mice survival. This improvement was further enhanced when combined with immunization with Rad.h5T4, followed by post-CR T cell treatment with BMDC in the active therapy model, possibly through mechanisms of enhancing Ag-specific cellular immune responses. This synergistic effect was lost without delivery of the BMDC. Our findings suggest that combining engineered T cells with specific vaccination strategies can improve the active tumor therapy.

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Isolation and characterization of 5T4, a tumour‐associated antigen

Cited by 61 publications

References 40 publications

Epithelial-Mesenchymal Transition Events during Human Embryonic Stem Cell Differentiation

Epithelial-Mesenchymal Transition Events during Human Embryonic Stem Cell Differentiation

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Combination of Vaccination and Chimeric Receptor Expressing T Cells Provides Improved Active Therapy of Tumors

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