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Epithelial Junction Opener JO-1 Improves Monoclonal Antibody Therapy of Cancer

Ines Beyer, Ruan van Rensburg, Robert Strauss, ZongYi Li, Hongjie Wang, Jonas Persson, Roma Yumul, Qinghua Feng, Hui Song, Jiri Bartek, Pascal Fender, André Lieber

Cancer Res. 2011 Nov 15;71(22):7080-90.

PMID: 21990319

Abstract:

The efficacy of monoclonal antibodies (mAb) used to treat solid tumors is limited by intercellular junctions which tightly link epithelial tumor cells to each another. In this study, we define a small, recombinant adenovirus serotype 3-derived protein, termed junction opener 1 (JO-1), which binds to the epithelial junction protein desmoglein 2 (DSG2). In mouse xenograft models employing Her2/neu- and EGFR-positive human cancer cell lines, JO-1 mediated cleavage of DSG2 dimers and activated intracellular signaling pathways which reduced E-cadherin expression in tight junctions. Notably, JO-1-triggered changes allowed for increased intratumoral penetration of the anti-Her2/neu mAb trastuzumab (Herceptin) and improved access to its target receptor, Her2/neu, which is partly trapped in tight junctions. This effect translated directly into increased therapeutic efficacy of trastuzumab in mouse xenograft models using breast, gastric, and ovarian cancer cells that were Her2/neu-positive. Furthermore, combining JO-1 with the EGFR-targeting mAb cetuximab (Erbitux) greatly improved therapeutic outcomes in a metastatic model of EGFR-positive lung cancer. A combination of JO-1 with an approach that triggered transient degradation of tumor stroma proteins elicited eradication of tumors. Taken together, our findings offer preclinical proof of concept to employ JO-1 in combination with mAb therapy.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
IAR42412090 Jo-1 human Jo-1 human Price
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