title: Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer.
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.
authors: Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA.
authors: Ines
authors: I
authors: Beyer
authors: Ruan
authors: R
authors: van Rensburg
authors: Robert
authors: R
authors: Strauss
authors: ZongYi
authors: Z
authors: Li
authors: Hongjie
authors: H
authors: Wang
authors: Jonas
authors: J
authors: Persson
authors: Roma
authors: R
authors: Yumul
authors: Qinghua
authors: Q
authors: Feng
authors: Hui
authors: H
authors: Song
authors: Jiri
authors: J
authors: Bartek
authors: Pascal
authors: P
authors: Fender
authors: André
authors: A
authors: Lieber
mesh_terms: D000260:Adenoviruses, Human / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D051301:Desmoglein 2 / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D000068878:Trastuzumab; D014764:Viral Proteins / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C495314:DSG2 protein, human; D051301:Desmoglein 2; C495315:Dsg2 protein, mouse; D011994:Recombinant Proteins; D014764:Viral Proteins; D000068878:Trastuzumab; D000068818:Cetuximab