Development of antibody drug conjugates targeting epithelial membrane protein 2-highly expressed lung cancer

Le résumé fourni par la source

Lung cancer is one of the most devastating types of cancer, and the treatment of lung cancer has been facing great challenges. Antibody-drug conjugates (ADCs), a new type of targeted therapy, have been widely used in cancer therapy and have opened up a new perspective for the treatment of lung cancer. Here, using a tissue-microarray-based antibody library screening, we identified the FK002 antibody that specifically binds to the tumor cell membrane across various tumor types. We determined that FK002 targets epithelial membrane protein 2 (EMP2), a member of the tetraspanin superfamily of proteins. Subsequently, we developed the EMP2-directed ADC, FK002-exatecan, with a potent DNA topoisomerase I inhibitor (exatecan). In-depth in vitro and in vivo experiments have shown the efficacy and specificity of the EMP2-directed ADC. We validated that the FK002-exatecan ADC effectively eradicated tumors in various lung cancer cell lines and xenograft mouse models, including patient-derived xenograft (PDX) and patient-derived tumor-like cell cluster (PTC) models, as well as xenograft tumors. Mechanistically, FK002-exatecan specifically bound to EMP2 and was internalized into tumor cells, followed by intracellular trafficking to the lysosome and exatecan release, which induced cell cycle arrest and apoptosis. This study identifies EMP2 as a novel molecular target for lung cancer therapy and establishes a foundation for developing ADCs that selectively eradicate lung cancer cells.

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