Abstract A83: Combinatorial approach to drastically enhance the monoclonal antibody efficacy in targeted tumor therapy.

Abstract

Abstract Antitumor therapy with monoclonal antibodies has shown great therapeutic benefits in clinics and a number of therapeutic antibodies have been approved for use in patients. Nevertheless, their efficacy is limited due to their insufficient inherent cell killing activity. In order to augment their antitumor efficacy, monoclonal antibodies may be modified with natural toxins to create a drug conjugate (immunotoxin) that comprises the dual functionality of monoclonal antibody (antagonistic binding to targeted receptors and interaction with the innate immune system) and the cell-killing activity of the toxin. In our investigations, two immunotoxins were prepared by chemically coupling the monoclonal antibodies trastuzumab (Herceptin®) and cetuximab (Erbitux®) to the plant derived toxin saporin via a cleavable disulfide bond. Impedance-based real-time viability assays and confocal live cell imaging revealed that the toxin is efficiently delivered to the targeted tumor cells. In addition, immunotoxin cytotoxicity was tremendously enhanced in combination with certain plant glycosides, which specifically mediate the endo/lysosmal release of the toxin moiety into the cytosol without damaging the biological membranes. The combinatorial approach was successful in achieving a complete cell death of human breast ductal carcinoma BT-474 cells, at a concentration of 1 nM of trastuzumab-saporin or 0.001 nM cetuximab-saporin in the presence of the glycosides. Furthermore, immunotoxins retained their ability to interact with the innate immune system and trigger antibody-dependent cell-mediated cytotoxicity. The combinatorial approach is conceived as a novel and promising way to increase the efficacy of monoclonal antibodies in targeted tumor therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A83. Citation Format: Roger Gilabert-Oriol, Mayank Thakur, Benedicta von Mallinckrodt, Thomas Hug, Burkhard Wiesner, Jenny Eichhorst, Matthias F. Melzig, Hendrik Fuchs, Alexander Weng. Combinatorial approach to drastically enhance the monoclonal antibody efficacy in targeted tumor therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A83.