The Antisense Oligonucleotide Trabedersen (AP 12009) for the Targeted Inhibition of TGF-β2

Frank      Jaschinski; Tanja      Rothhammer; Piotr      Jachimczak; Christian      Seitz; Anneliese      Schneider; Karl-Hermann      Schlingensiepen

Abstract

Despite remarkable advances in cancer research, patients with malignant tumors such as high-grade glioma or advanced pancreatic carcinoma still face a poor prognosis. Because of the severe morbidity and mortality of such malignant tumor types, the identification of suitable molecular drug targets for causal treatment approaches is an important area of current research. Transforming growth factor-beta 2 (TGF-β2) is an attractive target because it regulates key mechanisms of carcinogenesis, in particular immunosuppression and metastasis, and is frequently overexpressed in malignant tumors. Here we describe the development of the antisense phosphorothioate oligodeoxynucleotide trabedersen (AP 12009) which was designed for the specific inhibition of TGF-β2 biosynthesis. In vitro and in vivo experiments confirmed the mode of action, efficacy and tolerability of trabedersen and paved the way for clinical studies. In patients with high-grade glioma, intratumoral treatment with trabedersen is currently evaluated in a pivotal, randomized and activecontrolled phase III study. Intravenous application of trabedersen for the treatment of patients with advanced pancreatic carcinoma, metastasizing melanoma, or metastatic colorectal carcinoma is assessed in a currently ongoing phase I/II dose escalation study.

Keywords: Transforming growth factor beta, gene silencing, antisense oligonucleotide, cancer, immunosuppression, highgrade glioma, pancreatic cancer, molecular drug targets, metastatic colorectal carcinoma, intratumoral treatment, tumor cell growth, autoimmune or cancer diseases, mammalian genomes, latent TGF-β binding protein (LTBP)