32 Development of TGF-β-based Therapeutic Agents: Capitalizing on TGF-β’s Mechanisms of Action and Signal Transduction Pathways

Abstract

The early publications of more than 20 years ago that described the discovery and characterization of the biological activities of TGF-β in vivo were prophetic in describing how TGF-β would ultimately serve as a therapeutic target for stimulating wound repair, preventing pathological fibrosis, and inhibiting tumor growth and metastasis (Roberts et al. 1980; Sporn et al. 1983). Since the discovery of TGF-β, other growth factors have also been identified as therapeutic targets, taken through product development, and ultimately commercialized. These have included platelet-derived growth factor (Regranex) for the treatment of diabetic foot ulcers, tumor necrosis factor antagonists (Remicade, Humira, and Enbrel) for the treatment of Crohn’s disease and rheumatoid arthritis, and a vascular endothelial growth factor (VEGF) antagonist (Avastin) for the treatment of cancer. An obvious question is why there have been no successful therapeutic agents developed based on TGF-β as a target, given the more than 20,000 papers that have been published on its important role in health and disease. Part of the answer is associated with the very complex biology of TGF-β in tissue homeostasis and the fact that it seems to be involved in numerous disease states. This biological complexity has provided a significant challenge for the scientists, clinicians, and business professionals in industry who have considered TGF-β as a therapeutic target but have struggled to determine how to develop it commercially. Another major concern has been the issue of potential toxicity associated with modulating TGF-β function in vivo. This concern was primarily based on targeted inactivation...