Roland E Kontermann1, Peter Scheurich, Klaus Pfizenmaier. 1. Universität Stuttgart, Institut für Zellbiologie und Immunologie, Allmandring 31, 70569 Stuttgart, Germany +49 711 68566989 ; +49 711 68567484 ; roland.kontermann@izi.uni-stuttgart.de.
Abstract
BACKGROUND: TNF is a central mediator of inflammation and key target for intervention in inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's disease. The four at present approved protein therapeutics directly target TNF and inhibit binding to its two TNF receptors. Treatment with TNF antagonists results in significant clinical responses and is generally well tolerated. OBJECTIVE: Ten years of clinical experience with 1 million patients treated also revealed the limits of the available antagonists and potential therapy-associated risks, foremost being tuberculosis reactivation, but also neurologic and hematologic events, and even malignancies. These findings ask for improvement of established therapies. METHOD: We here review published literature on strategies interfering with TNF action and provide an overview of the now approved antagonists of TNF action as well as new reagents under development. CONCLUSION: Clinical experience with approved TNF antagonists shows that there is a demand for minimizing risks associated with persistent blocking of TNF action. With new TNF pathway-targeting reagents and new concepts based on receptor-selective intervention under development, it is foreseeable that efficacy and safety will be further improved and that TNF-targeting strategies will be exploited in further inflammatory and other diseases, including metabolic diseases and cancer.
BACKGROUND:TNF is a central mediator of inflammation and key target for intervention in inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's disease. The four at present approved protein therapeutics directly target TNF and inhibit binding to its two TNF receptors. Treatment with TNF antagonists results in significant clinical responses and is generally well tolerated. OBJECTIVE: Ten years of clinical experience with 1 million patients treated also revealed the limits of the available antagonists and potential therapy-associated risks, foremost being tuberculosis reactivation, but also neurologic and hematologic events, and even malignancies. These findings ask for improvement of established therapies. METHOD: We here review published literature on strategies interfering with TNF action and provide an overview of the now approved antagonists of TNF action as well as new reagents under development. CONCLUSION: Clinical experience with approved TNF antagonists shows that there is a demand for minimizing risks associated with persistent blocking of TNF action. With new TNF pathway-targeting reagents and new concepts based on receptor-selective intervention under development, it is foreseeable that efficacy and safety will be further improved and that TNF-targeting strategies will be exploited in further inflammatory and other diseases, including metabolic diseases and cancer.
Authors: Kirstin A Zettlitz; Verena Lorenz; Karlheinz Landauer; Sabine Münkel; Andreas Herrmann; Peter Scheurich; Klaus Pfizenmaier; Roland Kontermann Journal: MAbs Date: 2010-11-01 Impact factor: 5.857
Authors: Fabian Richter; Kirstin A Zettlitz; Oliver Seifert; Andreas Herrmann; Peter Scheurich; Klaus Pfizenmaier; Roland E Kontermann Journal: MAbs Date: 2018-10-02 Impact factor: 5.857
Authors: Fabian Richter; Timo Liebig; Eric Guenzi; Andreas Herrmann; Peter Scheurich; Klaus Pfizenmaier; Roland E Kontermann Journal: PLoS One Date: 2013-08-19 Impact factor: 3.240
Authors: Sarah K Williams; Olaf Maier; Roman Fischer; Richard Fairless; Sonja Hochmeister; Aleksandar Stojic; Lara Pick; Doreen Haar; Sylvia Musiol; Maria K Storch; Klaus Pfizenmaier; Ricarda Diem Journal: PLoS One Date: 2014-02-28 Impact factor: 3.240