The TNFR1 Antagonist Atrosimab Is Therapeutic in Mouse Models of Acute and Chronic Inflammation.

Roland E Kontermann,Kira Pichi,Arndt Vogel,Katharina John,Marie-Ann Dhaen,Camille Vaslin,Fabian Richter,Silke Marhenke,Klaus Pfizenmaier,Carina Huber,Henri Zanker,Sarah K Williams,Roman Fischer,Heike Bantel,Ricarda Diem,Richard Fairless,Stefanie Herrmann,Andreas Herrmann

doi:10.3389/fimmu.2021.705485

Abstract

Therapeutics that block tumor necrosis factor (TNF), and thus activation of TNF receptor 1 (TNFR1) and TNFR2, are clinically used to treat inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. However, TNFR1 and TNFR2 work antithetically to balance immune responses involved in inflammatory diseases. In particular, TNFR1 promotes inflammation and tissue degeneration, whereas TNFR2 contributes to immune modulation and tissue regeneration. We, therefore, have developed the monovalent antagonistic anti-TNFR1 antibody derivative Atrosimab to selectively block TNFR1 signaling, while leaving TNFR2 signaling unaffected. Here, we describe that Atrosimab is highly stable at different storage temperatures and demonstrate its therapeutic efficacy in mouse models of acute and chronic inflammation, including experimental arthritis, non-alcoholic steatohepatitis (NASH) and experimental autoimmune encephalomyelitis (EAE). Our data support the hypothesis that it is sufficient to block TNFR1 signaling, while leaving immune modulatory and regenerative responses via TNFR2 intact, to induce therapeutic effects. Collectively, we demonstrate the therapeutic potential of the human TNFR1 antagonist Atrosimab for treatment of chronic inflammatory diseases.

Highlights

Tumor necrosis factor (TNF) is recognized as a master pro-inflammatory cytokine that plays a dominant role in the initiation and perpetuation of chronic inflammation [1, 2]
Our data demonstrate that TNF receptor 1 (TNFR1) inhibition through Atrosimab administration efficiently blocked TNFR1-mediated inflammatory responses in a model of acute TNF-mediated inflammation and in experimental arthritis, non-alcoholic steatohepatitis (NASH) and EAE
This is in accordance with published data by us and others showing that TNFR1 inhibition is therapeutic for EAE [11, 17, 27,28,29], NASH [18] and experimental arthritis [13]

Summary

Introduction

Tumor necrosis factor (TNF) is recognized as a master pro-inflammatory cytokine that plays a dominant role in the initiation and perpetuation of chronic inflammation [1, 2]. Atrosimab In Vivo therapeutics and additional biosimilars thereof are approved and successfully used to treat autoimmune diseases, including rheumatoid arthritis (RA), juvenile RA, inflammatory bowel disease, psoriasis, and ankylosing spondylitis [4]. Despite their clinical success, these anti-TNF therapeutics have limitations. Clinical evaluation of an anti-TNF therapy in multiple sclerosis (MS) failed [6, 7] and anti-TNF therapy of juvenile rheumatoid arthritis resulted in development of MS-like exacerbations and demyelinating lesions in some patients [8]

Methods

Results

Conclusion