Browsing by Author "Vaslin, Camille"

Now showing 1 - 2 of 2

Open Access
Optimization of TNFR2-selective agonists with immunomodulatory properties : safety studies to support clinical development
(2025) Vaslin, Camille; Kontermann, Roland (Prof. Dr.)
Tumor Necrosis Factor (TNF) is a cytokine playing a major role in immune regulation. It exists as a trimeric protein, either soluble (sTNF) or transmembrane form (tmTNF). TNFa can bind selectively to two transmembrane receptors: Tumor Necrosis Factor Receptor 1 (TNFR1) or 2 (TNFR2). While sTNF can only bind to TNFR1, tmTNF can bind to both receptors. TNFR1 is commonly found on most cell types, whereas TNFR2 is mostly expressed on the surface of epithelial, endothelial, and immune cells. Those receptors induce opposite effects upon activation. TNFR1 activation leads to inflammatory response, apoptosis, and neurodegeneration, while TNFR2 promotes tissue homeostasis and neuroregeneration. Because of those antagonistic effects, TNF and TNFRs are considered as promising targets. Therapeutic approaches using TNF inhibitors have been developed in the context of auto-immune and inflammatory diseases. Unfortunately, this global TNF blockade often leads to detrimental side effects, with limited responsiveness and an increase of infections. The genetic engineering of TNFR2-selective agonist fusion proteins represents a promising target in immunomodulatory therapy development. In this project, TNFR2 selective agonist molecules, mimicking tmTNF were developed. It consists of a TNFR2-specific mutant single chain TNF trimer merged to an effector-deficient Fc domain. This study focuses on optimizing the human TNFR2-selective agonist and evaluating biosafety for further clinical development. Functional bioactivity assessments of the TNFR2-selective agonists were conducted to evaluate receptor selectivity, bioactivity, and potential cross-reactivity among different mammalian species. NfkB reporter cell lines were developed to further the bioactivity of the molecules. In vivo studies examined TNFR2 expression in both wild-type and humanized TNFR2 C57BL/6J mice, along with pharmacokinetic profiles and tolerance of murine and human TNFR2 selective agonists. This project contributes to understand TNFR2 selective agonist fusion proteins, providing valuable perspectives for their clinical development in immunomodulatory therapies.
Open Access
The TNFR1 antagonist Atrosimab is therapeutic in mouse models of acute and chronic inflammation
(2021) Richter, Fabian; Williams, Sarah K.; John, Katharina; Huber, Carina; Vaslin, Camille; Zanker, Henri; Fairless, Richard; Pichi, Kira; Marhenke, Silke; Vogel, Arndt; Dhaen, Marie-Ann; Herrmann, Stefanie; Herrmann, Andreas; Pfizenmaier, Klaus; Bantel, Heike; Diem, Ricarda; Kontermann, Roland E.; Fischer, Roman
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.