Innovative antibody design targets TNFR2 for safer, more effective treatments
The Beilhack and Wajant labs at Würzburg University Hospital have achieved a significant milestone in immunotherapy. Our latest study reveals innovative design principles for antibody-based TNFR2 agonists that operate independently of FcγR, marking a substantial advancement in treating autoimmune diseases and cancer.
In a succession of groundbreaking studies, our interdisciplinary research teams have unveiled novel design principles for antibody-based therapeutics targeting TNFR2. These innovative constructs activate TNFR2 independently of FcγR, overcoming limitations of traditional antibodies. This development promises safer and more effective treatments for autoimmune diseases, graft-versus-host disease, organ rejection, neurodegenerative disorders, and cancer.
Harald Wajant’s research team together with scientists from the Beilhack lab identified domain architecture as crucial for creating FcγR-independent TNFR2 agonists. By strategically positioning TNFR2 binding sites on antibody scaffolds, we developed constructs with strong intrinsic agonistic activity.
In a series of studies we show that anti-TNFR2 antibodies with binding sites on opposing sides of the scaffold or with six or more TNFR2 binding sites exhibit robust FcγR-independent agonism. This approach bypasses the need for FcγR engagement for maximal activity.
Our new antibody formats selectively activate TNFR2, promising therapeutic benefits for autoimmune diseases, neurodegenerative conditions, and cancer. These novel biologicals avoid the unpredictable outcomes of FcγR-dependent activation, enhancing safety and efficacy for clinical use.
This research provides a blueprint for developing TNFR2-specific agonists, simplifying the creation of therapeutic antibodies. By focusing on optimal domain architecture rather than traditional characteristics like epitope recognition and affinity, our study accelerates the path from research to clinical application. Potent TNFR2 agonists can now be generated from nearly any TNFR2-specific antibody, paving the way for precise and effective immunotherapies.
Patients with autoimmune and inflammatory diseases, neurodegenerative disorders, and cancer can greatly benefit from these advancements. The new TNFR2 agonists enhance Treg activation and expansion, promoting immune regulation and tissue homeostasis. Additionally, they hold promise for restoring anti-tumor immunity by co-stimulating CD8+ T-cells, potentially leading to more effective cancer treatments.
Our research team plans further preclinical and clinical evaluations to explore the full potential of these FcγR-independent TNFR2 agonists. These studies will assess their efficacy in various disease models and determine optimal therapeutic settings.
References:
Anany MA, Haack S, Lang I, Dahlhoff J, Gamboa Vargas J, Steinfatt T, Päckert L, Weisenberger D, Zaitseva O, Medler J, Kucka K, Zhang T, Van Belle T, van Rompaey L, Beilhack A*, Wajant H*. (2024). Generic design principles for antibody-based tumour necrosis factor (TNF) receptor 2 (TNFR2) agonists with FcγR-independent agonism. Theranostics 14(2):496-509.
Gamboa Vargas J*, Wagner J*, Shaikh H, Lang I, Medler J, Anany M, Steinfatt T, Peña Mosca J, Haack S, Dahlhoff J, Büttner-Herold M, Graf C, Arellano E, Einsele H, Wajant H*, Beilhack A*. (2022). A TNFR2-specific TNF fusion protein with improved in vivo activity. Front Immunol 13:888274.
Wajant H*, Beilhack A*. (2019). Targeting Regulatory T Cells by Addressing Tumor Necrosis Factor and Its Receptors in Allogeneic Hematopoietic Cell Transplantation and Cancer. Front Immunol 10: 2040.
Chopra M, Biehl M, Steinfatt T, Brandl A, Kums J, Amich J, Vaeth M, Kuen J, Holtappels R, Podlech J, Mottok A, Kraus S, Jordán Garrote AL, Bäuerlein CA, Brede C, Ribecchini E, Fick A, Seher A, Polz J, Ottmüller K, Baker J, Nishikii H, Ritz M, Mattenheimer K, Schwinn S, Winter T, Schäfer V, Krappmann S, Einsele H, Mueller TD, Reddehase MJ, Lutz MB, Männel DN, Berberich-Siebelt F, Wajant H*, Beilhack A*. (2016). Exogenous TNFR2 activation protects from acute GvHD by induction of host Treg expansion. J Exp Med 213:1881–1900.