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Theranostics 2024; 14(2):496-509. doi:10.7150/thno.84404 This issue Cite

Research Paper

Generic design principles for antibody-based tumour necrosis factor (TNF) receptor 2 (TNFR2) agonists with FcγR-independent agonism

Mohamed A. Anany1,2, Stefanie Haack3, Isabell Lang1, Julia Dahlhoff3, Juan Gamboa Vargas3, Tim Steinfatt3, Lea Päckert1, Daniela Weisenberger1, Olena Zaitseva1, Juliane Medler1, Kirstin Kucka1, Tengyu Zhang1, Tom Van Belle4, Luc van Rompaey4, Andreas Beilhack3,*, Harald Wajant1,*,✉

1. Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
2. Department of Microbial Biotechnology, Institute of Biotechnology, National Research Center, Dokki, Giza, Egypt.
3. Department of Internal Medicine II, Interdisciplinary Center for Clinical Research (IZKF) laboratory Würzburg, Center for Experimental Molecular Medicine, University Hospital Würzburg, Würzburg, Germany.
4. Dualyx NV, 9052 Zwijnaarde, Belgium.
* Equal contribution

✉ Corresponding author: harald.wajantuni-wuerzburg.de.

Citation:
Anany MA, Haack S, Lang I, Dahlhoff J, Vargas JG, Steinfatt T, Päckert L, Weisenberger D, Zaitseva O, Medler J, Kucka K, Zhang T, Van Belle T, van Rompaey L, Beilhack A, Wajant H. Generic design principles for antibody-based tumour necrosis factor (TNF) receptor 2 (TNFR2) agonists with FcγR-independent agonism. Theranostics 2024; 14(2):496-509. doi:10.7150/thno.84404. https://www.thno.org/v14p0496.htm
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Abstract

Graphic abstract

Background: Selective TNFR2 activation can be used to treat immune pathologies by activating and expanding regulatory T-cells (Tregs) but may also restore anti-tumour immunity by co-stimulating CD8+ T-cells. Oligomerized TNFR2-specific TNF mutants or anti-TNFR2 antibodies can activate TNFR2 but suffer either from poor production and pharmacokinetics or in the case of anti-TNFR2 antibodies typically from the need of FcγR binding to elicit maximal agonistic activity.

Methods: To identify the major factor(s) determining FcγR-independent agonism of anti-TNFR2 antibodies, we systematically investigated a comprehensive panel of anti-TNFR2 antibodies and antibody-based constructs differing in the characteristics of their TNFR2 binding domains but also in the number and positioning of the latter.

Results: We identified the domain architecture of the constructs as the pivotal factor enabling FcγR-independent, thus intrinsic TNFR2-agonism. Anti-TNFR2 antibody formats with either TNFR2 binding sites on opposing sites of the antibody scaffold or six or more TNFR2 binding sites in similar orientation regularly showed strong FcγR-independent agonism. The affinity of the TNFR2 binding domain and the epitope recognized in TNFR2, however, were found to be of only secondary importance for agonistic activity.

Conclusion: Generic design principles enable the generation of highly active bona fide TNFR2 agonists from nearly any TNFR2-specific antibody.

Citation styles

APA
Anany, M.A., Haack, S., Lang, I., Dahlhoff, J., Vargas, J.G., 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. https://doi.org/10.7150/thno.84404.

ACS
Anany, M.A.; Haack, S.; Lang, I.; Dahlhoff, J.; Vargas, J.G.; Steinfatt, T.; Päckert, L.; Weisenberger, D.; Zaitseva, O.; Medler, J.; Kucka, K.; Zhang, T.; Van Belle, T.; van Rompaey, L.; Beilhack, A.; Wajant, H. Generic design principles for antibody-based tumour necrosis factor (TNF) receptor 2 (TNFR2) agonists with FcγR-independent agonism. Theranostics 2024, 14 (2), 496-509. DOI: 10.7150/thno.84404.

NLM
Anany MA, Haack S, Lang I, Dahlhoff J, Vargas JG, Steinfatt T, Päckert L, Weisenberger D, Zaitseva O, Medler J, Kucka K, Zhang T, Van Belle T, van Rompaey L, Beilhack A, Wajant H. Generic design principles for antibody-based tumour necrosis factor (TNF) receptor 2 (TNFR2) agonists with FcγR-independent agonism. Theranostics 2024; 14(2):496-509. doi:10.7150/thno.84404. https://www.thno.org/v14p0496.htm

CSE
Anany MA, Haack S, Lang I, Dahlhoff J, Vargas JG, 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.

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