Ligand-Blocking and Agonist Antibodies Targeting TNFR2 Employ Distinct Modes of Action to Induce Antitumor Immunity

Although checkpoint inhibitors have revolutionized cancer treatment, responses are largely restricted to targeting CTLA-4 and PD-(L)1. TNFR2 has been identified as a promising target, but further therapeutic development requires a better understanding of whether agonists or blockers should be used and whether FcγR interactions promote efficacy. Here, we engineered two distinct α-TNFR2 antibody types: ligand-blocking FcγR-engaging versus non-ligand-blocking agonist antibodies. Both showed potent anti-tumor efficacy across multiple syngeneic mouse tumor models and combined effectively with α-PD-1. The ligand-blocking antibody depleted intratumoral Tregs and reprogrammed the myeloid compartment, directing monocytes towards a pro-inflammatory macrophage and dendritic cell trajectory. Interestingly, this effect depended on both inhibitory and activating FcγRs, reflecting the simultaneous action on Tregs and myeloid cells. In contrast, the agonist directly co-stimulated T and NK cells, partially through FcγR-independent mechanisms. Both antibodies converged on activating tumor-specific CD8+ T cells mediating tumor rejection. Clinical assessment of both ligand-blocking (BI-1808) and agonist (BI-1910) α-TNFR2 antibodies is currently ongoing.

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Publication Details

Journal
Cancer Research
Published
2026-07-17
DOI
https://doi.org/10.1158/0008-5472.can-26-0274
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
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article

Ligand-Blocking and Agonist Antibodies Targeting TNFR2 Employ Distinct Modes of Action to Induce Antitumor Immunity

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Cancer Research
Cancer Immunotherapy and Biomarkers
article

Ligand-Blocking and Agonist Antibodies Targeting TNFR2 Employ Distinct Modes of Action to Induce Antitumor Immunity

Monika Semmrich, Björn Frendéus, Mona Yazdani, Elin Birgersson, Mathilda Kovacek, Ulla‐Carin Tornberg, Osman Dadas, Alexandra G. Ferreira, Mimoza Bodén, Kirstie L.S. Cleary, David Ermert, Petra Holmkvist, Ingrid Teige, Sean H. Lim, Carolin Svensson, Ingrid Karlsson, Therese Blidberg, Stephen A. Beers, Martin C. Taylor, Mark Steven Cragg, Niyaz Yoosuf, Jenny Mattsson, Linda Mårtensson, Vicentiu Andrei Pitic
article en

Abstract

Although checkpoint inhibitors have revolutionized cancer treatment, responses are largely restricted to targeting CTLA-4 and PD-(L)1. TNFR2 has been identified as a promising target, but further therapeutic development requires a better understanding of whether agonists or blockers should be used and whether FcγR interactions promote efficacy. Here, we engineered two distinct α-TNFR2 antibody types: ligand-blocking FcγR-engaging versus non-ligand-blocking agonist antibodies. Both showed potent anti-tumor efficacy across multiple syngeneic mouse tumor models and combined effectively with α-PD-1. The ligand-blocking antibody depleted intratumoral Tregs and reprogrammed the myeloid compartment, directing monocytes towards a pro-inflammatory macrophage and dendritic cell trajectory. Interestingly, this effect depended on both inhibitory and activating FcγRs, reflecting the simultaneous action on Tregs and myeloid cells. In contrast, the agonist directly co-stimulated T and NK cells, partially through FcγR-independent mechanisms. Both antibodies converged on activating tumor-specific CD8+ T cells mediating tumor rejection. Clinical assessment of both ligand-blocking (BI-1808) and agonist (BI-1910) α-TNFR2 antibodies is currently ongoing.

Cancer Research
BioInvent (Sweden) (SE), University of Southampton (GB)
Good health and well-being
Openalex Percentile: Top 11%
Cancer Immunotherapy and Biomarkers
DOIOpen Access PDFOpenAlex
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