Authors
Linda Mårtensson, Petra Holmkvist, Kirstie L Cleary, Carolin Svensson, Monika Semmrich, Niyaz Yoosuf, Alexandra Gabriela Ferreira, Mathilda Kovacek, Mimoza Bodén, Therese Blidberg, Osman Dadas, Jenny Mattsson, David Ermert, Elin Birgersson, Vicentiu-Andrei Pitic, Martin C Taylor, Mona Yazdani, Ulla-Carin Tornberg, Ingrid Karlsson, Sean H Lim, Stephen A Beers, Mark S Cragg, Björn Frendéus, Ingrid Teige
Published in
Cancer research. Jul 17, 2026. Epub Jul 17, 2026.
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.
PMID:
42466984
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.
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