Teige, I. | Search bioRxiv

bioRxiv2026

Leveraging TNFR2 for antitumour immunity: T reg depletion and myeloid reprogramming versus T cell costimulation

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 target of interest, but a lack of understanding of whether agonists or blockers should be used, and whether Fc{gamma}R interactions promote effcacy, has hampered therapeutic antibody development. Here, we engineered two distinct -TNFR2 types: ligand-blocking Fc{gamma}R-engaging versus non-ligand-blocking agonist antibodies. Both showed potent anti-tumor effcacy across multiple syngeneic mouse tumor models and combined effectively with -PD-1. The ligand-blocking antibody depleted intratumoral T regs and reprogrammed the myeloid compartment, directing monocytes towards a pro-inflammatory macrophage and dendritic cell trajectory. Surprisingly, this effect depended on both inhibitory and activating Fc{gamma}Rs. In contrast, the agonist directly co-stimulated T and NK cells, through partially Fc{gamma}R-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) -TNFR2 antibodies is currently ongoing. Graphical abstractO_LILigand-blocking anti-TNFR2 mAbs (BI-1808 and 3F10) deplete CCR8+ T regs and activate myeloid cells, remodeling the TME and leading to CD8+ T cell killing of cancer cells. T reg depletion and myeloid activation are mediated through interaction with activating Fc{gamma}Rs and the inhibitory Fc{gamma}RIIB, respectively. C_LIO_LIAgonist anti-TNFR2 mAbs (BI-1910 and 5A05) intrinsically agonize TNFR2 on T cells and NK cells, which is enhanced by Fc{gamma}RIIB crosslinking. The resulting broad lymphocyte activation mediates cancer cell killing. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/697572v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@3ecc17org.highwire.dtl.DTLVardef@c936a7org.highwire.dtl.DTLVardef@23189aorg.highwire.dtl.DTLVardef@243a05_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

Previous data suggests that anti-OX40 mAb can elicit anti-tumour effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. The contributions of these different effector mechanisms has not previously been systematically evaluated, particularly for mAb directed to human OX40. Therefore, we generated a novel human OX40 knock-in (KI) mouse to evaluate a panel of anti-hOX40 mAb and show that their activities relate directly to two key properties: 1) isotype – with mIgG1 mAb evoking receptor agonism and CD8+ T cell expansion and mIgG2a mAb evoking deletion of Treg and; 2) epitope - with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumour models by engaging these different mechanisms. These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T cell expansion or Treg depletion might be preferable according to the composition of different tumours.Summary Human trials with anti-OX40 antibodies have been disappointing indicating that optimal reagents have not yet been developed. Here, using a new panel of antibodies, we show that isotype and epitope combine to determine agonistic and therapeutic activity.Competing Interest StatementMSC is a retained consultant for BioInvent International and has performed educational and advisory roles for Baxalta and Boehringer Ingleheim. He has received research funding from Roche, Gilead, Bioinvent International and GSK. BF, IT, LM and MS are employees of Bioinvent International.View Full Text

immunology↗