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Preprint WatchModerateJune 26th, 2026

Bispecific Antibody Architecture and TNFRSF Target Selection Determine CD8+ T Cell Differentiation and Anti-tumour Immunity

Widdess MA, Wilkinson L, Metcalfe HJ, Pakidi A, Chan HC, Kim J, Inzhelevskaya T, Turaj A, Lim SH, Thirdborough SM, Beers SA, Cragg MS, Al-Shamkhani A

Among TNFRSF co-stimulatory targets, 4-1BB (TNFRSF9) drives the strongest cytotoxic CD8+ T cell differentiation and antitumour response, but efficacy requires bivalent 4-1BB engagement and tumour-associated B7-H3, identifying antibody architecture as a key determinant.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reinforces 4-1BB (TNFRSF9) as the most active TNFRSF co-stimulatory target for CD8 T cell-driven antitumour immunity, but it shows that activity depends on antibody architecture, since a dual-bivalent 2x2 bispecific was maximally agonistic while monovalent 4-1BB engagement was weak, and on tumour-associated B7-H3 for localisation. Both indexed 4-1BB failures fit that frame. prs-344-s095012-tnfrsf9-4-1bb-pdl1-solid-tumors-phase1-2-sponsor-termination paired 4-1BB with PD-L1 and was stopped on a sponsor decision, and acasunlimab-tnfrsf9-pdl1-4-1bb-bispecific-melanoma-phase2-strategic-termination, another 4-1BB by PD-L1 bispecific, was halted for strategic reasons. The preprint does not contradict the target biology. It argues that format and antigen anchoring, not the receptor itself, set the efficacy ceiling, which is consistent with two 4-1BB programs that reached the clinic and were dropped without a clear efficacy verdict.

Abstract excerpt

Tumour necrosis factor receptor superfamily (TNFRSF)-targeting bispecific antibodies (bsAb) enable tumour-localised T cell co-stimulation, yet how antibody architecture and receptor choice govern activity remains unclear. Here we define how bsAb format and TNFRSF target selection shape CD8+ T cell responses and anti-tumour immunity. Using B7-H3 as a tumour-associated antigen, we show that dual-bivalent 2x2 bsAb elicit maximal agonistic activity, whereas the corresponding monovalent 1x1 format is least active. A 2x1 format retaining TNFRSF bivalency but monovalent B7-H3 binding preserves substantial activity, identifying co-stimulatory receptor bivalency as a key determinant of efficacy. Across TNFRSF targets, 4-1BB drives the strongest cytotoxic CD8+ T cell differentiation and anti-tumour response. This superiority is conserved in human T cells and reproduced by cognate ligands, indicating that the observed functional hierarchy reflects receptor-intrinsic biology. Mechanistically, efficacy requires tumour-associated B7-H3 and T cell-dependent 4-1BB signalling. Together, these findings establish general principles linking antibody architecture and receptor biology to co-stimulatory bsAb efficacy and provide a framework for rational design leading to optimal therapeutics.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.