Fig 2: Comparison of human TNF-UCB-8733 free and antibody-complexed structures.a Alignment of human TNF from the compound (UCB-8733)-only structure (red ribbons) with human TNF (plus UCB-8733) from the CA1974 Fab-human TNF-UCB-8733-TNFR1 complex structure (green ribbons) (Fab and receptors have been removed for clarity). Monomers A, B, and C are labelled. Red circles highlight a region of flexibility containing Tyr87 (sticks) on each monomer. b Detail showing the change in position of Tyr87 (sticks) in monomer A when Fab CA1974 is bound (green ribbon) compared to its position in the human TNF UCB-8733-only structure (red ribbon). Further details of residue movements are shown in Supplementary Table 2.

Fig 3: CA1974 binding to human TNF in complex with small molecule inhibitors.a TNF–small molecule (UCB-8733 and UCB-9260) complex or apo TNF (blue) were captured via TNFR1 which was pre-coated onto a 384-well ELISA plate. CA1974 Fab at a range of concentrations was then added to the plate to detect TNF–small molecule complex. Comparisons are presented as ratios of geometric means (points) and 95% confidence intervals for the ratios (error bars), i.e., Comparison of TNF-UCB-8733 complex and TNF-UCB-9260 (blue); Comparison of TNF-UCB-8733 complex and apo TNF (red); Comparison of TNF-UCB-9260 complex and apo TNF (green). b Human TNF-UCB-9260 complex at 25 ng/ml (blue), 250 ng/ml (green) or apo TNF (250 ng/ml) with DMSO (0.4%) (red) was added to HEK-293 Jump In cells expressing human TNFR1. CA1974 IgG at 10 µg/ml was used to detect TNF–small molecule complex bound to the surface of cells using flow cytometry. The binding was revealed using a goat anti-mouse IgG Alexa Fluor 488 secondary antibody. Data is shown for cells present in a gate which defines viable single cells and excludes doublets and other cell debris (Supplementary Fig. 1). Cell count (y-axis) is normalised to mode. Source data are provided as a Source Data file.

Fig 4: Detail of the epitope of CA1974 Fab.a Complex of human TNF (green surface rendered), CA1974 Fab (blue ribbons), and human TNFR1 (pink ribbons) with epitope residues highlighted in red. b Head-on view of the CA1974 Fab epitope spanning monomers A & C on human TNF (highlighted in red). For clarity CA1974 Fab has been removed and monomers A and C have been labelled. c CA1974 Fab epitope with residues that vary in mouse TNF marked in blue. d Equivalent view with residues that vary in cynomolgus monkey TNF marked in blue. Residues that vary between the species are highlighted in Supplementary Table 2.