Bimekizumab (Bimzelx)

A dual-specificity antibody targeting both IL-17A and IL-17F, developed by UCB. Presented by Alistair Henry at Session I.

Mechanism

One antibody, selective for A and F only out of five IL-17 isoforms, blocking receptors A and C. Not a bispecific — a superimposition: two binding sites on top of each other that switch between A and F.

Design Process (Pre-AI)

• Crystal structure existed for lead bound to IL-17A; no IL-17F structure — used a homology model
• Took ~20,000 non-redundant high-resolution PDB structures (≤2 Å)
• Asked at the atom level: when nature places a side chain in one orientation, what binders does nature put opposite?
• Cross-referenced to what an antibody scaffold would tolerate naturally
• >28,000 variants → ~20 sequences → 5 made → 1 drug
• Equal potency on A, gained F. Sequences entirely human-like

Key Insight: IL-17A vs. IL-17F

In human peripheral blood under chronic inflammation, the temporal/cellular signal is clear: IL-17A initiates, IL-17F drives the late phase. Mouse shows no IL-17F signature — human pathobiology won the internal argument at UCB.

Back-Translation Discoveries

Reverse expression profiling on the psoriasis transcriptome with bimekizumab on board showed near-complete normalization, with two surprises:

1. Biology was monocyte-driven to a degree the field had under-appreciated
2. Signatures placed IL-23 as an upstream regulator of IL-17A/F, complicating the textbook IL-23 → IL-17 “waterfall” model

UCB is now testing whether overlapping signatures across IL-17–driven pathologies can predict prospectively which co-connecting pathways matter.