Crystal structure of bimekizumab Fab fragment in complex with IL-17F provides molecular basis for dual IL-17A and IL-17F Inhibition

DOI: 10.1016/j.jid.2024.03.037

Authors: Ralph Adams (UCB Pharma) , Christopher G. Bunick (Yale University) , Alastair D. G. Lawson (UCB Pharma) , Braulio Gomez (UCB Pharma) , Stevan Shaw (UCB Pharma)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Investigative Dermatology , VOL 11

State: Published (Approved)
Published: April 2024

Abstract: Psoriasis (PSO) and psoriatic arthritis (PsA) are Th17-driven inflammatory diseases where interleukin (IL)-17 cytokines like IL-17A and IL-17F promote disease pathogenesis. There are six IL-17 isoforms (IL-17A–F) and five IL-17 receptors (IL-17RA–E; Liu et al., 2020 ). IL-17 cytokines primarily function as homodimers, although IL-17A and IL-17F can heterodimerize ( Brembilla et al., 2018 ). IL-17A and IL-17F genes share the same chromosomal location (6p12), their proteins share ∼55% sequence homology, and both cytokines signal through the IL-17RA/RC heterodimeric complex ( Brembilla et al., 2018 , Liu et al., 2020 ). Inhibition of the IL-17 pathway using IL-17A targeted (secukinumab and ixekizumab) or IL-17RA targeted (brodalumab) biologics is effective in PSO and PsA. In contrast to these therapies, bimekizumab (BKZ) is a novel humanized IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A with binding affinities of 23 pM and 3.2 pM, respectively ( Adams et al., 2020 ). The clinical efficacy of BKZ warrants increased utility in patients with PSO, thereby necessitating a deeper molecular understanding of its mechanism of action ( Reich et al., 2021b , Waters et al., 2021 , Wilson et al., 2022 ).

Diamond Keywords: Psoriasis

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 24/04/2024 10:17

Discipline Tags:

Non-Communicable Diseases Autoimmune Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)