Crystal Structure of Bimekizumab Fab Fragment in Complex with IL-17F Provides Molecular Basis for Dual IL-17A and IL-17F Inhibition

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 Liu X. Sun S. Liu D. IL-17D: a less studied cytokine of IL-17 family. International Archives of Allergy and Immunology. 2020; 181: 618-623 Crossref Scopus (24) Google Scholar ). IL-17 cytokines primarily function as homodimers, although IL-17A and IL-17F can heterodimerize ( Brembilla et al., 2018 Brembilla N.C. Senra L. Boehncke W.-H. The IL-17 family of cytokines in psoriasis: IL-17A and beyond. Frontiers in immunology. 2018; 9: 1682 Crossref PubMed Scopus (302) Google Scholar ). 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 Brembilla N.C. Senra L. Boehncke W.-H. The IL-17 family of cytokines in psoriasis: IL-17A and beyond. Frontiers in immunology. 2018; 9: 1682 Crossref PubMed Scopus (302) Google Scholar , Liu et al., 2020 Liu X. Sun S. Liu D. IL-17D: a less studied cytokine of IL-17 family. International Archives of Allergy and Immunology. 2020; 181: 618-623 Crossref Scopus (24) Google Scholar ). 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 Adams R. Maroof A. Baker T. Lawson A.D. Oliver R. Paveley R. et al. Bimekizumab, a novel humanized IgG1 antibody that neutralizes both IL-17A and IL-17F. Frontiers in Immunology. 2020; 11: 1894 Crossref PubMed Scopus (79) Google Scholar ). 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 Reich K. Warren R.B. Lebwohl M. Gooderham M. Strober B. Langley R.G. et al. Bimekizumab versus secukinumab in plaque psoriasis. New England Journal of Medicine. 2021; 385: 142-152 Crossref PubMed Scopus (157) Google Scholar , Waters et al., 2021 Waters L.C. Veverka V. Strong S.L. Muskett F.W. Dedi N. Lawson A.D. et al. Conformational dynamics in interleukin 17A and 17F functional complexes is a key determinant of receptor A affinity and specificity. Cytokine. 2021; 142155476 Crossref Scopus (4) Google Scholar , Wilson et al., 2022 Wilson S.C. Caveney N.A. Yen M. Pollmann C. Xiang X. Jude K.M. et al. Organizing structural principles of the IL-17 ligand–receptor axis. Nature. 2022; 609: 622-629 Crossref PubMed Scopus (15) Google Scholar ).