THU0038 Bimekizumab dual inhibition of IL-17A and IL-17F provides evidence of IL-17F contribution to chronic inflammation in disease-relevant cells

Background IL-17A and IL-17F share structural homology and have similar biological function 1 . Although the contribution of IL-17A to immune-mediated inflammatory diseases has been widely reported 1–3 , the role of IL-17F is less well characterised in human tissue inflammation. Bimekizumab, a humanised monoclonal IgG1 antibody, was developed to neutralise both IL-17A and IL-17F potently and selectively, and is under clinical development as a treatment for psoriatic arthritis (PsA) and other immune-mediated conditions such as psoriasis. Objectives To assess the involvement of IL-17F in chronic inflammation in tissue from patients with PsA and disease-relevant cells, and to determine the effect of dual neutralisation of IL-17A and IL-17F in suppressing inflammation, compared with blockade of IL-17A. Methods Synovial and lesional skin tissue from patients with PsA was probed by immunostaining for expression of IL-17F protein. Normal dermal fibroblasts and synoviocytes, in the presence of TNFα, were stimulated with recombinant IL-17A and IL-17F to assess the inflammatory response. Using cytokine-specific blocking antibodies, the individual and combined effects of IL-17A and IL-17F were explored with: pro-inflammatory cytokine expression in a complex in vitro model (synoviocytes from patients with PsA and normal dermal fibroblasts were treated with pro-inflammatory mediators from supernatant [SN] of sorted Th17 cells), microarray and cell migration studies. Results IL-17F expression was observed in tissue biopsies from patients with PsA. In normal dermal fibroblasts, normal synoviocytes and synoviocytes from patients with PsA, stimulation with recombinant IL-17F promoted production of pro-inflammatory mediators, such as IL-6 and IL-8, though to a lesser extent than with recombinant IL-17A. Treatment of Th17 SN-stimulated synoviocytes from patients with PsA with bimekizumab (neutralising IL-17A and IL-17F) led to greater reductions of IL-6 (42% lower p CXCL1 , CXCL2 , CXCL3 and IL-15RA , were lower with dual neutralisation of IL-17A and IL-17F by bimekizumab versus inhibition of IL-17A. Suppression of migration of neutrophils (Fig.) and monocytes, both involved in tissue destruction in immune-mediated diseases, was substantially greater with bimekizumab treatment than with single blockade of IL-17A. Conclusions Dual neutralisation of IL-17A and IL-17F provides evidence for the contribution of IL-17F to inflammation in joints and skin beyond IL-17A alone. As a result, dual inhibition of IL-17A and IL-17F by bimekizumab may provide an effective treatment for immune-mediated inflammatory diseases such as PsA. References C Johansen et al. Br J Dermatol 2009:160:319–24. AL Lima et al. Br J Dermatol 2016:174:514–21. C Doe et al. Chest 2010:138:1140–7. Disclosure of Interest A. Maroof Employee of: UCB Pharma, R. Okoye Employee of: UCB Pharma, T. Smallie Employee of: UCB Pharma, D. Baeten Grant/research support from: UCB Pharma, Consultant for: AbbVie, Pfizer, MSD, Roche, BMS, Novartis, Eli Lilly, Boehringer Ingelhaim and Glenmark, S. Archer Employee of: UCB Pharma, C. Simpson Employee of: UCB Pharma, M. Griffiths Consultant for: UCB Pharma, Employee of: UCB Pharma, S. Shaw Employee of: UCB Pharma