THU0038 Bimekizumab dual inhibition of IL-17A and IL-17F provides evidence of IL-17F contribution to chronic inflammation in disease-relevant cells
Authors: A Maroof, R Okoye, T Smallie, D Baeten, S Archer, C Simpson, M Griffiths, S Shaw
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> IL-17A and IL-17F share structural homology and have similar biological function<sup>1</sup>. Although the contribution of IL-17A to immune-mediated inflammatory diseases has been widely reported<sup>1–3</sup>, 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. <h3>Objectives</h3> 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. <h3>Methods</h3> 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 <i>in vitro</i> 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. <h3>Results</h3> 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&lt;0.05) and IL-8 (35% lower p&lt;0.05) production than IL-17A inhibition. Bimekizumab treatment of Th17 SN-stimulated normal dermal fibroblasts also reduced production of IL-6 (35% lower p&lt;0.0001) and IL-8 (57% lower p&lt;0.0001) more than IL-17A alone. Combining IL-17A + IL-17F monoclonal antibodies produced similar results to bimekizumab. Levels of expression of 27 inflammation-linked genes, including <i>CXCL1</i>, <i>CXCL2</i>, <i>CXCL3</i> and <i>IL-15RA</i>, 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. <h3>Conclusions</h3> 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. <h3>References</h3> 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. <h3>Disclosure of Interest</h3> 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