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THU0038 Bimekizumab dual inhibition of IL-17A and IL-17F provides evidence of IL-17F contribution to chronic inflammation in disease-relevant cells
  1. A Maroof1,
  2. R Okoye1,
  3. T Smallie1,
  4. D Baeten2,
  5. S Archer1,
  6. C Simpson1,
  7. M Griffiths1,
  8. S Shaw1
  1. 1UCB Pharma, Slough, United Kingdom
  2. 2UCB Pharma, Brussels, Belgium

Abstract

Background IL-17A and IL-17F share structural homology and have similar biological function1. Although the contribution of IL-17A to immune-mediated inflammatory diseases has been widely reported1–3, 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<0.05) and IL-8 (35% lower p<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<0.0001) and IL-8 (57% lower p<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 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

  1. C Johansen et al. Br J Dermatol 2009:160:319–24.

  2. AL Lima et al. Br J Dermatol 2016:174:514–21.

  3. C Doe et al. Chest 2010:138:1140–7.

References

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

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