Background/Purpose: IL-17A and IL-17F share structural homology and have similar biologic function.¹ Although the contribution of IL-17A to immune-mediated inflammatory diseases has been widely reported,^1,2 the role of IL-17F is less well characterized. Bimekizumab, a humanized monoclonal IgG1 antibody, developed to neutralize both IL-17A and IL-17F potently and selectively, is under clinical development as a treatment for immune-mediated diseases such as PsA and psoriasis. This study aimed 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 neutralization of IL-17A and IL-17F in suppressing inflammation, compared with blockade of IL-17A alone.

Methods: Synovial and lesional skin tissue from patients with PsA was probed by immunostaining for expression of IL-17F protein. Primary normal human dermal fibroblasts (NHDFs) and synoviocytes from patients with PsA, in the presence of TNF, were stimulated with recombinant IL-17A and IL-17F. Using cytokine-specific blocking antibodies, the individual and combined effects of IL-17A and IL-17F were explored using a complex in vitro model (synoviocytes from patients with PsA and primary NHDFs were treated with proinflammatory mediators from supernatant [SN] of sorted Th17 cells) and transcriptional as well as migratory studies were performed.

Results: IL-17F expression was observed in tissue biopsies from patients with PsA. In primary NHDFs and synoviocytes from patients with PsA, stimulation with recombinant IL-17F promoted production of proinflammatory 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 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 primary NHDFs 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 neutralization of IL-17A and IL-17F by bimekizumab versus IL-17A inhibition. Suppression of neutrophil and monocyte (Fig.) migration was substantially greater with bimekizumab than with blockade of IL-17A alone.

Conclusion: Dual neutralization of IL-17A and IL-17F provides evidence for the contribution of IL-17F to inflammation in joints and skin beyond IL-17A alone. Dual inhibition of IL-17A and IL-17F by bimekizumab may provide an effective treatment for immune-mediated inflammatory diseases such as PsA.

References:

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

²van Baarsen L et al. Arthritis Res Ther 2014;16:426