Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation

Abstract

ObjectiveInterleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone.MethodsPreclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease-relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated.ResultsIL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals.ConclusionsThese data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions.Trial registration numberNCT02141763; Results.

Presence, function, and regulation of IL‐17F‐expressing human CD4+ T cells

“…However, in the experimental colitis mouse model neutralization of both IL-17A and IL-17F ameliorated colitis, whereas neutralization of IL-17A or IL-17F alone had limited effect [19]. Of relevance, a recent report using human in vitro models suggest that dual blockade of IL-17A and IL-17F in Th17 supernatants was more effective at reducing the secretion of pro-inflammatory mediators from target cells than blockade of IL-17A alone [20]. Finally, early clinical studies with bimekizumab, a dual IL-17A and IL-17F neutralizing antibody, have shown rapid and profound clinical responses in psoriasis [21] and PsA [20] patients suggesting an unappreciated role for IL-17F in addition to IL-17A in promoting inflammation.…”

“…A limited number of studies have identified the expression of IL-17F in RA and PsA synovial tissue when compared with osteoarthritis (OA) samples via immunohistochemistry analysis [14,25]. In addition, a recent study showed detectable levels of IL17F mRNA in six out of 14 PsA synovial tissue samples [20]. A different study, however, reported that while IL-17A protein was detected in the supernatant of stimulated RA synovial fluid mononuclear cells, no IL-17F protein was detectable [18].…”

Assessment of transcriptional activity genes associated with the IL‐17 signaling pathway in skin fibroblasts under the influence of adalimumab

“…Observations made by Wang et al (Glatt et al, ) indicate the presence of synergistic effects of IL‐17 and TNF on the intensity of the molecular basis of pigmentation changes observed in psoriasis. In addition, IL‐17 levels have been shown to be one of the factors determining the efficacy of anticytokine therapy (Berthuy, Blum, & Marquette, ; Codreanu et al, ).…”

“…Observations made by Wang et al (Glatt et al, 2018) determining the efficacy of anticytokine therapy (Berthuy, Blum, & Marquette, 2016;Codreanu et al, 2018).…”

Translational drug discovery and development with the use of tissue‐relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy

“…The advantages of bispecific antibodies are that they may be more selective, they may be efficacious at lower dosages, they may hit two or more pathways simultaneously, thus preventing escape mechanisms, and with specific modulation of their three-dimensional structure, pharmacokinetic properties of those antibodies may be intentionally determined. [26,27] An additional strategy could involve specific binding to certain tissues/ cells to result in a target organ specific enrichment of the antibody with higher local efficacy and less systemic side effect potential. [25] The most advanced example of a currently ongoing late-stage clinical development programme for a multi-specific targeting strategy is in Ph3 with bimekizumab targeting IL17A/F in psoriasis and psoriatic arthritis.…”