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Interleukin (IL)-17A is a key driver of inflammation and the principal target of anti-IL-17 therapeutic monoclonal antibodies. IL-17A, and its structurally similar family member IL-17F, have been shown to be functionally dysregulated in certain human immune-mediated inflammatory diseases such as psoriasis, psoriatic arthritis, and axial spondyloarthritis. Given the overlapping biology of these two cytokines, we postulated that dual neutralization of IL-17A and IL-17F may provide a greater depth of clinical response in IL-17-mediated diseases than IL-17A inhibition alone. We identified 496.g1, a humanized antibody with strong affinity for IL-17A but poor affinity for IL-17F. Affinity maturation of 496.g1 to 496.g3 greatly enhanced the affinity of the Fab fragment for IL-17F while retaining strong binding to IL-17A. As an IgG1, the affinity for IL-17A and IL-17F was 3.2 pM and 23 pM, respectively. Comparison of 496.g3 IgG1 with the commercially available anti-IL-17A monoclonal antibodies ixekizumab and secukinumab, by surface plasmon resonance and in a human IL-17A functional assay, showed that 496.g3 and ixekizumab display equivalent affinity for IL-17A, and that both antibodies are markedly more potent than secukinumab. In contrast to ixekizumab and secukinumab, 496.g3 exhibited the unique feature of also being able to neutralize the biological activity of IL-17F. Therefore, antibody 496.g3 was selected for clinical development for its ability to neutralize the biologic function of both IL-17A and IL-17F and was renamed bimekizumab (formerly UCB4940). Early clinical data in patients with psoriasis, in those with psoriatic arthritis, and from the Phase 2 studies in psoriasis, psoriatic arthritis, and ankylosing spondylitis, are encouraging and support the targeted approach of dual neutralization of IL-17A and IL-17F. Taken together, these findings provide the rationale for the continued clinical evaluation of bimekizumab in patients with immune-mediated inflammatory diseases.

IL-23 is considered a critical regulator of IL-17 in Th17 cells; however, its requirement for inducing IL-17 production in other human immune subsets remains incompletely understood. Mucosal associated invariant T (MAIT) cells uniformly express retinoic acid receptor-related orphan receptor gamma t (RORγt) but only a minor population have been shown to produce IL-17A. Here we show that IL-17F is the dominant IL-17 isoform produced by MAIT cells, not IL-17A. For optimal MAIT cell derived IL-17A and IL-17F production, T cell receptor (TCR) triggering, IL-18 and monocyte derived IL-12 signaling is required. Unlike Th17 cells, this process is independent of IL-23 signaling. Using an in vitro skin cell activation assay, we demonstrate that dual neutralization of both IL-17A and IL-17F resulted in greater suppression of inflammatory proteins than inhibition of IL-17A alone. Finally, we extend our findings by showing that other innate-like lymphocytes such as group 3 innate lymphoid cells (ILC3) and gamma delta (γδ) T cells are also capable of IL-23 independent IL-17A and IL-17F production. These data indicate both IL-17F and IL-17A production from MAIT cells may contribute to tissue inflammation independently of IL-23, in part explaining the therapeutic disconnect between targeting IL-17 or IL-23 in certain inflammatory diseases.

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.

BackgroundIL-17A is an established target in several chronic immune-mediated inflammatory diseases; IL-17F, sharing significant structural homology and overlapping biological function with IL-17A,1 is a relatively understudied cytokine. Bimekizumab is a humanised monoclonal IgG1 antibody that potently and selectively neutralises the biological function of both IL-17A and IL-17F. Using preclinical human in vitro models we studied the contribution of IL-17F to inflammation, via stimulation and blocking assays, in joint cells from patients with psoriatic arthritis (PsA).Materials and methodsImmunostaining was performed on synovial tissue from patients with PsA to probe for IL-17F. Recombinant IL-17A and IL-17F, with/without TNFα, were added to synoviocytes from patients with PsA, to examine their effect on inflammatory cytokine production. A complex in vitro assay was developed, using pro-inflammatory mediators from sorted Th17 cells, to explore the mechanism of action of bimekizumab and relative contributions of IL-17A and IL-17F to chronic disease. The Th17-cell supernatant profile had a complex mix of disease-relevant pro-inflammatory cytokines akin to those found elevated in joint tissue biopsies from patients with PsA. IL-17-isoform-specific blocking antibodies provided an overview of the individual and collective influence of IL-17A and IL-17F in regulating key disease-pathology-relevant cytokine and chemokine production.ResultsIL-17F protein was detected in inflamed synovium from patients with PsA. Stimulation of normal synoviocytes with recombinant IL-17A or IL-17F promoted qualitatively similar responses, notably induction of key pro-inflammatory mediators (eg, IL-8 and IL-6), albeit to a lesser extent with IL-17F than IL-17A. Similar results were obtained in synoviocytes from patients with PsA, stimulated in the presence of TNFα. When synoviocytes from patients with PsA were stimulated with Th17-cell supernatant, dual IL-17A and IL-17F inhibition with bimekizumab resulted in a greater downregulation of IL-6 (42% lower; p<0.05) and IL-8 (35.4% lower; p<0.05) expression than inhibition of IL-17A alone. Similar results were obtained using monospecific anti-IL-17A and anti-IL-17F antibodies.ConclusionsData support hypotheses that IL-17F contributes to human tissue inflammation in joints, beyond IL-17A alone, and that dual inhibition of IL-17A and IL-17F may be therapeutically beneficial in immune-mediated inflammatory diseases.AcknowledgementsThe authors thank the subjects and their caregivers in addition to the investigators and their teams who contributed to this study. This study was funded by UCB Pharma. The authors acknowledge the contributions of Tim Smallie, of UCB, Louise Healy, formerly of UCB, for their work on functional characterisation of bimekizumab. The authors also acknowledge the contribution of Catherine Simpson, of UCB, for flow cytometry cell sorting support, Remi Okoye, of UCB, for the immunohistochemistry work, and Iris Blijdorp of the Academic Medical Centre, Amsterdam, for work on blockade experiments in synoviocytes. The authors would like to acknowledge Ailsa Dermody, PhD, of iMed Comms, an Ashfield Company, part of UDG Healthcare plc, for editorial assistance that was funded by UCB Pharma.ReferenceJohansen C, Usher PA, Kjellerup RB, et al,.. Characterisation of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol 2009; 160(2): 319-24.

BackgroundIL-17A is an established target in several chronic immune-mediated inflammatory diseases; IL-17F, sharing significant structural homology and overlapping biological function with IL-17A,1 is a relatively understudied cytokine. Bimekizumab is a humanised monoclonal IgG1 antibody that potently and selectively neutralises the biological function of both IL-17A and IL-17F. Using preclinical human in vitro models we studied the contribution of IL-17F to inflammation, via stimulation and blocking assays, in joint cells from patients with psoriatic arthritis (PsA).Materials and methodsImmunostaining was performed on synovial tissue from patients with PsA to probe for IL-17F. Recombinant IL-17A and IL-17F, with/without TNF alpha , were added to synoviocytes from patients with PsA, to examine their effect on inflammatory cytokine production. A complex in vitro assay was developed, using pro-inflammatory mediators from sorted Th17 cells, to explore the mechanism of action of bimekizumab and relative contributions of IL-17A and IL-17F to chronic disease. The Th17-cell supernatant profile had a complex mix of disease-relevant pro-inflammatory cytokines akin to those found elevated in joint tissue biopsies from patients with PsA. IL-17-isoform-specific blocking antibodies provided an overview of the individual and collective influence of IL-17A and IL-17F in regulating key disease-pathology-relevant cytokine and chemokine production.ResultsIL-17F protein was detected in inflamed synovium from patients with PsA. Stimulation of normal synoviocytes with recombinant IL-17A or IL-17F promoted qualitatively similar responses, notably induction of key pro-inflammatory mediators (eg, IL-8 and IL-6), albeit to a lesser extent with IL-17F than IL-17A. Similar results were obtained in synoviocytes from patients with PsA, stimulated in the presence of TNF alpha . When synoviocytes from patients with PsA were stimulated with Th17-cell supernatant, dual IL-17A and IL-17F inhibition with bimekizumab resulted in a greater downregulation of IL-6 (42% lower; p<0.05) and IL-8 (35.4% lower; p<0.05) expression than inhibition of IL-17A alone. Similar results were obtained using monospecific anti-IL-17A and anti-IL-17F antibodies.ConclusionsData support hypotheses that IL-17F contributes to human tissue inflammation in joints, beyond IL-17A alone, and that dual inhibition of IL-17A and IL-17F may be therapeutically beneficial in immune-mediated inflammatory diseases.AcknowledgementsThe authors thank the subjects and their caregivers in addition to the investigators and their teams who contributed to this study. This study was funded by UCB Pharma. The authors acknowledge the contributions of Tim Smallie, of UCB, Louise Healy, formerly of UCB, for their work on functional characterisation of bimekizumab. The authors also acknowledge the contribution of Catherine Simpson, of UCB, for flow cytometry cell sorting support, Remi Okoye, of UCB, for the immunohistochemistry work, and Iris Blijdorp of the Academic Medical Centre, Amsterdam, for work on blockade experiments in synoviocytes. The authors would like to acknowledge Ailsa Dermody, PhD, of iMed Comms, an Ashfield Company, part of UDG Healthcare plc, for editorial assistance that was funded by UCB Pharma.ReferenceJohansen C, Usher PA, Kjellerup RB, et al,.. Characterisation of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol 2009; 160(2): 319-24.

Colony-stimulating factor-1 (CSF-1) regulates the survival, proliferation and differentiation of macrophages. CSF-1-deficient mice are osteopetrotic due to a lack of osteoclasts, while their tissue macrophage deficiencies and an absence of CSF-1 regulation of CSF-1 receptor-expressing cells in the female reproductive tract contribute to their pleiotropic phenotype. To further understand CSF-1 regulation of macrophages in vivo, we developed a neutralizing anti-mouse CSF-1 antibody which was expressed as a recombinant Fab′ fragment and coupled to 40 kDa polyethylene glycol. As developmental regulation by CSF-1 is highest during the early post-natal period, the ability of this anti-CSF-1 reagent to inhibit development was tested by regular subcutaneous injection of mice from post-natal days 0.5–57.5. Antibody treatment decreased growth rate, decreased osteoclast number, induced osteopetrosis, decreased macrophage density in bone marrow, liver, dermis, synovium and kidney and decreased adipocyte size in adipose tissue, thereby inducing phenotypes shared by CSF-1- and CSF-1 receptor-deficient mice. While the antibody blocked macrophage development in some tissues, macrophage densities in other tissues were initially high and were reduced by treatment, proving that the antibody also blocked macrophage maintenance. Since cell surface CSF-1 is sufficient for the maintenance of normal synovial macrophage densities, these studies suggest that anti-CSF-1 Fab′-PEG efficiently neutralizes all three CSF-1 isoforms in vivo, namely the secreted proteoglycan, secreted glycoprotein and cell surface glycoprotein. Since CSF-1 has been shown to enhance chronic disease development in a number of mouse model systems, these studies demonstrate the feasibility of neutralizing CSF-1 effects in these models with an anti-CSF-1 antibody.