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.
In: Annals of the Rheumatic Diseases, Jg. 77 (2018-04-01), Heft 4, S. 523-532
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Zugriff:
Objective: Interleukin (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. Methods: Preclinical 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. Results: IL-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. Conclusions: These 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 Number: NCT02141763; Results. [ABSTRACT FROM AUTHOR]
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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.
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Autor/in / Beteiligte Person: | Glatt, Sophie ; Baeten, Dominique ; Baker, Terry ; Griffiths, Meryn ; Ionescu, Lucian ; Lawson, Alastair D. G. ; Maroof, Ash ; Oliver, Ruth ; Popa, Serghei ; Strimenopoulou, Foteini ; Vajjah, Pavan ; Watling, Mark I. L. ; Yeremenko, Nataliya ; Miossec, Pierre ; Shaw, Stevan |
Zeitschrift: | Annals of the Rheumatic Diseases, Jg. 77 (2018-04-01), Heft 4, S. 523-532 |
Veröffentlichung: | 2018 |
Medientyp: | academicJournal |
ISSN: | 0003-4967 (print) |
DOI: | 10.1136/annrheumdis-2017-212127 |
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