Clinical and Molecular Effects of Interleukin-17 Pathway Blockade in Psoriasis

February 2020 | Volume 19 | Issue 2 | Original Article | 138 | Copyright © February 2020

Published online January 17, 2020

Lawrence Green , Jeffrey M. Weinberg , Alan Menter , Jennifer Soung , Edward Lain , Abby Jacobson

aGeorge Washington University School of Medicine, Washington, DC bIcahn School of Medicine at Mount Sinai, New York, NY cBaylor Scott & White, Dallas, TX dSouthern California Dermatology, Santa Ana, CA eAustin Institute for Clinical Research, Pflugerville, TX fOrtho Dermatologics, Bridgewater, NJ

via the IL-17 receptor.15,26,29 Ixekizumab is a humanized monoclonal antibody that selectively binds with IL-17A and inhibits its interaction with the IL-17 receptor.26,30 Secukinumab is a highaffinity, fully human monoclonal antibody that selectively binds and neutralizes IL-17A.29 Fully human monoclonal antibodies, such as brodalumab and secukinumab, have no murine sequence, whereas humanized monoclonal antibodies contain murine sequence–derived complementarity-determining regions engrafted into human-derived V regions.31 Of note, fully human monoclonal antibodies may have a lower potential for immunogenicity than humanized monoclonal antibodies.32

Pharmacologic Effects of IL-17 Pathway Inhibition in Psoriasis
In early-phase human studies, brodalumab normalized psoriatic gene expression profiles and led to significantly decreased keratinocyte hyperproliferation, reduced epidermal thickening, and fewer numbers of infiltrating T cells in the skin of patients with psoriasis.28,33 Within 1 week, expression of IL-23 and IL-12 subunit genes was reduced, indicating that brodalumab may reduce inflammatory markers upstream of IL-17 receptor A.28,34 Within 2 weeks, IL-17A, IL-17C, and IL-17F were downregulated in a dose-dependent manner.28 In a punch biopsy subset of patients enrolled in three phase 3 clinical trials of brodalumab, extensive improvement in clinical features of psoriasis was accompanied by near-complete resolution of histologic and genomic features of psoriasis, including a transcriptome of lesional skin that resembled nonlesional skin after brodalumab treatment.34

In an early study of secukinumab that included patients with plaque psoriasis, reductions in clinical disease activity were associated with reductions of histomorphologic signs of acanthosis and epidermal hyperplasia and changes in gene expression of IL-17A pathway markers.35 For example, expression of IL-17A and IL-22 was markedly reduced after secukinumab therapy, as was the area occupied by dermal IL17A+CD3+ T cells.35

Skin lesions from patients with psoriasis in a phase 1 study of ixekizumab demonstrated significant dose-dependent reductions from baseline in keratinocyte proliferation, hyperplasia, epidermal thickness, and dermal and epidermal infiltration by T cells and dendritic cells.36 These changes were accompanied by decreased expression of cytokines from multiple T-cell subsets, including interferon-γ, IL-17A/F, and IL-22 and the dendritic cell cytokine IL-23.36