A Review of Brodalumab, an IL-17 Receptor Antagonist, for Moderate-to-Severe Plaque Psoriasis

Yun Tong, MD; Andrew J. Peranteau, MD; Zeena Nawas, MD; Stephen K. Tyring, MD, PhD


Skin Therapy Letter. 2017;22(1) 

In This Article

Rationale for Il-17 Inhibitors

The main physiological function of IL-17 is protection from extracellular bacteria and fungi by inducing the production of chemokines and cytokines such as TNF-α to recruit inflammatory cells to local sites of infection.[8] Additionally, IL-17 has a role in vascular dysfunction and hypertension.[5] In psoriasis, the IL-17 pathway is altered.[7] Activities of IL-17 and TNF-α are additive and synergistic drivers of inflammation upregulation that lead to a self-sustaining keratinocyte hyperproliferation of psoriasis.[3,9] Given the importance of IL-17 in inducing and mediating proinflammatory responses, it is also linked to other immune mediated diseases including rheumatoid arthritis, spondyloarthritis, uveitis, Crohn's disease, multiple sclerosis, andasthma.[10]

T-helper (Th)-17 cells and IL-17 messenger RNA (mRNA) are increased in psoriasis plaques[11] and synovial fluid of psoriatic arthritis patients.[12] Many cells are rich sources of IL-17, including gamma/delta (γδ) T-cells, which appear to have a central role in the development of psoriasis, Tc17 (a subset of CD8+, T-cells that are critical in cellular immune response), mast cells, macrophages, natural killer (NK) cells, and neutrophils.[3,7,8,11,13,14]

Current US FDA-approved IL-17 inhibitors include secukinumab and ixekizumab, and brodalumab is still under regulatory review at the time of this writing. Secukinumab and ixekizumab are directed against IL-17, whereas brodalumab is a human G2 monoclonal antibody directed against the IL-17 receptor. Under clinical investigation, brodalumab appears to benefit patients with psoriatic disease, thus further supporting the view that IL-17 and the cells that produce it play a pivotal role in disease onset and perpetuation.[14]

Several clinical psoriasis trials have confirmed that these three IL-17 inhibitors have significantly higher efficacy rates vs. placebo and TNF-α inhibitors, which are currently first-line therapy for psoriasis.[1,3,7] More established monoclonal antibody biologics are directed against TNF-α, causing generalized immunosuppression.[15] Additionally, some patients receiving anti-TNF therapy do not achieve adequate response or experience a secondary loss in efficacy due to formation of anti-TNF-α antibodies.[16]

The IL-17 family is composed of 6 different ligand homodimers, labeled A-F, and 5 receptors subtypes A-E.[17] IL-17A is the most prevalent and prototypical isomer generally referred to as IL-17 when no distinction is made.[16] Both secukinumab and ixekizumab are monoclonal antibodies that bind to and neutralize IL-17A. Additionally, IL-17A is the most potent, with 10–30 times greater effect than IL-17F.[9] However, IL-17C, IL-17F, and IL-17A/F heterodimer are all capable of inducing the expression of psoriasis-related proinflammatory molecules in keratinocytes.[18] IL-17C has been reported as the most abundant isoform in psoriatic lesions.[7] All 3 cytokines require a heteromeric receptor for biological activity.[10]

IL-17 receptors are complexes composed of heteromeric subunits. Brodalumab targets IL-17 receptor A (IL-17RA) with high affinity and inhibits the activities of IL-17 ligands A, C, E (IL-25), F, and A/F heterodimer, all of which require subunit IL-17RA in their respective receptor complexes. IL-17A and IL-17F, which are homodimers, share a common IL-17RA/IL-17RC receptor complex.[17] IL-17C mediates further signaling by docking to an IL-17RA/IL-17RE complex. IL-17E ligand interacts with an IL-17RA/IL-17RB complex. Perhaps broader coverage through blockade of a shared receptor may allow for better effect on controlling psoriasis but may lead to increased risk.[10]