In a recent study published in the Journal of Investigative Dermatology, researchers employed X-ray crystallography to gain insights into how bimekizumab (Bimzelx; UCB) binds to interleukin (IL)-17F. Adams et al aimed to better understand how this unique mechanism of action can benefit patients with psoriasis and psoriatic arthritis.
Bimekizumab, which was approved by the U.S. Food and Drug Administration in October 2023, became the first and only IL-17A and IL-17F inhibitor approved for the treatment of adults with moderate-to-severe plaque psoriasis. The approval came after the success of three Phase 3 studies which evaluated the safety and efficacy of bimekizumab.
During recent research, Adams et al explain that while other IL-17-targeted agents such as secukinumab and ixekizumab target the IL-17A isoform and brodalumab targets the IL-17A receptor, bimekizumab, a humanized IgG1 monoclonal antibody, selectively inhibits two IL-17 isoforms, both IL-17A and IL-17F. In addition, both IL-17A and IL-17F have been shown to promote disease pathogenesis, and unlike the other IL-17 cytokines, they can heterodimerize. The researchers further noted that IL-17A is 100-fold more potent than IL-17F, while IL-17F is approximately 30-fold more abundant in inflamed tissues. According to Adams et al, these features of an “overlapping biology” are the rationale for targeting IL-17A and IL-17F.
When studying the structure of bimekizumab, it was found that it strongly binds IL-17A and IL-17F through a combination of hydrogen bonds and aliphatic/hydrophobic interactions. The authors note that “This biochemical mechanism of dual inhibition may explain the high levels of efficacy and durability of clinical responses as observed in patients with PSO and psoriatic arthritis receiving BKZ across all clinical studies.”
Adams et al reported that “Together, selective inhibition of IL-17F in addition to IL-17A with BKZ normalizes inflammatory gene expression in lesional biopsies leading to high levels of skin clearance in patients with PSO and a unique dosing posology within the IL-17 class.” They concluded that data from the study supported the evidence that links the unique structural features of bimekizumab with the deep and sustained clinical response that were observed in patients with psoriasis and psoriatic arthritis.
Christopher G. Bunick, MD, PhD, study author and associate professor of dermatology and translational biomedicine at Yale University School of Medicine states “As the Bunick lab recently showed in its investigation of the epitopes used by IL-23 specific biologics, the epitope targeted by psoriasis therapeutics matters for clinical efficacy. The work here on bimekizumab further supports this concept, and future research to understand the biochemical characteristics of drug epitopes is critical to advancing innovation and clinical understanding of drug efficacy in psoriasis and more broadly throughout dermatology.”
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Sources:
- Kaitlyn Bader, Senior Editor. (2024, July 8). Crystal structure of bimekizumab FAB fragment supports efficacy of IL-17 dual inhibition. Dermatology Times. https://www.dermatologytimes.com/view/crystal-structure-of-bimekizumab-fab-fragment-supports-efficacy-of-il-17-dual-inhibition
- BIMZELX[®] Approved by the U.S. FDA for the Treatment of Adults with Moderate to Severe Plaque Psoriasis | UCB. (n.d.). https://www.ucb.com/stories-media/Press-Releases/article/BIMZELXR-Approved-by-the-US-FDA-for-the-Treatment-of-Adults-with-Moderate-to-Severe-Plaque-Psoriasis
- Crystal Structure of Bimekizumab Fab Fragment in Complex with IL-17F Provides Molecular Basis for Dual IL-17A and IL-17F Inhibition
