Crystal Structure of Bimekizumab Fab Fragment Supports Efficacy of IL-17 Dual Inhibition

Chronic plaque psoriasis | Image credit: DermNet

In a recent scientific paper published in the Journal of Investigative Dermatology,¹ Adams et al sought to better understand how bimekizumab (Bimzelx; UCB) binds to interleukin (IL)-17F and how bimekizumab’s unique mechanism of action can benefit patients with psoriasis and psoriatic arthritis. In Adams et al’s research, the technique of X-ray crystallography was used: crystals of bimekizumab fragment antigen-binding (Fab) in complex with IL-17F (BKZ –IL-17F) were generated using hanging drop vapor diffusion, an X-ray diffraction dataset was collected, and the crystal structure was determined by molecular replacement using coordinates of an in-house Fab and IL-17F.

"It was a privilege to be a part of this investigation elucidating the structural mechanism of bimekizumab inhibition of IL-17A/F. The main takeaway for practicing dermatologists is that bona fide molecular science backs up and explains the potent clinical efficacy observed in patients when using this biologic. In day-to-day practice, dermatologists can reassure psoriasis patients that bimekizumab’s exceptional results are strongly supported and explained by its unique molecular and structural properties," said Christopher Bunick, MD, PhD, study author, associate professor of dermatology and translational biomedicine at Yale University School of Medicine in New Haven, Connecticut, and Dermatology Times’ 2024 Winter Editor in Chief.

Background

Bimekizumab was approved for the treatment of adults with moderate to severe plaque psoriasis in October 2023 as the first and only FDA-approved IL-17A and IL-17F inhibitor for plaque psoriasis.² According to Adams et al, there are 6 IL-17 isoforms (IL-17A – F) and 5 IL-17 receptors (IL-17RA – E). The researchers also noted that IL-17 cytokines mostly function as homodimers, however, IL-17A and IL-17F can heterodimerize.

In psoriasis and psoriatic arthritis, inhibiting the IL-17 pathway with IL-17A-targeted biologics (secukinumab and ixekizumab) or IL-17RA – targeted biologics (brodalumab) is successful. In comparison, bimekizumab is a novel humanized IgG1 antibody that selectively inhibits IL-17F and IL-17A, with binding affinities of 23 and 3.2 pM, respectively, according to Adams et al.

“The clinical efficacy of BKZ warrants increased utility in patients with PSO, thereby necessitating a deeper molecular understanding of its mechanism of action,” wrote the researchers.

Adams et al noted that the logic of dual targeting of IL-17A and IL-17F is their “overlapping biology.” Il-17A is 100-fold more potent than IL-17F, yet IL-17F is approximately 30-fold more abundant in inflamed tissues, according to the researchers.

Results

From their testing, Adams et al found that the binding of bimekizumab Fab to IL-17F is mostly mediated by the light chain with a buried surface area of 852 A°² (68.7%) compared with 388 A°² (31.3%) of the heavy chain. The bimekizumab heavy chain binds to one IL-17F monomer, while the bimekizumab light chain contacts both monomers in the homodimer. Additionally, binding by heavy chain is mediated by complementarity-determining region 3. 

“In contrast, all 3 complementarity-determining regions, along with residues in frameworks 2 and 3 (conserved regions within the variable portion of the antibody), mediate binding by light chain. The main regions of contact for light chain are with unstructured peptides from both monomers,” wrote Adams et al.

Additional findings include bimekizumab Fab binding 45.5% of residues recognized by IL-17RC and that the superposition of BKZ – IL-17F onto IL-17A demonstrated that bimekizumab Fab may bind 41.5% of the residues recognized by IL-17RA. According to Adams et al, their findings are consistent with “potent neutralization of both IL-17F and IL-17A in functional cell assay.”

Adams et al determined that bimekizumab strongly binds IL-17A and IL-17F through a combination of hydrogen bonds and aliphatic/hydrophobic interactions while burying approximately 1240 A°² total surface area at the BKZ – IL-17 interface. “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,” wrote Adams et al.

“As the Bunick lab recently showed in its investigation of the epitopes used by IL-23 specific biologics,³ 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," said Bunick.

Regarding clinical efficacy, results from the phase 3b BE RADIANT (NCT03536884) clinical trial evaluating bimekizumab showed PASI 100 superiority when compared head-to-head with an IL-17A – targeted biologic at all measured time points. Adams et al noted that the molecular analysis of the psoriasis transcriptome before and after treatment with bimekizumab demonstrated transcriptome normalization and “indistinguishable characteristics” compared with nonlesional skin, all of which are consistent with the biochemical and clinical data.

"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. BKZ does not require an induction/loading dose and can maintain high levels of clinical response with an every 8-week dosing regimen. In conclusion, these data provide supportive evidence linking the unique structural features of BKZ with the deep and sustained clinical response observed in patients with PSO and psoriatic arthritis,” concluded Adam et al.

References

1. Adams R, Bunick CG, Lawson ADG, Gomez B, Shaw S. Crystal structure of bimekizumab fab fragment in complex with IL-17F provides molecular basis for dual IL-17A and IL-17F inhibition. J Invest Dermatol. Published online April 16, 2024. doi:10.1016/j.jid.2024.03.037
2. BIMZELX approved by the U.S. FDA for the treatment of adults with moderate to severe plaque psoriasis. UCB. October 18, 2023. Accessed June 29, 2024. 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
3. Daniele SG, Eldirany SA, Damiani G, Ho M, Bunick CG. Structural basis for p19 targeting by anti-IL-23 biologics: correlations with short- and long-term efficacy in psoriasis. JID Innov. 2024;4(2):100261. Published 2024 Jan 20. doi:10.1016/j.xjidi.2024.100261