Diverse by Design: The Unique Molecular Footprints of IL-23 Biologics in Psoriasis

Recent findings from a groundbreaking new study have elucidated the structural underpinnings of IL-23 targeted biologic therapies herald a new era in the management of psoriasis. Published in JID Innovations, “Structural Basis for p19 Targeting by Anti–IL-23 Biologics: Correlations with Short- and Long-Term Efficacy in Psoriasis,” provides invaluable insights into how these therapies bind to the IL-23 p19 subunit, shedding light on their molecular properties and their implications for clinical efficacy.

Psoriasis, a chronic inflammatory skin condition affecting millions in the United States, has long been a focus of therapeutic innovation. Central to its pathogenesis is the cytokine IL-23, a pivotal player in the immune cascade that drives the psoriatic process. The study maps the binding sites of IL-23 inhibitors, such as risankizumab, tildrakizumab, and guselkumab, revealing that each binds uniquely to the p19 subunit, distinct from ustekinumab which targets the p40 subunit shared with IL-12.

One of the most striking findings is the correlation between the epitope’s surface area on the IL-23 molecule and the biologic’s binding affinity and clinical efficacy. The study demonstrates that a larger epitope surface area correlates with stronger binding affinity and, crucially, with improved clinical outcomes, both in the short and long term. This correlation underscores the importance of molecular interaction in the effectiveness of biologic therapies, offering a clearer understanding of why certain treatments may be more efficacious than others.

Furthermore, the study delves into the epitope’s chemical properties, revealing variations in hydrophobicity and charge that distinguish each biologic. This detailed molecular characterization not only enhances our understanding of how these treatments work but also paves the way for the development of more targeted and effective therapies.

“The implications of this study are profound, providing a molecular basis for the selection of biologic therapies in clinical practice,” Christopher Bunick, MD, PhD, an associate professor of dermatology at the Yale University School of Medicine and principal investigator on the study, told Practical Dermatology. “It suggests that understanding the structural nuances of biologics can inform more personalized treatment strategies, potentially leading to better patient outcomes.” 

The study findings also offer a blueprint for future drug development. By elucidating the structural factors that influence therapeutic efficacy, drug discovery scientists can design new biologics with optimized binding characteristics, heralding a new frontier in psoriasis treatment.

From Molecule to Outcome: How Structural Properties Shape IL-23 Inhibitors’ Efficacy

Dr. Bunick and his team sought to answer a legitimate question: Why do anti-IL-23 biologics approved for psoriasis differ in clinical efficacy?  

To answer this question, Dr. Bunick’s lab utilized a combination of hydrogen-deuterium exchange and crystallographic experiments to meticulously map the binding epitopes of IL-23 inhibitors on the IL-23 molecule, focusing particularly on the p19 subunit.  This approach allowed the team to accurately determine the locations, hydrophobicity, and surface charge of the inhibitor epitopes. By comparing these molecular characteristics, they were able to establish the unique binding mechanisms of each biologic, including risankizumab, tildrakizumab, guselkumab, and ustekinumab.

Furthermore, the study employed linear regression analysis to correlate the molecular properties of each biologic epitope, such as solvent-accessible surface area, with their binding affinity and kinetic values. This analysis extended to examining the relationship between the structural properties of the biologics and their clinical efficacy in treating plaque psoriasis, as measured by PASI-90 response rates over both short-term (10-16 weeks) and long-term (44-60 weeks) periods.  Based on a network meta-analysis, risankizumab demonstrated the highest efficacy among all anti-IL-23 biologics.  

Not all Anti-IL-23 Biologics Are Created Equal

The researchers attributed risankizumab’s highest efficacy to its large epitope surface area (SA) on the IL-23 p19 subunit. Risankizumab demonstrated the largest SA among the examined IL-23 inhibitors, which correlated strongly with higher binding affinity to IL-23. The linear regression analysis within the study showed a significant inverse relationship between epitope SA and the equilibrium dissociation constant (KD), indicating that a larger epitope SA is associated with stronger binding affinity. Furthermore, this larger SA was also inversely related to the dissociation rate constant (koff), suggesting that risankizumab forms more stable complexes with IL-23, leading to a prolonged therapeutic effect.

This strong correlation between the size of the epitope SA, higher binding affinity, and slower dissociation rate underlies the structural basis for risankizumab’s superior clinical efficacy in treating plaque psoriasis. The study highlighted that these molecular characteristics, particularly the larger epitope SA, play a crucial role in the biologic’s effectiveness, as reflected in its higher PASI-90 response rates in both short-term and long-term treatments.

The study represents a significant leap forward in our understanding of IL-23 targeted biologic therapies for psoriasis. By unraveling the complex interplay between molecular structure and clinical efficacy, it not only enhances our understanding of current treatments but also lights the path toward more effective therapies in the future. As we continue to decipher the molecular landscapes of disease, the prospects for patients with psoriasis and other inflammatory conditions have never been brighter. 

1. Danaiele S, Eldirany S, Damiani G, et al. Structural Basis for p19 Targeting by Anti–IL-23 Biologics: Correlations with Shortand Long-Term Efficacy in Psoriasis. JID Innovations. 2024;4(2):100261.