Study Details Epitope Binding, Efficacy of IL-23 Inhibitors in Plaque Psoriasis

Chris Bunick, MD, PhD
Credit: Yale School of Medicine

An analysis of structural basis for p19 targeting by IL-23 inhibitors is providing clinicians with new insight that study investigators suggest could help guide treatment decisions with biologics in psoriasis.

Performed by Christopher Bunick, MD, and colleagues, the study examined the structural composition of the IL-23 binding epitopes of risankizumab, tildrakizumab, ustekinumab, and guselkumab and assessed their relationship with short- and long-term efficacy observed in previous data.¹

“Computational structural analysis of IL-23 inhibitor epitopes revealed important molecular differences among p19-specific psoriasis biologics that have direct relevance to patient outcomes,” wrote investigators. “Strong correlations between inhibitor epitope SA, binding affinity, dissociation kinetics, and PASI-90 response rates exemplify how biochemical and molecular data are critical for explaining clinical observations. Furthermore, structure–function–clinical response relationships can inform future pharmacologic innovation”

Analysis of IL-23 binding mechanisms revealed risankizumab, tildrakizumab, and guselkumab epitopes exist exclusively on p19, whereas ustekinumab binds exclusively on p40. Results also revealed risankizumab has the largest epitope surface area (SA), followed by guselkumab, whereas ustekinumab and tildrakizumab binded a significantly smaller epitope SA.¹

Analysis of correlations between epitope SA and binding affinity and kinetics suggested a greater epitope SA was associated with more stable immune complexes with IL-23. Specifically, results of a linear regression analysis provided evidence of a correlation between epitope SA and an inhibitor's dissociation equilibrium constant (R2 = 0.9772, P = .0115), with further analysis suggesting individual epitope SA was also inversely correlated with an inhibitor's dissociation rate constant (R2 = 0.9489, P = .0259) but this was not observed between epitope SA and association rate constant (R2 = 0.4330, P = .3420).¹

When assessing correlation of IL-23 epitope molecular properties with short-term clinical efficacy, investigators found the efficacy of IL-23–targeting biologics, assessed by PASI-90 response within 10–16 weeks, correlates directly with epitope SA and inversely with mean inhibitor epitope equilibrium dissociation constant (K_D) and dissociation rate constant (k_off), but not with association rate constant (k_on). Additionally, total residue hydrophobicity, polarity, and charge composition demonstrated no correlation with short-term PASI-90 clinical response, with the mean PASI-90 responses across tildrakizumab, guselkumab, ustekinumab, and risankizumab ranging from 38.8%, with tildrakizumab, to 71.6%, with risankizumab.¹

Analysis of long-term efficacy of IL-23–targeting biologics, which was assessed by PASI-90 response over 44 to 60 weeks, suggested efficacy directly correlates with epitope surface area size and inversely with mean inhibitor epitope equilibrium dissociation constant (K_D) and dissociation rate constant (k_off), while mean inhibitor association rate constant (k_on) shows no correlation with long-term PASI-90 response rate. Investigators also pointed out total residue hydrophobicity, polarity, and charge composition demonstrate no correlation with long-term PASI-90 clinical response. Across guselkumab, ustekinumab, and risankizumab, mean long-term PASI-90 responses ranged from 52.4%, with ustekinumab, to 79.4%, with risankizumab.¹

Of note, for both the short- and long-term efficacy analyses, investigators pooled PSI-90 responses from a 2020 meta-analysis and mean K_D, k_off, and k_on values are derived from a study published in 2021.^2,3

Investigators called attention to a multitude of limitations to consider when interpreting the findings of this study. These limitations included, but were not limited to, lack of detailed biologic–cytokine structures for the medications presented in this paper, reliance on biochemical, noncrystallographic data acquired from hydrogen–deuterium exchange experiments, and absence of long-term clinical response data for all agents included in the study.¹

“Our work deepens the molecular understanding of IL-23 inhibitors by characterizing and differentiating the chemistry and structure of their binding epitopes. In doing so, we provide the molecular rationale underpinning not only preclinical findings but also the short- and long-term clinical efficacy of these medications in the treatment of plaque psoriasis,” wrote investigators.¹

References:

1. 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
2. Armstrong AW, Puig L, Joshi A, et al. Comparison of Biologics and Oral Treatments for Plaque Psoriasis: A Meta-analysis. JAMA Dermatol. 2020;156(3):258-269. doi:10.1001/jamadermatol.2019.4029
3. Zhou L, Wang Y, Wan Q, et al. A non-clinical comparative study of IL-23 antibodies in psoriasis. MAbs. 2021;13(1):1964420. doi:10.1080/19420862.2021.1964420