The following is a summary of “Structural Basis for p19 Targeting by Anti–IL-23 Biologics: Correlations with Short- and Long-Term Efficacy in Psoriasis,” published in the March 2024 issue of Dermatology by Daniele, et al.
IL-23 plays a central role in the pathogenesis of psoriasis, and biologics targeting IL-23 are essential therapies for this condition. Risankizumab, tildrakizumab, and guselkumab inhibit IL-23 by binding to its p19 subunit, while ustekinumab binds to p40. However, the structural composition of the IL-23-binding epitopes and their relationship to clinical efficacy remained unclear. For a study, researchers sought to map the epitope locations of IL-23 inhibitors, assess their hydrophobicity and surface charge, and investigate how these molecular properties relate to clinical efficacy in psoriasis treatment.
Epitope data derived from hydrogen-deuterium exchange or crystallographic experiments were utilized to map inhibitor epitope locations, hydrophobicity, and surface charge onto the IL-23 surface. Molecular properties of each inhibitor epitope, including solvent-accessible surface area, were correlated with binding affinity, kinetic values, and clinical efficacy scores for plaque psoriasis using linear regression analysis.
Each IL-23 inhibitor binds to an epitope with a unique size, composition, and location, except for a 10-residue overlap region outside the IL-23 receptor epitope. Strong correlations were observed between epitope surface area and binding affinity (KD) and dissociation rate (koff), but no association rate (kon). Epitope surface area, KD, and koff were further associated with short-term (10–16 weeks) and long-term (44–60 weeks) clinical efficacy, as measured by PASI-90 responses, with risankizumab demonstrating the highest efficacy among IL-23 biologics. Conversely, kon, epitope hydrophobicity, polarity, and charge content did not correlate with efficacy.
The findings illustrated how molecular principles of medications within a therapeutic class can elucidate their differential clinical responses, providing valuable insights into the mechanisms underlying the efficacy of IL-23 inhibitors in psoriasis treatment.
Reference: sciencedirect.com/science/article/pii/S2667026724000079