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Updated: Jul 1, 2025
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Lymphocyte Isolation from Human Skin for Phenotypic Analysis and Ex Vivo Cell Culture
Published on: April 8, 2016
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Structural Basis for p19 Targeting by Anti-IL-23 Biologics: Correlations with Short- and Long-Term Efficacy in
Stefano G Daniele1, Sherif A Eldirany2, Giovanni Damiani3,4,5
1MD-PhD Program, Yale School of Medicine, New Haven, Connecticut, USA.
Summary
Interleukin-23 (IL-23) inhibitors show varying clinical efficacy in psoriasis. Epitope surface area, binding affinity, and dissociation rates correlate with treatment success, explaining differences among IL-23 biologics.
Area of Science:
- Immunology
- Dermatology
- Structural Biology
Background:
- Interleukin-23 (IL-23) is a key driver in psoriasis development.
- Biologics targeting IL-23 are effective psoriasis treatments, but their varying clinical efficacy is not fully understood.
- Current IL-23 inhibitors include p19-subunit binders (risankizumab, tildrakizumab, guselkumab) and a p40-binder (ustekinumab).
Purpose of the Study:
- To investigate the structural and molecular properties of IL-23 inhibitor epitopes.
- To correlate these epitope properties with binding kinetics and clinical efficacy in plaque psoriasis.
- To explain the differential clinical responses observed among IL-23 biologics.
Main Methods:
- Epitope mapping using hydrogen-deuterium exchange or crystallographic data.
- Analysis of epitope location, hydrophobicity, surface charge, and solvent-accessible surface area.
- Linear regression analysis correlating molecular properties with binding affinity (KD, kon, koff) and clinical efficacy (PASI-90).
Main Results:
- Each IL-23 inhibitor targets a unique epitope on the IL-23 surface.
- Epitope surface area showed strong correlation with binding affinity (KD) and dissociation rate (koff), but not association rate (kon).
- Larger epitope surface area, lower KD, and lower koff were associated with higher short-term and long-term PASI-90 responses, with risankizumab showing the greatest efficacy.
Conclusions:
- Molecular properties of IL-23 inhibitor epitopes, particularly surface area, significantly influence binding kinetics and clinical efficacy.
- Epitope surface area and associated binding parameters explain the differential efficacy among IL-23 biologics for psoriasis.
- This study provides molecular insights into the varying clinical outcomes of IL-23 targeted therapies.
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