Structural basis for differential p19 targeting by IL-23 biologics.

Area of Science:

• Immunology and Molecular Biology: Investigating the structural basis of drug action in autoimmune diseases.
• Dermatology: Focusing on the pathogenesis and treatment of plaque psoriasis.

Background:

• Interleukin-23 (IL-23) is a key driver in the development of plaque psoriasis.
• Current IL-23 inhibitors (risankizumab, tildrakizumab, guselkumab) target the p19 subunit, differing from ustekinumab which targets the p40 subunit.
• A gap exists in understanding the structural epitopes of these inhibitors and their link to clinical effectiveness.

Approach:

• Epitope mapping of IL-23 inhibitors (risankizumab, tildrakizumab, guselkumab, ustekinumab) using hydrogen-deuterium exchange and crystallographic data.
• Analysis of epitope location, hydrophobicity, surface charge, and solvent accessible surface area (SASA) on the IL-23 molecule.
• Correlation of structural epitope characteristics with clinical efficacy data (PASI-90 rates) and binding affinity (K_D).

Key Points:

• p19-specific inhibitor epitopes vary in size, location, and composition.
• Epitope surface area (SA) showed a strong correlation with PASI-90 rates (R² = 0.9969) and binding affinity (K_D, R² = 0.9772).
• Epitope hydrophobicity, polarity, and charge did not correlate with clinical efficacy.

Conclusions:

• Epitope surface area is a critical molecular determinant of early drug efficacy in plaque psoriasis.
• Structural insights explain clinical observations and can guide the development of novel IL-23 inhibitors.
• This analysis aids clinicians in selecting appropriate IL-23 inhibitors for individual patients.