INTRODUCTION
Psoriasis is a chronic inflammatory skin disease affecting over 7.5 million adults in the United States, and over 41 million people worldwide.1,2 Among the key players in its pathogenesis is the cytokine Interleukin (IL)-23, making it a prime target for biologic therapies. IL-23 is a heterodimer composed of the p19 and p40 subunits.3,4 The biologics that target IL-23, such as risankizumab, tildrakizumab, and guselkumab, focus on the p19 subunit, while ustekinumab targets the p40 subunit. In this brief review, we discuss the findings of a study by Daniele SG et al, published in JID Innovations in 2024, which analyzes the structural properties of these IL-23 biologics and thereby provides a molecular rationale as to why risankizumab stands out as highly efficacious in psoriasis.5
Understanding IL-23 Biologics
IL-23 biologics are designed to bind to specific regions (epitopes) on the p19 or p40 subunits, preventing IL-23 from activating its receptor and triggering the inflammatory cascade responsible for psoriasis. The study compared the binding characteristics of four IL-23 inhibitors:
- Risankizumab
- Tildrakizumab
- Guselkumab
- Ustekinumab
Key Structural Findings
The study focused on several structural properties of these inhibitors, including:
Clinical Implications
- Epitope Location: Each inhibitor binds to a unique epitope on the IL-23 molecule, which does not have to be in the IL-23R binding site region for clinical efficacy.
- Epitope Chemistry: Each epitope is made up of a unique composition of polar, basic, acidic, and hydrophobic amino acid residues, all of which do not correlate with clinical efficacy.
- Epitope Surface Area: Larger surface areas correlate with stronger and more stable binding, as well as greater clinical efficacy.
- Binding Affinity (KD): This measures how strongly the inhibitor binds to IL-23 and is indirectly correlated with epitope surface area and clinical efficacy.
- Dissociation Rate (koff): This measures how quickly the inhibitor-IL-23 complex falls apart and is indirectly related to epitope surface area and clinical efficacy.
1. Epitope Surface Area and Binding Affinity:
- Risankizumab has the largest epitope surface area (2400 Ų), allowing it to bind more tightly and stably to IL-23.
- Larger surface areas correlate with lower KD values, indicating stronger binding affinity.
2. Dissociation Rate:
- Risankizumab has the slowest dissociation rate (koff), meaning it remains bound to IL-23 for a longer duration, enhancing its therapeutic effect.
3. Clinical Efficacy:
- These structural properties translate into higher clinical efficacy, measured by the PASI-90 response rate (a 90%improvement in the Psoriasis Area and Severity Index).
- Short-term (10-16 weeks) and long-term (44-60 weeks) clinical efficacy, measured by PASI-90 response rates, were highest for risankizumab, followed by guselkumab, based on network meta-analysis.6 Tildrakizumab exhibited the lowest efficacy, which aligns with its smallest epitope surface area (1290 Ų).
Clinical Implications
1. Drug Selection:
- Clinicians can use these insights to guide clinical management, selecting the most effective biologic for their patients. Given its binding properties, less frequent dosing schedule, and clinical outcomes, risankizumab may be preferred for patients with moderate and severe plaque psoriasis.
