Structural Insights: What Makes Some IL-23 Biologics More Effective in Psoriasis

October 2024 | Volume 23 | Issue 10 | 903 | Copyright © October 2024


Stefano G. Daniele MD PhDa, Fabrizio Galimberti MD PhDb, Christopher G. Bunick MD PhDc

aDepartment of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Harvard Combined Dermatology Residency Training Program, Boston, MA
bDepartment of Dermatology, Conway Medical Center Conway, SC
cDepartment of Dermatology, Yale University, New Haven, CT; Program in Translational Biomedicine, Yale University School of Medicine, New Haven, CT

Abstract

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:
  1. Risankizumab
  2. Tildrakizumab
  3. Guselkumab
  4. Ustekinumab
Key Structural Findings
The study focused on several structural properties of these inhibitors, including:
  • 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.
Why Some IL-23 Biologics Are Better
1. Epitope Surface Area and Binding Affinity:
  • Risankizumab has the largest epitope surface area (2400 A²), 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, as 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 A²).
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.
2. Biologic Switching:
  • If a patient does not respond to one IL-23 inhibitor, switching to another within the same class may still be effective. The distinct structural characteristics of each biologic mean that a lack of response to one agent does not preclude success with another.
  • A real-world study on switching rates among psoriasis patients initiating biologics over a 24-month period shows that risankizumab had the lowest switch rate at 8.5% followed by guselkumab at 15.7%.7
3. Mechanistic Insights:
  • Understanding the molecular basis of how these drugs work can help clinicians anticipate their effectiveness and tailor treatments more precisely.

CONCLUSION

Structural properties of IL-23 inhibitors, such as epitope size, binding affinity, and dissociation rate, are important determinants of their clinical efficacy. As such, the highest efficacy outcomes of risankizumab in treating moderate and severe plaque psoriasis may be explained by its larger epitope surface area and slower dissociation rate. These insights empower clinicians to make more informed decisions, optimizing treatment strategies to achieve better patient outcomes.

DISCLOSURES

FG has served as a consultant and/or speaker for AbbVie, Almirall, Arcutis, BMS, Galderma, Janssen, Leo, Novartis, Pfizer, Sanofi, Sunpharma, and UCB. CGB has served as an investigator for AbbVie and Sun Pharma and a consultant for AbbVie, Arcutis, Novartis, Takeda, and UCB. SGD does not have any disclosures to report.

REFERENCES

  1. Armstrong AW, Mehta MD, Schupp CW, et al. Psoriasis prevalence in adults in the United States. JAMA Dermatol. 2021;157(8):940-6. 
  2. Damiani G, Bragazzi NL, Karimkhani Aksut C, et al. The global, regional, and national burden of psoriasis: results and insights from the global burden of disease 2019 study. Front Med. 2021;8:743180. 
  3. Chan TC, Hawkes JE, Krueger JG. Interleukin 23 in the skin: role in psoriasis pathogenesis and selective interleukin 23 blockade as treatment. Ther Adv Chronic Dis. 2018;9(5):111-9. 
  4. Lebwohl M. Interleukin-23 blockade: another breakthrough in the treatment of psoriasis. Lancet. 2019;394(10198):544-6. 
  5. Daniele SG, Eldirany SA, Damiani G, et al. Structural basis for differential p19 targeting by anti-il-23 biologics: correlations with short-and long-term clinical efficacy in psoriasis. JID Innovations. 2024:100261. 
  6. Armstrong AW, Puig L, Joshi A, et al. Comparison of biologics and oral treatments for plaque psoriasis: a meta-analysis. JAMA Dermatology. 2020;156(3):258-69. 
  7. Armstrong AW, Patel M, Li C, et al. Real-world switching patterns and associated characteristics in patients with psoriasis treated with biologics in the United States. J Dermatol Treat. 2023;34(1):2200870. 

AUTHOR CORRESPONDENCE

Christopher G. Bunick MD PhD christopher.bunick@yale.edu
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