Comparative Mechanisms of IL-23 Inhibitors

Comparative IL-23 inhibitor mechanisms: guselkumab vs risankizumab vs tildrakizumab

All three — guselkumab, risankizumab, and tildrakizumab — target the IL-23p19 subunit, blocking the IL-23/Th17 axis upstream of IL-17A, IL-17F, and IL-22. But despite sharing the same target, they differ meaningfully in antibody structure, receptor-binding mode, epitope size, and Fc-region behavior. These differences translate into measurable differences in preclinical potency and, to some extent, clinical response.

Antibody structure and Fc region

Guselkumab is a fully human IgG1 with a native Fc region; risankizumab is a humanized IgG1 with a deliberately mutated Fc region; tildrakizumab is a humanized IgG1 with a native Fc region. The mutation in risankizumab abolishes FcγR binding, which turns out to have significant functional consequences that distinguish it from guselkumab.

Receptor interaction and allosteric behavior

Risankizumab and guselkumab both act as competitive inhibitors of the p19/IL-23Rα interaction — they physically block IL-23 from docking with its receptor. Tildrakizumab does neither: it reduces IL-23's affinity for IL-23Rα without fully blocking the interaction, behavior consistent with negative allosteric modulation rather than direct competitive inhibition. A non-clinical comparative study published in mAbs confirmed this: risankizumab and guselkumab completely blocked TH17 terminal differentiation in vitro, while tildrakizumab had minimal impact. In an IL-23-induced ear-swelling mouse model, tildrakizumab was essentially ineffective at comparable doses.

Epitope size and binding affinity

The three drugs also bind distinct epitopes on p19 that differ in size and physicochemical character. Daniele et al. used hydrogen-deuterium exchange data to map the binding footprints: risankizumab covers roughly 2,400 Ų and guselkumab about 2,240 Ų, while tildrakizumab contacts only ~1,290 Ų. Risankizumab and guselkumab epitopes are predominantly non-hydrophobic, while tildrakizumab's is 56% hydrophobic. Critically, epitope surface area correlated strongly with both binding affinity and short-term PASI-90 rates. Potency-wise, a non-clinical comparison found risankizumab is roughly 3-fold more potent than guselkumab and about 50-fold more potent than tildrakizumab at inhibiting IL-23 signaling in bioassays.

Guselkumab's CD64-binding mechanism

The native Fc region of guselkumab enables a mechanism the other two lack. CD64 (FcγRI) is highly expressed on myeloid cells in lesional psoriatic skin, and these same CD64+ macrophages are the dominant local source of IL-23. Guselkumab binds CD64 via its Fc region, tethering the antibody to the very cells producing IL-23. A recent paper showed that CD64-anchored guselkumab simultaneously captures IL-23 secreted from those cells, and live-cell confocal imaging demonstrated that the drug-cytokine complex is subsequently internalized into low-pH compartments for degradation. Risankizumab, with its mutated Fc, cannot do any of this. In a co-culture model where IL-23-producing THP-1 cells were placed next to an IL-23-responsive reporter line, guselkumab showed enhanced potency over risankizumab specifically because of Fc-CD64 engagement; in simple assays with exogenously added IL-23, the two drugs perform equivalently. This positions guselkumab as being enriched in the inflamed tissue microenvironment, neutralizing IL-23 at source, which the developers argue underlies the observed clinical durability advantages.

Downstream pathway effects

All three suppress the IL-23/Th17 axis, reducing IL-17A, IL-17F, and IL-22. An ECLIPSE substudy showed that guselkumab produced significantly greater reductions in serum IL-17F and IL-22 than secukinumab (an IL-17A blocker) at weeks 24 and 48, demonstrating the upstream advantage: blocking IL-23 suppresses multiple effector cytokines simultaneously rather than just IL-17A. Confirmation studies showed that guselkumab more effectively normalized skin transcriptomics and suppressed Th17 serum cytokines than ustekinumab.

Clinical translation

In real-world data, risankizumab tends to show faster and deeper responses, while guselkumab and tildrakizumab are more comparable in short-term PASI reduction; tildrakizumab's lower preclinical potency doesn't fully manifest as inferior PASI responses in practice, likely because approved doses are calibrated for clinical equivalence at the tissue level. A recent Italian real-world registry study found risankizumab offered faster response onset, but tildrakizumab 200 mg was an effective long-term option particularly in higher-BMI or more refractory patients, supporting a personalized selection approach. A Danish retrospective study showed no statistically significant difference in achieving PASI ≤ 2 between the three agents.

The mechanistic picture is thus: risankizumab has the largest epitope footprint and highest raw potency; guselkumab adds a tissue-enrichment mechanism through CD64 engagement that may confer durability advantages in inflamed tissue; tildrakizumab acts via allosteric modulation with a smaller, more hydrophobic epitope and substantially lower potency — a mechanistic distinction that likely explains both its clinical positioning at higher approved doses and the real-world data showing somewhat slower initial response kinetics. A deeper search would surface additional structural studies and long-term durability data across indications.