# 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.