Several monoclonal antibodies that inhibit IL-23 through interaction with either the p19 or p40 subunit, have been developed for the treatment of moderate-to-severe plaque psoriasis in adults. In this study we present non-clinical data comparing ustekinumab, guselkumab, tildrakizumab and risankizumab with regards to IL-23 binding affinity, mode of action, in vitro potency and in vivo efficacy in an animal model.

Risankizumab and guselkumab are high affinity antibodies, whereas ustekinumab and tildrakizumab have off-rates that are 8 to 10-fold faster than risankizumab. In a biacore study, risankizumab and guselkumab inhibit the binding of IL-23 to the IL23Rα subunit as expected for competitive inhibitors of the p19/IL23Rα interaction, whereas tildrakizumab did not. Tildrakizumab reduces the IL-23 affinity for IL23Rα, but does not completely block the interaction. This unusual mechanism of inhibition suggests that tildrakizumab is a negative allosteric modulator. Ustekinumab is a competitive inhibitor of the p40/IL-12Rβ1 interaction and, as expected, did not inhibit the binding of IL-23 to IL23Rα. The differences in affinity and mode of inhibition result in potency differences in bioassays in which risankizumab is about 2-3 fold more potent than guselkumab, 4-10 fold more potent than ustekinumab and tildrakizumab in inhibiting IL-23 signaling. The in vivo efficacy of the antibodies was evaluated in a human IL-23 induced ear-swelling mouse model. Risankizumab and guselkumab robustly inhibited ear swelling at doses ranging from 1-25 mg/kg whereas the effects with ustekinumab were milder at comparable doses and tildrakizumab was ineffective. In a head-to-head study at low dose, risankizumab was more effective than guselkumab in reducing IL-17, IL-22 and keratinocyte gene expression. Risankizumab’s unique ability to achieve biological activity in the inflamed mouse ear tissue at low systemic antibody concentration (1 µg/mL) is currently being investigated.

IL-23 Antibodies in Psoriasis – a Non-Clinical Perspective