A non-clinical comparative study of IL-23 antibodies in psoriasis

Abstract

Four antibodies that inhibit interleukin (IL)-23 are approved for the treatment of moderate-to-severe plaque psoriasis. Here, we present non-clinical data comparing ustekinumab, guselkumab, tildrakizumab and risankizumab with regard to thermostability, IL-23 binding affinity, inhibitory-binding mode, <i>in vitro</i> potency and <i>in vivo</i> efficacy. Risankizumab and guselkumab exhibited 5-fold higher affinity for IL-23 and showed more potent inhibition of IL-23 signaling than ustekinumab and tildrakizumab. Risankizumab and guselkumab completely blocked the binding of IL-23 to IL-23Rα as expected, whereas tildrakizumab did not. <i>In vitro</i>, risankizumab and guselkumab blocked the terminal differentiation of T_H17 cells in a similar manner, while tildrakizumab had minimal impact on T_H17 differentiation. In a human IL-23-induced ear-swelling mouse model, risankizumab and guselkumab were more effective than ustekinumab and tildrakizumab at reducing IL-17, IL-22, and keratinocyte gene expression. Our results indicate that the four clinically approved antibodies targeting IL-23 differ in affinity and binding epitope. These attributes contribute to differences in <i>in vitro</i> potency, receptor interaction inhibition mode and <i>in vivo</i> efficacy in preclinical studies as described in this report, and similarly may affect the clinical performance of these drugs.