Structural Basis for p19 Targeting by Anti–IL-23 Biologics: Correlations with Short- and Long-Term Efficacy in Psoriasis
Stefano G. Daniele, Sherif A. Eldirany, Giovanni Damiani, Minh Ho, Christopher G. Bunick
Abstract
IL-23 is central to psoriasis pathogenesis. Biologics targeting IL-23 are important therapies against psoriasis. IL-23 inhibitors risankizumab, tildrakizumab, and guselkumab bind the IL-23 p19 subunit, whereas ustekinumab binds p40; however, the structural composition of the IL-23 binding epitopes and how these molecular properties relate to clinical efficacy is not known. Utilizing epitope data derived from hydrogen-deuterium exchange or crystallographic experiments, we mapped inhibitor epitope locations, hydrophobicity, and surface charge onto the IL-23 surface. Molecular properties of each inhibitor epitope, including solvent accessible surface area, were correlated to binding affinity, kinetic values, and clinical efficacy scores for plaque psoriasis via linear regression analysis. Each IL-23 inhibitor binds an epitope with a unique size, composition, and location except for a 10-residue overlap region outside of the IL-23 receptor epitope. We observed strong correlations between epitope surface area and KD and koff, but not kon. Epitope surface area, KD, and koff further associated with short- (10-16 weeks) and long-term (44-60 weeks) clinical efficacy according to Psoriasis Area Severity Index-90 responses. In contrast, kon, epitope hydrophobicity, polarity, and charge content did not correlate with efficacy. These data exemplify how molecular principles of medications within a therapeutic class can explain their differential clinical responses.