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- W4366184474 abstract "The purpose of this study was to characterize and differentiate the structural epitopes of the IL-23 inhibitors risankizumab, guselkumab, tildrakizumab, and ustekinumab, and correlate their molecular characteristics with clinical response in plaque psoriasis therapy. Utilizing epitope data derived from hydrogen-deuterium exchange studies for risankizumab, tildrakizumab, and guselkumab, and crystallographic data for ustekinumab, we mapped drug epitope locations, hydrophobicity, and surface charge onto the IL-23 molecular surface (using Protein Data Bank ID Code 3D87 and UCSF Chimera software). Epitope composition was determined by classifying residues as acidic, basic, polar, or hydrophobic and calculating their contribution to epitope solvent accessible surface area (SASA). In doing so, we determined that IL-23 inhibitor epitopes differ in location and size, with risankizumab (2400 Å2) and guselkumab (2240 Å2) having similarly large epitope surface areas (SA), and tildrakizumab (1290 Å2) and ustekinumab (1390 Å2) having smaller SA. The composition of the tildrakizumab epitope was mostly hydrophobic (56% SASA), while guselkumab, risankizumab, and ustekinumab epitopes displayed >50% non-hydrophobic residues. Risankizumab and ustekinumab exhibited strongly acidic surface character, while tildrakizumab and guselkumab were net neutral. Importantly, IL-23 inhibitors with larger epitope SA demonstrated a stark correlation with higher 3-month Psoriasis Area and Severity Index (PASI) 90 response rates (R2 = 0.9969, p= 0.0016). Therefore, structural analysis of IL-23 inhibitor epitopes reveals strong association between epitope SA and early drug efficacy in plaque psoriasis therapy, exemplifying structure-function relationships and how molecular data can explain clinical observations and inform future innovation." @default.
- W4366184474 created "2023-04-19" @default.
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- W4366184474 date "2023-05-01" @default.
- W4366184474 modified "2023-09-28" @default.
- W4366184474 title "1097 The structure of IL-23 inhibitor epitopes correlates with short-term clinical efficacy in plaque psoriasis" @default.
- W4366184474 doi "https://doi.org/10.1016/j.jid.2023.03.1109" @default.
- W4366184474 hasPublicationYear "2023" @default.
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