Session Information
Session Type: Poster Session A
Session Time: 10:30AM-12:30PM
Background/Purpose: IL-23 is implicated in the pathogenesis of psoriasis (PsO), and myeloid cells that express FcγRI (CD64) have been identified as a primary source of IL-23 in lesional PsO skin tissue.1 Incidence and prevalence of PsA increases with PsO severity,2 and joint disease activity is positively correlated with peripheral CD64+ monocyte frequency.3 Guselkumab (GUS) and risankizumab (RZB) are mAbs that bind the IL-23p19 subunit. GUS is a fully human IgG1 mAb with a native Fc region; RZB is a humanized IgG1 mAb with a mutated Fc region. We evaluated CD64 and IL-23 expression in PsO patient skin biopsies, binding of GUS and RZB to CD64, and functional consequences of CD64 binding by IL-23p19 subunit mAbs, in vitro.
Methods: Expression of CD64, IL-23p19 subunit, and IL-23p40 subunit mRNA transcripts were analyzed from bulk and single-cell RNAseq datasets. Binding of mAbs to IFNγ-primed human monocytes, as well as binding to IL-23–secreting inflammatory monocytes and capture of endogenously secreted IL-23, were assessed by flow cytometry. Internalization of IL-23, GUS, and RZB within CD64+ macrophages were evaluated using live cell confocal imaging. GUS and RZB potency for inhibiting IL-23 signaling was determined in a co-culture of THP-1 cells (CD64+ IL-23-producing monocyte cell line) and an IL-23 reporter cell line (measuring biologically active IL-23). IL-23p19 mRNA transcript expression in the co-culture was measured by quantitative PCR.
Results: Analyses of RNAseq datasets showed increased expression of CD64, IL-23p19, and IL-23p40 mRNA transcripts in lesional versus non-lesional PsO skin, and myeloid cell types co-expressing CD64 and IL-23p19 mRNA transcripts were increased in lesional skin. In in vitro assays, GUS, but not RZB, showed Fc-mediated binding to CD64 on IFNγ-primed monocytes. Moreover, CD64-bound GUS simultaneously captured IL-23 secreted from the same cells. GUS, but not RZB, bound to the surface of CD64+ macrophages and mediated internalization of IL-23 to low pH intracellular compartments. GUS and RZB demonstrated similar potency for inhibiting signaling by IL-23 present in THP-1–conditioned medium. However, in a co-culture of IL-23–producing THP-1 cells with an IL-23–responsive reporter cell line, GUS demonstrated enhanced potency compared to RZB for inhibiting IL-23 signaling. GUS did not alter IL-23p19 mRNA transcript expression in the co-culture.
Conclusion: Our transcriptomic analysis confirmed CD64+ myeloid cells as a key source of IL-23 production in lesional PsO skin tissue. GUS binding to CD64 on IL-23–producing cells likely contributed to the enhanced functional potency of GUS compared to RZB for inhibition of IL-23 signaling in the co-culture assay. These data support a hypothesis for optimal localization of GUS in inflamed tissues, where CD64+ IL-23–producing myeloid cells are increased and in proximity to IL-23–responsive lymphoid cells, enhancing GUS neutralization of IL-23 at its source of production.
1Mehta H, et al. J Invest Dermatol. 2021;141:1707.
2Merola J, et al. J Am Acad Dermatol. 2022;86:748.
3Matt P, et al. Scand J Rheumatol. 2015;44:464.
To cite this abstract in AMA style:
McGonagle D, Atreya R, Abreu M, Krueger J, Eyerich K, Bissonnette R, Greving C, Li H, Freeman T, Hart A, Keyes B, Stoveken B, Hartman J, Leppard K, Parrett J, Wertheimer J, Sarabia I, Deming J, Kohler K, Ritchlin C, McInnes I, Allez M, Fourie A, Sachen K. Guselkumab Binding to CD64+ IL-23–Producing Myeloid Cells Enhances Potency for Neutralizing IL-23 Signaling [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/guselkumab-binding-to-cd64-il-23-producing-myeloid-cells-enhances-potency-for-neutralizing-il-23-signaling/. Accessed .« Back to ACR Convergence 2024
ACR Meeting Abstracts - https://acrabstracts.org/abstract/guselkumab-binding-to-cd64-il-23-producing-myeloid-cells-enhances-potency-for-neutralizing-il-23-signaling/