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Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling

Sachen KL, Hammaker D, Sarabia I, Stoveken B, Hartman J, Leppard KL, Manieri NA, Bao P, Greving C, Lacy ER, DuPrie M, Wertheimer J, Deming JD, Brown J, Hart A, Li H, Freeman TC, Keyes B, Kohler K, White I, Karpowich N, Steele R, Elloso MM, Fakharzadeh S, Goyal K, Lavie F, Abreu MT, Allez M, Atreya R, Bissonnette R, Eyerich K, Krueger JG, McGonagle D, McInnes IB, Ritchlin C, Fourie AM (2025)

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Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 16

Article Number: 1532852

DOI: 10.3389/fimmu.2025.1532852

Abstract

IL-23 is implicated in the pathogenesis of immune-mediated inflammatory diseases, and myeloid cells that express Fc gamma receptor 1 (FcγRI or CD64) on their surface have been recently identified as a primary source of IL-23 in inflamed tissue. Our complementary analyses of transcriptomic datasets from psoriasis and IBD showed increased expression of CD64 and IL-23 transcripts in inflamed tissue, and greater abundance of cell types with co-expression of CD64 and IL-23. These findings led us to explore potential implications of CD64 binding on the function of IL-23–targeting monoclonal antibodies (mAbs). Guselkumab and risankizumab are mAbs that target the IL-23p19 subunit. Guselkumab has a native Fc domain while risankizumab contains mutations that diminish binding to FcγRs. In flow cytometry assays, guselkumab, but not risankizumab, showed Fc-mediated binding to CD64 on IFNγ-primed monocytes. Guselkumab bound CD64 on IL-23–producing inflammatory monocytes and simultaneously captured IL-23 secreted from these cells. Guselkumab binding to CD64 did not induce cytokine production. In live-cell confocal imaging of CD64⁺ macrophages, guselkumab, but not risankizumab, mediated IL-23 internalization to low-pH intracellular compartments. Guselkumab and risankizumab demonstrated similar potency for inhibition of IL-23 signaling in cellular assays with exogenous addition of IL-23. However, in a co-culture of IL-23–producing CD64⁺ THP-1 cells with an IL-23–responsive reporter cell line, guselkumab demonstrated Fc-dependent enhanced potency compared to risankizumab for inhibiting IL-23 signaling. These in vitro data highlight the potential for guselkumab binding to CD64 in inflamed tissue to contribute to the potent neutralization of IL-23 at its cellular source.

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How to cite

APA:

Sachen, K.L., Hammaker, D., Sarabia, I., Stoveken, B., Hartman, J., Leppard, K.L.,... Fourie, A.M. (2025). Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling. Frontiers in Immunology, 16. https://doi.org/10.3389/fimmu.2025.1532852

MLA:

Sachen, Kacey L., et al. "Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling." Frontiers in Immunology 16 (2025).

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