Bibliographic Details
| Title: |
Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling |
| Authors: |
Kacey L. Sachen, Deepa Hammaker, Indra Sarabia, Brian Stoveken, John Hartman, Kristin L. Leppard, Nicholas A. Manieri, Phuc Bao, Carrie Greving, Eilyn R. Lacy, Matthew DuPrie, Joshua Wertheimer, Janise D. Deming, Joseph Brown, Amy Hart, He (Hurley) Li, Tom C. Freeman, Brice Keyes, Kristen Kohler, Ian White, Nathan Karpowich, Ruth Steele, M. Merle Elloso, Steven Fakharzadeh, Kavitha Goyal, Frédéric Lavie, Maria T. Abreu, Matthieu Allez, Raja Atreya, Robert Bissonnette, Kilian Eyerich, James G. Krueger, Dennis McGonagle, Iain B. McInnes, Christopher Ritchlin, Anne M. Fourie |
| Source: |
Frontiers in Immunology, Vol 16 (2025) |
| Publisher Information: |
Frontiers Media S.A., 2025. |
| Publication Year: |
2025 |
| Collection: |
LCC:Immunologic diseases. Allergy |
| Subject Terms: |
IL-23, IL-23p19 subunit inhibitors, guselkumab, risankizumab, CD64, in vitro cellular assays, Immunologic diseases. Allergy, RC581-607 |
| More Details: |
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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1664-3224 |
| Relation: |
https://www.frontiersin.org/articles/10.3389/fimmu.2025.1532852/full; https://doaj.org/toc/1664-3224 |
| DOI: |
10.3389/fimmu.2025.1532852 |
| Access URL: |
https://doaj.org/article/8bdb8bc0ba1c48b187aee2e41e087d7f |
| Accession Number: |
edsdoj.8bdb8bc0ba1c48b187aee2e41e087d7f |
| Database: |
Directory of Open Access Journals |
