P504 Guselkumab, an IL-23p19 subunit–specific monoclonal antibody, binds CD64+ myeloid cells and potently neutralises IL-23 produced from the same cells
| Autor: | R Atreya, M T Abreu, J G Krueger, K Eyerich, K Sachen, C Greving, D Hammaker, P Bao, E Lacy, I Sarabia, J Deming, M M Elloso, C Ritchlin, I B McInnes, M Allez, A Fourie |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Journal of Crohn's and Colitis. 17:i634-i635 |
| ISSN: | 1876-4479 1873-9946 |
| Popis: | Background Monoclonal antibodies targeting the interleukin (IL)-23p19 subunit are effective in the treatment of inflammatory bowel diseases (IBD), but have different molecular attributes that may translate to differences in clinical efficacy. Within this class, guselkumab (GUS) is a fully human IgG1 monoclonal antibody with a native Fc region, and risankizumab (RIS) is a humanised IgG1 antibody with a mutated Fc region. Binding of these therapeutic antibodies to Fcγ receptor (FcγR) I, or CD64, is of particular interest, as CD64+ IL-23-producing myeloid cells are increased in the inflamed colon in IBD and correlated with endoscopic disease severity (Chapuy L, et al. Mucosal Immunol. 2019; Chapuy et al. J Crohns Colitis. 2020). Here, we compared functional characteristics of the antigen-binding and Fc regions of GUS and RIS. Methods IL-23 binding affinity of GUS and RIS was compared in vitro using KinExA and surface plasmon resonance. In vitro cellular potency of GUS and RIS was measured by impact on IL-23-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in human peripheral blood mononuclear cells. Binding of GUS and RIS to FcγRs was assessed in cells transfected with individual FcγRs. In primary human “inflammatory” monocytes differentiated with granulocyte-macrophage colony-stimulating factor and interferon-γ (IFN-γ) followed by toll-like receptor stimulation to induce IL-23 production, binding of GUS and RIS to CD64 and capture of endogenously secreted IL-23 was assessed using flow cytometry. The potential impact of GUS binding to CD64 was assessed in IFN-γ primed monocytes using a human 41-plex cytokine bead assay. Results GUS and RIS displayed comparable picomolar binding affinity for IL-23 and equivalent high potency for inhibition of IL-23-induced STAT3 phosphorylation. GUS showed strongest binding to CD64 compared with other FcγRs, whereas RIS had negligible binding to any FcγR. GUS, but not RIS, showed dose-dependent Fc-mediated binding to CD64 in primary human “inflammatory” monocytes. Moreover, CD64-bound GUS was able to simultaneously capture IL-23 endogenously secreted from the same cells (Figure). GUS binding to CD64 on monocytes did not induce cytokine production. Conclusion GUS, but not RIS, can simultaneously bind CD64+ myeloid cells via its Fc region and neutralise IL-23 with high affinity and potency. Our in vitro data suggest a mechanistic benefit through enhanced localization of GUS within the inflamed colon, where CD64+ IL-23-producing myeloid cells are increased, and GUS can potently neutralise IL-23 at its source of production. These findings may contribute to differences in therapeutic profiles between antibodies. |
| Databáze: | OpenAIRE |
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