Guselkumab, an IL23p19 subunit–specific monoclonal antibody, binds CD64⁺myeloid cells and potently neutralizesIL-23 produced from the same cells

Introduction Monoclonal antibodies (MAb) targeting the interleukin (IL)-23p19 subunit are effective in treating inflammatory bowel diseases (IBD), but with different molecular attributes translating into clinical efficacy differences. Guselkumab (GUS) is a fully human IgG1 MAb with a native Fc region. Risankizumab (RIS) is a humanized IgG1 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.

Objective: To compare functional characteristics of the antigen-binding and Fc regions of GUS and RIS.

Methodology Comparison of GUS and RIS IL-23 binding affinity was carried out using KinExA and surface plasmon resonance; cellular potency was measured by impact on IL-23-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in human peripheral blood mononuclear cells. Binding to FcγRs was assessed in individual FcγRs transfected cells; binding to CD64 and endogenously secreted IL-23 capture was assessed by flow cytometry in primary human “inflammatory” monocytes differentiated with granulocyte-macrophage colony-stimulating factor and interferon-γ (IFN-γ), followed by toll-like receptor stimulation for IL-23 production. Potential impact of GUS binding to CD64 was assessed in IFN-γ primed monocytes by human 41-plex cytokine bead assay.

Outcome: 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 vs other FcγRs, whereas RIS had negligible binding to any FcγR. GUS, 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 ([Abb. 1]). GUS binding to CD64 on monocytes didn`t induce cytokine production.

Abb. 1  

Conclusion GUS, not RIS, can simultaneously bind CD64⁺myeloid cells via its Fc region and neutralize 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 neutralize IL-23 at its source of production. These findings may contribute to differences in therapeutic profiles between antibodies.

 

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Publikationsverlauf

Artikel online veröffentlicht:
28. August 2023