047 Differentiation of Therapeutic Antibodies Targeting Interleukin-23

Clinically relevant differences amongst therapeutic antibodies against the same target may relate to their unique molecular attributes. Differences in therapeutic profile across the domains of psoriatic disease between guselkumab (GUS) and risankizumab (RIS) have been observed. To explore potential mechanisms underpinning this, we studied GUS, a fully human IgG1 specific for interleukin (IL)-23 with a native Fc region, and RIS, a humanized anti-IL-23 IgG1 with a mutated Fc region. We compared binding and functional characteristics of the antigen-binding and Fc regions of these antibodies. GUS and RIS displayed comparable picomolar affinities for binding IL-23 by KinExA and surface plasmon resonance assays, and equivalent potency (IC50=0.2 nM) for inhibition of IL-23-induced STAT-3 phosphorylation in human peripheral blood mononuclear cells. However, in cells transfected with individual Fcg receptors (FcgRs), GUS showed strongest binding to CD64 (FcgR1), while RIS showed negligible binding to any FcgRs, by virtue of its mutated Fc region. Furthermore, in interferon (IFN)g-primed human monocytes, labeled GUS showed dose-dependent binding to CD64 by flow cytometry, while RIS did not. GUS binding to CD64 on monocytes did not trigger activation as shown by lack of cytokine or chemokine production. Importantly, CD64-bound GUS was able to bind IL-23, as detected by anti-p40 staining. In conclusion, compared with RIS, GUS uniquely binds both CD64+ myeloid cells and IL-23. CD64+ mononuclear phagocytes are enriched in psoriatic skin and serve as the dominant IL-23 source. Taken together, GUS presence may be enriched within the inflamed tissue microenvironment by binding to CD64, neutralizing IL-23 at its cellular source, potentially leading to durable response and observed therapeutic differences within the class. Further studies are warranted to generate additional evidence supporting this hypothesis.