Background/Purpose: Clinically relevant differences between therapeutic antibodies against the same target may relate to their unique molecular attributes. Differences in therapeutic profiles across the domains of psoriatic disease between guselkumab (GUS) and risankizumab (RIS) have been observed, although there are no direct comparator studies in the clinical setting.

Methods: To explore potential mechanisms underpinning the therapeutic profiles, we studied GUS, a fully human immunoglobulin G1 (IgG1) specific for interleukin (IL)-23 with a native fragment crystallizable (Fc) region, and RIS, a humanized anti-IL-23 IgG1 with a mutated Fc region. We compared the binding and functional characteristics of the antigen-binding and Fc regions of these antibodies.

Results: GUS and RIS displayed comparable picomolar affinities for binding IL-23 by the kinetic exclusion assay (KinExA) and surface plasmon resonance assays, and equivalent potency (half maximal inhibitory concentration [IC₅₀] 0.2 nM) for the inhibition of IL-23-induced Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation in human peripheral blood mononuclear cells. However, in cells transfected with individual Fc gamma receptors (FcγRs), GUS showed the strongest binding to Cluster of Differentiation 64 (CD64) (FcγR1), while RIS showed negligible binding to any FcγRs, by virtue of its mutated Fc region. Furthermore, in interferon-gamma (IFNγ)-primed human monocytes, the 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 the lack of cytokine or chemokine production. Importantly, CD64-bound GUS was able to bind IL-23, as detected by anti-p40 staining.

Conclusion: Compared with RIS, GUS uniquely binds both CD64⁺ myeloid cells and IL-23. CD64⁺ mononuclear phagocytes are enriched in the 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.

« Back to ACR Convergence 2022

ACR Meeting Abstracts - https://acrabstracts.org/abstract/differentiation-of-therapeutic-antibodies-targeting-interleukin-il-23/