Differentiation of Therapeutic Monoclonal Antibodies Targeting IL-23 for the Treatment of Psoriatic Disease

Background: Differences in therapeutic profiles between IL-23 inhibitors have been observed across psoriatic disease domains, which may be related to their unique molecular attributes. Guselkumab is an IL-23p19-specific human IgG1 antibody, while risankizumab and tildrakizumab are humanized anti-IL- 23p19 IgG1 antibodies. Guselkumab and tildrakizumab have native Fc regions, while risankizumab has a mutated Fc region. We compared binding and functional characteristics of antigen-binding and Fc regions of these antibodies. Guselkumab displayed higher binding affinity for IL-23 (by surface plasmon resonance) than tildrakizumab but was comparable to risankizumab. Guselkumab also demonstrated higher potency (by inhibition of IL-23-induced STAT3 phosphorylation in human peripheral blood mononuclear cells) than tildrakizumab but was equivalent to risankizumab. In Fcy receptor (FcyR)- transfected cells, guselkumab and tildrakizumab showed strongest binding to CD64 (FcyRI); risankizumab had negligible binding to any FcyR. In interferon-y-primed human monocytes, guselkumab and tildrakizumab, but not risankizumab, showed dose-dependent binding to CD64 by flow cytometry. CD64- bound guselkumab and tildrakizumab were also able to bind IL-23. Guselkumab binding to CD64 on monocytes did not induce cytokine production. In conclusion, compared with risankizumab and tildrakizumab, guselkumab has unique attributes that confer the ability to neutralize IL-23 with high affinity and potency, as well as Fc binding to CD64+ myeloid cells. CD64+ mononuclear phagocytes are the dominant IL-23 source in psoriatic skin; therefore, guselkumab may be enriched within the inflamed tissue microenvironment by binding CD64 and poised to effectively neutralize IL-23 at its source, potentially leading to durable response and observed therapeutic differences within the class.