LB989 Differentiation of therapeutic antibodies targeting IL-23

Clinically relevant differences between therapeutic antibodies against the same target may relate to their unique molecular attributes. Differences in profile across domains of psoriatic disease guselkumab (GUS) and risankizumab (RIS) have been observed. To explore potential mechanisms underpinning this, we studied GUS, a fully human IgG1 specific for IL-23 with native Fc region, RIS, humanized anti-IL-23 mutated region. We compared binding functional characteristics antigen-binding regions these antibodies. GUS RIS displayed comparable picomolar affinities by KinExA surface plasmon resonance assays, equivalent potency (IC50 0.2 nM) inhibition IL-23-induced STAT3 phosphorylation peripheral blood mononuclear cells. However, cells transfected individual Fcγ receptors (FcγRs), showed strongest CD64 (FcγR1), while negligible any FcγRs, virtue its Furthermore, IFNγ-primed monocytes, labeled dose-dependent flow cytometry, did not. on monocytes not trigger activation as shown lack cytokine or chemokine production. Importantly, CD64-bound was able bind IL-23, detected anti-p40 staining. In conclusion, uniquely binds both CD64+ myeloid IL-23. phagocytes are enriched skin serve dominant source. Taken together, presence be within inflamed tissue microenvironment CD64, neutralizing at cellular source, potentially leading durable response observed class. Further studies warranted generate additional evidence supporting this hypothesis.