Session Type: Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Monoclonal antibodies (mAbs) targeting the interleukin (IL)-23p19 subunit are effective in treating psoriatic disease; however, their molecular attributes may translate to differences in clinical efficacy. Guselkumab (GUS) is a fully human anti-IL-23p19 subunit IgG1 mAb with a native Fc region, whereas risankizumab (RZB) is a humanized anti-IL-23p19 subunit IgG1 mAb with a mutated Fc region. Binding of mAbs to Fcγ receptors (FcγRs) is of particular interest, because FcγRI (CD64)+ IL-23–producing myeloid cells are increased within inflamed tissue of patients with psoriatic disease. Furthermore, in psoriatic arthritis, joint disease activity is positively correlated with the frequency of peripheral CD64+ monocytes. Here, in vitro functional characteristics of the antigen-binding and Fc regions of GUS and RZB, as well as implications of CD64 binding for mAb function and IL-23 neutralization, were explored.
Methods: IL-23 binding affinity of GUS and RZB was evaluated using a kinetic exclusion assay. Cellular potency was measured by mAb impact on IL-23–induced STAT3 phosphorylation in human peripheral blood mononuclear cells. Binding of GUS and RZB to FcγRs was assessed in cells transfected with individual FcγRs. Primary human monocytes differentiated into an inflammatory state were utilized in flow cytometry assays to assess GUS and RZB binding to CD64 and capture of locally produced endogenous IL-23. Cellular activation following mAb binding to CD64 on inflammatory monocytes was assessed using a 41-plex cytokine bead assay. Internalization of IL-23, GUS, and RZB within CD64+ macrophages was assessed using live cell confocal imaging.
Results: GUS and RZB displayed comparable picomolar binding affinity for IL-23 and similar high potency for inhibiting IL-23–induced STAT3 phosphorylation. GUS showed the strongest binding to CD64 versus other FcγRs; RZB had negligible binding to any FcγR. GUS, but not RZB, showed dose-dependent Fc-mediated binding to CD64 on inflammatory monocytes, and CD64-bound GUS was able to capture endogenous IL-23 secreted from the same cells. GUS binding to CD64 on inflammatory monocytes did not induce or enhance cytokine production. GUS, but not RZB, bound to the cell surface of CD64+ macrophages and mediated internalization of IL-23 to low pH intracellular compartments.
Conclusion: Compared with RZB, GUS has unique attributes that allow it to simultaneously bind CD64+ myeloid cells via its native Fc region and neutralize IL-23 with high affinity and potency. These data suggest a potential mechanistic benefit through enrichment of GUS within inflamed tissue of patients with psoriatic disease, where CD64+ IL-23–producing myeloid cells are increased, enabling potent neutralization of IL-23 at its source and removal of IL-23 from inflamed tissue via internalization.
To cite this abstract in AMA style:McGonagle D, atreya r, Abreu M, Krueger J, Eyerich K, Bissonnette R, Sachen K, Greving C, Stoveken B, Hammaker D, Leppard K, Hartman J, Bao P, Lacy E, Sarabia I, Deming J, Duprie M, Brown J, Ritchlin C, McInnes I, Allez M, Fourie A. Guselkumab, an IL-23p19 Subunit–specific Monoclonal Antibody, Is Able to Bind CD64+ Myeloid Cells, Potently Neutralize IL-23 Produced from the Cells, and Mediate Internalization of IL-23 [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/guselkumab-an-il-23p19-subunit-specific-monoclonal-antibody-is-able-to-bind-cd64-myeloid-cells-potently-neutralize-il-23-produced-from-the-cells-and-mediate-internalization-of-il-23/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/guselkumab-an-il-23p19-subunit-specific-monoclonal-antibody-is-able-to-bind-cd64-myeloid-cells-potently-neutralize-il-23-produced-from-the-cells-and-mediate-internalization-of-il-23/