Background/Purpose: CD40-CD40L interactions play a pivotal role in systemic lupus erythematosus (SLE) pathogenesis by orchestrating a range of immune and inflammatory responses involving B cells, T cells, and antigen-presenting cells (APCs).¹ Dapirolizumab pegol (DZP) is a polyethylene glycol-conjugated antigen-binding fragment lacking a functional Fc domain that inhibits CD40L,² under investigation in a phase 3 trial in SLE (PHOENYCS GO; NCT04294667). This post hoc pharmacodynamic analysis explores the impact of DZP on T cell and APC pathways using data from the phase 2b trial in SLE (RISE; NCT02804763).²

Methods: In RISE, patients (pts) received placebo (PBO) or DZP (6/24/45 mg/kg) alongside standard of care (SOC) for 24 weeks (wks); adults with active SLE with moderate-to-severe disease manifestations receiving stable doses of SOC treatments were included in the trial.² Analyses focused on a subgroup of pts from RISE similar to the PHOENYCS GO population, namely those who had acute flare with low complement or persistent disease activity (n=131), previously identified as predictors of a lower response to SOC+PBO.³ Results are shown for PBO and DZP 24 mg/kg.

Protein analysis was conducted on serum samples at baseline (BL) and Wks 2, 8, and 24, using the Olink^® Target 96 Inflammation panel of protein biomarkers. RNA sequencing was performed on blood samples at BL and Wks 2, 4, 12, and 24.

Gene expression changes were analyzed for pathways relevant to SLE immunopathology using competitive gene set tests.⁴ Differential expression results for DZP treatment were corrected for SOC effects. Pts were stratified post hoc by BL T cell-associated gene expression using a T cell gene signature derived from single cell gene expression data.⁵

Results: Of 92 proteins measured, DZP significantly downregulated 4 proteins (CCL19, IL12B, TNFRSF9 [CD137], and TNFA) across all timepoints, and 3 proteins (TNFB, CXCL9, and CD6) at Wks 2 and 8 vs BL, compared with PBO vs BL. These were mostly associated with T cell activation, including co-stimulatory proteins IL12B (primarily produced by professional APCs)⁶ and TNFSFR9, and CCL19 and CXCL9 chemokines.

At BL, across all treatment arms, 54/120 (45%) pts had high T cell-associated gene expression. In these pts, DZP significantly downregulated expression of genes associated with T cell activation and related adaptive immune processes, including antigen processing/presentation and type II interferon (IFN-γ) responses.

All effects were observed as early as Wk 2 following a single DZP dose.

Conclusion: Beyond its known effects on B cells and IFN signaling,⁷ these data demonstrate targeted effects of DZP on T cell activation, antigen presentation, and proinflammatory cytokines, such as IFN-γ, involved in adaptive immune responses related to SLE. These findings support the broad mechanism of action of DZP in modulating multiple aspects of SLE immunopathology.

References: 1. Ramanujam M. Autoimmun Rev. 2020;19(11):102668; 2. Furie RA. Rheumatology (Oxford). 2021;60:5397–407; 3. Askanase A. Ann Rheum Dis. 2023;82(Suppl 1); 4. Wu D. Nucleic Acids Res. 2012;40(17):e133; 5. Mandric I. Nat Commun. 2020;11(1):5504; 6. Ullrich KA. EXCLI J. 2020;19:1563–89; 7. Cutcutache I. Arthritis Rheumatol. 2023;75(suppl 9).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dapirolizumab-pegol-impacts-important-immunologic-pathways-in-systemic-lupus-erythematosus-pharmacodynamic-analysis-of-t-cell-and-antigen-presenting-cell-pathways-from-a-phase-2b-trial/