POS0297 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
Authors: A. S. Powlesland, I. Cutcutache, A. Skelton, A. Shock, M. Page, E. Bame, J. Gaiha-Rohrbach, G. Stojan, A. Skowera, C. Stach, T. Dörner
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> The pivotal role of CD40-CD40L interactions in systemic lupus erythematosus (SLE) pathogenesis stems from the orchestration of a range of immune and inflammatory responses involving B cells, T cells, and other antigen-presenting cells.[1] Dapirolizumab pegol (DZP) is a polyethylene glycol-conjugated antigen-binding fragment lacking a functional Fc domain that inhibits CD40L,<sup>2</sup> and is under investigation in a phase 3 trial in patients (pts) with SLE (PHOENYCS GO; NCT04294667). In the phase 2b RISE trial (NCT02804763), DZP was associated with improvements in several measures of disease activity.[2] <h3>Objectives:</h3> To conduct a post hoc pharmacodynamic analysis to explore the impact of DZP on T cell responses and serum cytokine levels using data from the phase 2b RISE trial.[2] <h3>Methods:</h3> In RISE, 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 with persistent active SLE or acute worsening of SLE in the scope of frequent flaring/relapsing-remitting disease (n=131), previously identified as predictors of a lower response to SOC+PBO.[3] Results are shown for the PBO and DZP 24 mg/kg arms. Protein analysis was conducted on all available serum samples at baseline and Wks 2, 8, and 24, using the Olink<sup>®</sup> Target 96 Inflammation panel of protein biomarkers. RNA sequencing was performed on available blood samples at baseline and Wks 2, 4, 12, and 24. Samples were not available for all pts at all timepoints. Gene expression changes were analyzed and competitive gene set analyses performed for pathways relevant to SLE immunopathology, selected from Gene Ontology Biological Processes and augmented with gene signatures that discriminate immune cell types in SLE.[4-6] Differential expression results for DZP treatment were corrected for SOC effects. Pts were also stratified post hoc by baseline T cell-associated gene expression using a T cell gene signature derived from single cell gene expression data.[5] <h3>Results:</h3> Of the 92 proteins measured, DZP significantly downregulated 4 proteins (CCL19, IL12B, TNFRSF9 [CD137], and TNF [TNFA]) across all timepoints, and 3 (TNFB, CXCL9, and CD6) at Wks 2 and 8, compared with PBO. These were mostly co-stimulatory proteins associated with T cell activation, including IL12B (primarily produced by professional antigen presenting cells)[7] and the co-stimulatory molecule TNFSFR9 (CD137), which alongside CD40 play critical roles in T cell activation. The proinflammatory cytokines TNF and TNFB were also significantly downregulated. At baseline, across all treatment arms, 54/120 (45%) pts showed high T cell-associated gene expression. In pts with high baseline expression, DZP significantly downregulated various biological pathways associated with T cell activation and related adaptive immune processes, including antigen processing/presentation and type II interferon (IFN-γ) responses, compared with PBO. All effects described above were observed as early as Wk 2 following a single DZP dose. <h3>Conclusion:</h3> Beyond its known effects on B cells and IFN signaling,[8] these data demonstrate targeted effects of DZP on T cell activation and additional proinflammatory cytokines, such as IFN-γ, involved in T cell activation and adaptive immune responses related to SLE. The identified biomarkers will undergo further validation in planned pharmacodynamic studies in relation to clinical efficacy. <h3>REFERENCES:</h3> [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):272. [4] Wu D. Nucleic Acids Res. 2012;40(17):e133. [5] Mandric I. Nat Commun. 2020;11(1):5504. [6] Gene Ontology Consortium. Nucleic Acids Res. 2021;49(D1):D325–34. [7] Ullrich KA. EXCLI J. 2020;19:1563–89. [8] Cutcutache I. Arthritis Rheumatol. 2023;75(suppl 9). <h3>Acknowledgements:</h3> Funded by UCB Pharma and Biogen Inc. Medical writing support provided by Costello Medical and funded by UCB Pharma and Biogen Inc. <h3>Disclosure of Interests:</h3> Alex S. Powlesland Former employee of UCB Pharma, Ioana Cutcutache Shareholder of UCB Pharma, Employee of UCB Pharma, Andrew Skelton Shareholder of UCB Pharma, Employee of UCB Pharma, Anthony Shock Shareholder of UCB Pharma, Employee of UCB Pharma, Matthew Page Shareholder of UCB Pharma, Employee of UCB Pharma, Eris Bame Shareholder of Biogen Inc., Employee of Biogen Inc., Janine Gaiha-Rohrbach Shareholder of Biogen Inc., Employee of Biogen Inc., George Stojan Shareholder of UCB Pharma, Employee of UCB Pharma, Ania Skowera Shareholder of UCB Pharma, Employee of UCB Pharma, Christian Stach Shareholder of UCB Pharma, Employee of UCB Pharma, Thomas Dörner Received travel support to KCR 2023 from Novartis, Received honoraria for conducting clinical trials (paid to the university) and honoria for scientific advice from AbbVie, Eli Lilly, Janssen, Roche/GNE, and UCB Pharma.