Th117 - Synovial Expression Levels of PD-1, the Target of Rosnilimab, Correlate with Disease Activity and Persist Across Disease Stages and Lines of Therapy in Rheumatoid Arthritis

Abstract Text: Rosnilimab is an investigational PD-1 agonist that aims to regulate T cell activity for the treatment of inflammatory diseases, including rheumatoid arthritis, through depletion of PD-1high T cells and agonism of the PD-1 co-inhibitory receptor. In RA synovium, approximately 80% of T cells are PD-1+ with enrichment of CXCL13 secreting PD-1high T follicular (Tfh)/peripheral helper (Tph) cells, which drive B cell differentiation to autoantibody-producing plasma cells. Synovial PD-1-associated genes from three published RA cohorts were evaluated for potential target populations for rosnilimab therapy: (1) treatment-naive early RA; (2) conventional synthetic disease-modifying antirheumatic drugs (csDMARD)-inadequate responders (IRs); and (3) anti-tumor necrosis factor (TNF)-IRs. RA synovium PD-1 expression was characterized across all T cell subtypes annotated from the Accelerating Medicines Partnership (AMP) single-cell data, while bulk transcript expression was assessed in all three cohorts.
Tfh/Tph cells demonstrated the highest PD-1 expression compared with minimal to low PD-1 expression in naïve and regulatory T cells, respectively. Across all cohorts, PD-1 and CXCL13 transcript levels were positively correlated with disease activity at baseline. T cell activation markers and CXCL13 expression correlated with CD3 expression across disease stages, indicating synovial T cells maintained an activated Tph-like phenotype. Irrespective of treatment, a correlation of PD-1 and CXCL13 expression with disease activity persisted, suggesting the importance of PD-1 in disease pathogenesis and a rationale for exploring rosnilimab’s therapeutic potential. This will be evaluated in the RENOIR study, an ongoing Phase 2 trial of rosnilimab in moderate-to-severe RA patients (NCT06041269).