DOP81 Rosnilimab, a novel PD-1 agonist monoclonal antibody, reduces T cell proliferation, inflammatory cytokine secretion, and PD-1high expressing CD4 and CD8 T cells: Results from a Phase 1 healthy volunteer clinical trial

Abstract Background Programmed cell death protein 1 (PD-1) is expressed on activated T cells and is a key co-inhibitory node in immune regulation. By targeting regulatory mechanisms to modulate immune cells driving disease, there is an opportunity to restore immune balance. Rosnilimab is a PD-1 agonist antibody designed to reduce T cell proliferation and inflammatory cytokine secretion and deplete PD-1high T follicular helper, T peripheral helper, and T effector cells. It is being studied for ulcerative colitis (UC), where PD-1+ T cells are prevalent in inflamed lamina propria (>40%) and the periphery. The primary objective of this healthy volunteer Phase 1 study was to assess the safety and tolerability of single ascending doses (SAD) and multiple ascending doses (MAD) of rosnilimab. Findings from pharmacokinetic (PK) and pharmacodynamic (PD) assessments are summarized. Methods This single-centre study included 14 cohorts in SAD and 3 cohorts in MAD. Each cohort had 8 participants (6 active, 2 placebo [PBO]). Cohorts were enrolled sequentially in each phase. Intravenous (IV) and subcutaneous (SC) administration were assessed in SAD; SC route was assessed in MAD. Results A total of 144 participants were enrolled; 90 to active SAD cohorts, 18 to active MAD cohorts, and 30 and 6 to SAD and MAD PBO cohorts, respectively. Rosnilimab was well tolerated with no dose-limiting toxicities or deaths. Two serious adverse events were reported in SAD (deemed unrelated to treatment) and 0 in MAD. PD-1 expressing cells were reduced by ~50% in both CD4+ and CD8+ subsets, in a dose-dependent manner and in correlation with full receptor occupancy (RO) through Day 30 in SAD. PD activity was rapid with sustained reduction in PD-1+ T cells, and ex-vivo stimulation resulted in reduced T cell functional activity. This reduction was maximized on PD-1high expressing T cells: ~90% reduction vs baseline. There was no significant impact on the overall total T cell or regulatory T (Treg) cell numbers, resulting in restoration of T cell composition to a less activated state and a positive shift in the Treg:Teff ratio. An antigen-specific functional T cell assay measuring ex vivo interferon-gamma release in response to antigen challenge was inhibited up to ~90% vs baseline and the response lasted for more than 30 days following a single dose. Rosnilimab had a favourable PK profile consistent with full RO, a 2-week half-life, and dose-proportional exposure in IV and SC dosing. Conclusion Rosnilimab demonstrated favourable safety, PK, and PD activity. The role of PD-1 in UC pathophysiology coupled with these results and translational data, demonstrate proof of mechanism and support progression into a Phase 2 study of rosnilimab in UC. (NCT06127043)