Abstract Text: Checkpoint agonism represents a promising class of therapies for the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis (RA) and ulcerative colitis (UC), where unmet needs persist despite available therapies. Rosnilimab is an investigational PD-1 agonist IgG1 antibody designed to optimize inhibitory signaling through the PD-1 receptor. Rosnilimab depletes PD-1[high] pathogenic T cells and agonizes remaining PD-1[int] T cells. Binding to membrane proximal regions of checkpoint receptors and simultaneous Fc interactions with Fc receptors on opposing cells contributes to immune synapse formation between the immune cell and the antigen presenting cell, leading to clustering and agonistic activity. Similar binding properties also optimize the potential for depletion of high PD-1 expressing T cells. The binding epitope of rosnilimab was mapped to a membrane proximal region of the PD-1 receptor, while the epitope of a reference antibody (ref1) was mapped to a membrane distal region. Rosnilimab demonstrated greater reduction of T cell proliferation, inflammatory cytokines and genes related to T cell activation, and depletion of PD-1+ T cells compared to ref1 in vitro, consistent with the hypothesis that membrane proximal binding improves agonistic activity and target cell depletion. These mechanistic data, translational in vivo and in vitro data, robust Phase 1 healthy volunteer data, and unmet needs provide rationale for ongoing global Phase 2 studies of rosnilimab in RA (NCT06041269) and UC (NCT06127043).
