Th111 - S-4321, a Novel Dual-Cell Bidirectional PD-1:FcγRIIb Selective Agonist Antibody for the Treatment of Autoimmune Disease

Abstract Text: The dysregulation of immune checkpoint receptors on T cells and antigen presenting cells (APCs) drives autoimmunity while receptor agonism is expected to restore immune homeostasis in diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, and giant cell arteritis. PD-1 is a checkpoint receptor expressed on T cells, including Tfh and Treg subtypes. Strong PD-1 agonism requires super-clustering, which can be achieved by therapeutic antibodies binding to Fc gamma receptors (FcγR) on APCs. S-4321 is a novel dual-cell bidirectional (DcB) PD-1:FcγRIIb antibody that agonizes the inhibitory PD-1 receptor on T cells (Fab domain) and selectively engages the inhibitory FcγRIIb on APCs (Fc domain), eliciting an inhibitory signal at the immune cell synapse to re-establish homeostasis.
S-4321 achieves prolonged agonism by binding to PD-1 with low affinity (similar to PD-L1) thus allowing for the retention of PD-1 expression on the T cell surface. This ensures continued presence of target and maintains a regulatory check on effector cell activity. In contrast, higher affinity PD-1 agonists decrease surface PD-1, associated with increased IL-2 production in SEB activated cultures. S-4321 also selectively engages FcγRIIb, avoiding the induction of proinflammatory cytokines and undesirable depletion of PD-1 expressing T cells, such as Tregs, by antibody-dependent cellular cytotoxicity (ADCC) through engagement of activating FcγR. In summary, S-4321 engages inhibitory receptors on both sides of the T cell-APC synapse, decreases T cell activation, preserves target expression and does not result in the elimination of PD1+ T cells important for the maintenance of a normal immune homeostasis.