S-4321 Is a Novel, Non-Depleting, Bifunctional PD-1:FcγRIIB Selective Agonist Antibody for the Treatment of Immune-Mediated Diseases 2333621

Abstract

Abstract Introduction Inhibitory receptors upregulated on activated lymphocytes play a critical role in restoring and maintaining immune homeostasis to control autoimmunity. Strong PD-1 agonism requires super-clustering, which is achieved when antibodies bind to Fc gamma receptors (FcγR) on aAPCs. Several PD-1-targeted antibodies have been investigated in autoimmunity with mixed clinical results, however, rather than agonizing PD-1, these first-generation antibodies primarily deplete PD-1+ T cells, as demonstrated in human trials. S-4321 is a novel bifunctional antibody that agonizes PD-1 on T cells through a different binding site than its natural ligands, PD-L1 and PD-L2, while selectively engaging the inhibitory FcγRIIb on B cells and APCs. Therefore, by avoiding liabilities seen with first-generation PD-1 binders, such as Treg depletion and reduced PD-1 expression, S-4321 is expected to restore immune homeostasis in cell-mediated autoimmunity. Methods PD-1 and FcγRIIb agonism were assessed using in vitro functional assays and in vivo studies in naïve mice and a murine GvHD model. Results S-4321 achieves prolonged agonism by binding to PD-1 with low affinity, which preserves PD-1 expression on T cells, unlike first generation PD-1 depleters. S-4321 also selectively binds and signals through FcγRIIb, avoiding the induction of proinflammatory cytokines and undesirable depletion of PD-1+ T cells by ADCC. S-4321 reduces T cell expansion and proinflammatory cytokine production in a murine model of GvHD. Conclusion In contrast to first generation PD-1 depleters, treatment with S-4321 does not result in loss of PD-1 expression on T cells, induction of proinflammatory cytokines, or depletion of PD-1+ Tregs. By coupling PD-1 agonism with inhibitory FcγRIIb engagement, S-4321 has the potential to restore immune homeostasis in cell-mediated autoimmunity. A Phase 1 clinical study is ongoing to assess safety, tolerability, PK/PD and immunogenicity. Funding Source N/A Topic Categories Therapeutic Approaches to Autoimmunity (THER)