Session Information
Date: Monday, October 27, 2025
Title: (0978–1006) T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster
Session Type: Poster Session B
Session Time: 10:30AM-12:30PM
Background/Purpose: S-4321 is a novel antibody that agonizes the inhibitory PD-1 checkpoint receptor on T cells without competing for binding with its natural ligand, PD-L1, while selectively engaging and signaling through the inhibitory FcγRIIb on B cells/antigen presenting cells (APCs). S-4321 is expected to restore immune homeostasis in diseases such as RA, SLE, GCA, and IBD.
Methods: PD-1 expression was measured on activated T cells after culturing with S-4321 or benchmark PD-1 agonists. FcγRIIb selectivity of the S-4321 Fc domain was demonstrated via binding assays. The lack of proinflammatory activity of the S-4321 Fc domain was assessed using TNFα production from activated monocyte-derived dendritic cells or antibody-dependent cellular cytotoxicity (ADCC) of target Tregs by human NK cells. S-4321 was tested in in vitro Treg differentiation assays. S-4321 was assessed in vivo using the B6D2F1 model of GvHD and naïve mice and in cynomolgus monkeys.
Results: Treatment with S-4321 in vivo does not result in loss of PD-1 target expression, unlike first-generation PD-1 agonists. S-4321 enhances induced Treg (iTreg) differentiation (p< 0.05) in vitro. In vivo, S-4321 reduces T cell expansion and proinflammatory cytokine production (p< 0.05) in a murine model of GvHD and induces TIGIT expression on the surface of PD-1+ T cells in naïve mice. S-4321 demonstrates dose-proportional exposure and ~70% bioavailability with subcutaneous dosing in cynomolgus monkeys.
Conclusion: In contrast to first-generation PD-1 agonists, 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. S-4321 enhances TIGIT expression on PD-1+ T cells. S-4321 has the potential to restore immune homeostasis in cell-mediated autoimmune diseases and its high bioavailability will allow for convenient drug administration.
To cite this abstract in AMA style:
Manasson J, Cianci M, Borah M, Grebinoski S, Vitlip J, Lutz S, Sharma I, Wittenberg E, Colthart A, Perry S, Ramello M, Parker Harp C, Visweswaraiah J, Peckner R, Pellerin A, Vital H, Sundy J, Higginson-Scott N, Otipoby K, Cipolletta D. S-4321, a novel dual-cell bifunctional PD-1:FcγRIIb selective agonist antibody for autoimmune disease, maintains expression of PD-1 on target cells and enhances inhibitory receptor expression on T cells in vivo [abstract]. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/s-4321-a-novel-dual-cell-bifunctional-pd-1fc%ce%b3riib-selective-agonist-antibody-for-autoimmune-disease-maintains-expression-of-pd-1-on-target-cells-and-enhances-inhibitory-receptor-expression-on/. Accessed .« Back to ACR Convergence 2025
ACR Meeting Abstracts - https://acrabstracts.org/abstract/s-4321-a-novel-dual-cell-bifunctional-pd-1fc%ce%b3riib-selective-agonist-antibody-for-autoimmune-disease-maintains-expression-of-pd-1-on-target-cells-and-enhances-inhibitory-receptor-expression-on/