S-4321 / Seismic Therap - LARVOL DELTA

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study of S‑4321, a Non-Depleting Bifunctional PD-1/FcγRIIb Agonist, in Healthy Participants (EULAR 2026) - "Conclusions In healthy participants, single ascending doses of S-4321 demonstrated a favorable safety and tolerability profile, dose-proportional PK and target engagement while avoiding PD-1+ cell depletion or loss of target expression. These data support further clinical evaluation of biologic and clinical responses to S-4321 in patients with autoimmune and immunologic diseases."

Clinical • IO biomarker • P1 data • Immune Modulation • Immunology • PD-1

S-4321, a First-in-class Dual-cell Bifunctional PD-1:FcγRIIB Selective Agonist Antibody That Preserves PD-1 Expression, Prevents Fc-mediated Depletion of Target Cells, and Enhances Inhibitory Receptor Expression (FOCIS 2026) - "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."

IO biomarker • Graft versus Host Disease • Immunology • PD-L1 • PD-L2 • TIGIT • TNFA

Study of S-4321 in Participants With an Autoimmune or Immune-mediated Disease (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Seismic Therapeutic AU Pty Ltd | Not yet recruiting ➔ Recruiting | Trial completion date: Jun 2027 ➔ Sep 2027 | Initiation date: Feb 2026 ➔ Jun 2026 | Trial primary completion date: Jun 2027 ➔ Sep 2027

Biomarker • Enrollment open • Pan tumor • Trial completion date • Trial initiation date • Trial primary completion date • Atopic Dermatitis • Cutaneous Lupus Erythematosus • Dermatitis • Dermatology • Immunology • Inflammatory Arthritis • Lupus • Psoriasis • Psoriatic Arthritis • Rheumatoid Arthritis • Rheumatology • Seronegative Spondyloarthropathies

S-4321 is a novel, non-depleting, bifunctional PD-1:FcγRIIb selective agonist antibody for the treatment of immune-mediated diseases (SID 2026) - "S-4321 maintains PD-1 expression on T cells, avoids proinflammatory cytokine induction, and does not deplete PD-1+ T cells. The favorable nonhuman primate safety profile supports continued clinical development for immune-mediated dermatologic disease. A Phase 1 clinical study is ongoing to assess safety, tolerability, PK/PD and immunogenicity."

IO biomarker • Graft versus Host Disease • Immunology • Inflammation • PD-1

S-4321 IS A NOVEL, NON-DEPLETING, BIFUNCTIONAL PD-1:FcγRIIB SELECTIVE AGONIST ANTIBODY FOR THE TREATMENT OF IMMUNE-MEDIATED DISEASES (IMMUNOLOGY 2026) - "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."

IO biomarker • Late-breaking abstract • Graft versus Host Disease • Immunology • PD-1 • PD-L1 • PD-L2

Study of S-4321 in Participants With an Autoimmune or Immune-mediated Disease (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Seismic Therapeutic AU Pty Ltd

Biomarker • New P1 trial • Pan tumor • Atopic Dermatitis • Cutaneous Lupus Erythematosus • Dermatitis • Dermatology • Immunology • Inflammatory Arthritis • Lupus • Psoriasis • Psoriatic Arthritis • Rheumatoid Arthritis • Rheumatology • Seronegative Spondyloarthropathies

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 (ACR Convergence 2025) - "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."

IO biomarker • Preclinical • Graft versus Host Disease • Immunology • Inflammatory Arthritis • PD-L1 • TIGIT • TNFA

S-4321, a Novel Dual-Cell Bidirectional PD-1:FcγRIIb Selective Agonist Antibody for the Treatment of Autoimmune Disease (FOCIS 2025) - "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."

IO biomarker • Giant Cell Arteritis • Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Sjogren's Syndrome • Systemic Lupus Erythematosus • IL2 • PD-1 • PD-L1

Seismic Therapeutic Doses First Cohort in Phase 1 Clinical Trial of S-4321, a Novel Bifunctional Antibody that Agonizes PD-1 and FcγRIIb Inhibitory Receptors for the Treatment of Autoimmune Disease (Businesswire) - "Seismic Therapeutic, Inc....today announced the dosing of the first healthy subject cohort in a Phase 1 clinical trial of S-4321, a novel bifunctional antibody for the treatment of a range of autoimmune diseases....S-4321 has the potential to treat autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and lupus....The Phase 1 study is a randomized, placebo-controlled, double-blind clinical trial to assess the safety, tolerability, and pharmacokinetics of S-4321 in healthy subjects and will include measures of its pharmacodynamic activity."

Trial status • Immunology • Inflammatory Bowel Disease • Lupus • Rheumatoid Arthritis

S-4321, a Novel Dual-cell Bidirectional PD-1:FcγRIIb Selective Agonist Antibody for the Treatment of Autoimmune Disease (ACR Convergence 2024) - "S-4321 is a novel DcB PD-1:FcγRIIb agonist that engages inhibitory receptors on both sides of the T cell-APC synapse. It agonizes PD-1 without causing target or cell depletion and its high bioavailability allows for convenient administration. In vivo, S-4321 decreases T cell activation that contributes to the pathogenesis of autoimmune diseases and avoids the depletion of Tregs, important for restoring peripheral tolerance."

IO biomarker • Giant Cell Arteritis • Graft versus Host Disease • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Sjogren's Syndrome • Systemic Lupus Erythematosus • CD4 • IL2 • PD-1 • PD-L1 • TGFB1