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Clinical trial will assess safety, tolerability, pharmacokinetics and pharmacodynamic effects of S-4321
Company plans to develop S-4321 for treatment of a range of autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and lupus
Watertown, Mass., April 10, 2025 – Seismic Therapeutic, Inc., the machine learning immunology company, 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 agonizes PD‑1, an inhibitory receptor expressed on effector and regulatory T cells, and Fc-gamma receptor IIb (FcγRIIb), an inhibitory Fc receptor expressed on B cells and antigen presenting cells. The study will build on preclinical evidence of S-4321’s dual-functional properties as a non-depleting antibody with low-affinity binding to PD‑1 for optimal agonism on T cells and highly selective FcγRIIb binding with agonism on antigen-presenting cells. S-4321 has the potential to treat autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and lupus.
“We are excited to begin clinical investigation of S-4321, to explore its safety and pharmacodynamic biomarkers in human subjects. By engaging inhibitory receptors on both sides of the T cell/antigen presenting cell synapse, S-4321’s unique dual-cell activity has the potential for clinical benefit in diseases driven by dysregulated cell-mediated immunity,” said John Sundy, MD, PhD, Chief Medical Officer and Head of R&D at Seismic Therapeutic. “We believe S-4321 offers a differentiated approach as a non-depleting, bifunctional agonist antibody, and we are enthusiastic about its broad potential to treat a variety of autoimmune diseases in need of better therapeutic options.”
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. The study will be conducted in two parts, a single ascending dose stage followed by a multiple ascending dose stage. In addition to safety and tolerability, the trial will evaluate S-4321’s mechanistic activity of PD‑1 agonism and selective FcγRIIb binding in healthy subjects.
Further details about the S-4321 Phase 1 clinical trial can be found on ClinicalTrials.gov (NCT06877611).
“S-4321 targets dysregulated cell-mediated immunity and is our second candidate to enter the clinic this year. It closely follows the initiation of a clinical trial last month with S-1117, a pan-IgG protease therapy targeting dysregulated humoral immunity. We also have a third program, S-8484, an IgE protease for allergy and other diseases, that recently advanced into IND-enabling studies,” said Jo Viney, PhD, Chief Executive Officer of Seismic Therapeutic. “Together, these three programs along with our emerging pipeline, showcase the productivity and versatility of our IMPACT platform to engineer novel biologics to address the unmet needs of patients with autoimmune and allergic diseases.”
About S-4321
S-4321 is a novel bifunctional antibody engineered with Seismic’s IMPACT platform to agonize PD‑1 and FcγRIIb, two critically important inhibitory receptors expressed on different immune cell types. S-4321 binds PD‑1 with low affinity to optimally agonize the inhibitory receptor on T cells and also binds Fc-gamma receptor IIb (FcγRIIb) selectively (thereby avoiding the activation of other FcγRs) to agonize the inhibitory FcγRIIb receptor on antigen presenting cells. Unlike first generation PD‑1 agonists, S-4321 is designed to target PD‑1 without cell depletion, thus preserving regulatory T cells (Tregs), a cell type that is essential for maintaining normal immune homeostasis. Seismic plans to develop S-4321 for a range of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and lupus.
About Seismic Therapeutic
Seismic Therapeutic™ is a biotechnology company making a major shift in how immunology therapies are discovered and developed, enabled by machine learning. The company has a growing clinical and preclinical best-in-class and first-in-class biologics pipeline, derived from its integrated IMPACT platform, to control dysregulated adaptive immunity and address multiple autoimmune diseases. The company is backed by a strong syndicate of life sciences investors and is located in the Boston biotechnology hub. For more information, please visit www.seismictx.com and follow us on LinkedIn and on X @Seismic_Tx.
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