Seismic Therapeutic Presents New Preclinical Data for S-4321, a Next Generation PD 1:FcγRIIb-Selective Bifunctional Agonist Antibody for the Treatment of Autoimmune Disease, at ACR Convergence 2024

Novel dual-cell bidirectional antibody engages two independent inhibitory receptors on multiple cell types in a single molecule  

S-4321 is a low affinity PD-1 agonist with selective and functional FcγRIIb binding, without cell depleting activity

New preclinical data support differentiated profile, demonstrate induction of regulatory T cells and activity in a murine model of graft versus host disease

Company expects to initiate Phase 1 clinical trial of S-4321 in 1H 2025

Watertown, Mass., November 18, 2024 – Seismic Therapeutic, Inc., the machine learning immunology company, today announced the presentation of new data for S-4321, its next generation PD‑1: FcγRIIb‑selective bifunctional agonist antibody for the treatment of autoimmune disease, at ACR Convergence 2024, the annual meeting of the American College of Rheumatology, taking place in Washington, DC, on November 14-19, 2024. Based on the promising preclinical results, Seismic plans to initiate a Phase 1 clinical trial of S-4321 in healthy volunteers in the first half of 2025.

The presentation at ACR Convergence 2024 shows preclinical results supporting the mechanism of action of S-4321 and progress towards the clinic. S-4321 was designed using the Company’s IMPACT platform to agonize the inhibitory PD-1 receptor on T cells in the similar manner as its natural ligand, and to selectively bind and agonize the inhibitory FcγRIIb receptor on B cells/antigen presenting cells (APCs) without causing PD-1 expressing cell depletion.

Highlights of the poster presentation entitled, “S-4321, a novel dual-cell bidirectional PD-1:FcγRIIb selective agonist antibody for the treatment of autoimmune disease,” include:

• Optimized Fab antibody domain with low affinity PD-1 binding achieved prolonged PD-1 agonism without causing PD-1 target depletion or IL-2 production, maintaining “the brakes” on activated T effector cells.
• Machine learning-designed Fc antibody domain showed selective binding to the inhibitory FcγRIIb receptor over other FcγRs, avoiding the production of proinflammatory cytokines which may blunt efficacy and depletion of PD-1+ cells, including regulatory T cells (Tregs) which are needed for immune homeostasis. Moreover, the proprietary Fc domain in S-4321 agonizes FcγRIIb, adding B cell/APC inhibition in combination with PD-1 mediated T effector cell inhibition.
• S-4321 promoted the induction of Tregs and inhibits graft versus host disease (GvHD) progression in a murine model.
• Non-human primate studies demonstrated dose-proportional exposure and ~70% bioavailability of S-4321 with subcutaneous dosing, supporting the potential for a convenient self-administered regimen.

“We deliberately designed S-4321 as a novel bifunctional antibody with optimal agonism of both PD-1 and FcγRIIb inhibitory receptors in a single molecule,” said John Sundy, MD, PhD, Chief Medical Officer and Head of R&D at Seismic Therapeutic. “We believe the distinct profile of S-4321 will translate into superior drug activity and clinical benefit in a number of prevalent autoimmune diseases. We look forward to entering the clinic in healthy volunteers in the first half of 2025, where we will assess biomarkers of PD-1 agonist activity that are enabled by S‑4321’s differentiated mechanism.”

The poster for the data presented at ACR is available here on Seismic’s website.

At ACR Convergence 2024, Seismic also presented a poster on its second program preparing to initiate clinical development, S-1117, an engineered pan-IgG protease suitable for chronic administration, for the treatment of autoantibody-mediated diseases. The poster for the data presented at ACR is available here on Seismic’s website.

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 preclinical stage 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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