Seismic Therapeutic Presents Preclinical Data on S-8484 for Allergic Diseases
Seismic Therapeutic, Inc., a pioneering machine learning immunology company, has announced the presentation of preclinical data for its novel immunoglobulin E (IgE) protease, S-8484. The data reveal S-8484’s ability to rapidly and sustainably degrade IgE in plasma and on IgE B cell receptors, showcasing its potential efficacy in treating allergic diseases. The findings, based on both in vitro and in vivo studies, were presented at the 2025 American Academy of Allergy, Asthma, and Immunology (AAAAI) / World Allergy Organization (WAO) Joint Congress held in San Diego, California, from February 28 to March 3, 2025.
Seismic Therapeutic has leveraged its proprietary IMPACT platform, which integrates protein structure-augmented machine learning tools, to design S-8484. This candidate is the company’s third development-stage program and its second immunoglobulin protease pipeline candidate. S-8484 has been engineered with potent enzymatic activity and optimized therapeutic properties, positioning it as a potential breakthrough treatment for allergic diseases.
Kevin Otipoby, PhD, Chief Research Officer at Seismic Therapeutic, emphasized the innovative nature of their approach: “We believe we are at the forefront of an emerging field in which bacterial proteases are being designed as therapeutic drugs to address immune-driven diseases. Targeting IgE with a protease such as S-8484 offers the unique ability to directly degrade serum IgE antibodies and cleave IgE expressed on B cells, thereby addressing multiple mechanisms of humoral immune dysfunction in allergic diseases. This mechanism of action has the potential to induce a rapid and sustained reduction in IgE levels, which could provide significant clinical benefits for patients.”
Seismic’s preclinical research was presented in a poster session titled “Discovery and Characterization of a Novel Engineered Fc-Fused IgE Cleaving Enzyme for Treatment of IgE-Mediated Diseases” by first author Purvi Mande, PhD, Principal Scientist at Seismic Therapeutic. The poster details preclinical studies on S-8484 and Fc-fused IgE protease progenitor molecules, illustrating multiple mechanisms of action and demonstrating efficacy in vitro and in vivo.
Preclinical Study Findings
In Vitro Studies
Key findings from in vitro studies of S-8484 include:
- Potent and selective cleavage of soluble IgE: S-8484 rapidly and effectively degrades free IgE in plasma.
- Concentration-dependent cleavage of IgE B cell receptor: The protease effectively cleaves IgE that is bound to B cells in a dose-dependent manner.
- Reduction of high-affinity IgE Fc receptor expression: Bone marrow-derived mast cells from humanized mice exhibited decreased Fc receptor expression upon treatment with S-8484, potentially reducing mast cell activation and downstream allergic responses.
In Vivo Studies
Mouse model studies further demonstrated the therapeutic potential of S-8484, including:
- Comparable efficacy to approved anti-IgE therapy: S-8484 was shown to be as effective as existing anti-IgE biologics in animal models of anaphylaxis and allergy.
- Reduction in IgE-induced ear inflammation: Systemic administration of S-8484 resulted in significant reductions in ear inflammation, indicating strong tissue penetration and therapeutic potential.
- Rapid resolution of systemic anaphylaxis: In a therapeutic mouse model, S-8484 effectively alleviated anaphylactic reactions, underscoring its potential in severe allergic conditions.
- Reduction of serum IgE and eosinophils in allergen-induced asthma models: In a rat model of allergen-induced asthma, S-8484 significantly lowered serum IgE levels and reduced eosinophil counts in bronchoalveolar lavage fluid, demonstrating potential benefits for asthma patients.
Machine Learning-Driven Drug Design
Seismic Therapeutic’s proprietary IMPACT platform played a critical role in the design and optimization of S-8484. The platform integrates structure-augmented machine learning approaches to engineer proteases with high selectivity and potency. According to Nathan Higginson-Scott, PhD, Chief Technology Officer at Seismic Therapeutic, “The rapid advancement of S-8484 from research through preclinical development is a testament to our ability to design and optimize protease therapeutics using our IMPACT platform. By leveraging cutting-edge machine learning, we were able to overcome a key selectivity challenge that is often inherent in naturally occurring proteases. Our work has resulted in a molecule with high specificity and potency for IgE, derived from a precursor that weakly degraded multiple antibody isotypes.”
Seismic’s multi-objective optimization approach also ensured that S-8484 exhibits the desired biological properties while maintaining a robust manufacturability profile. Higginson-Scott further elaborated, “We are excited about S-8484’s differentiated profile, which targets IgE with the potential to address a significant unmet need in allergic diseases.”
Next Steps in Development
Seismic Therapeutic plans to advance S-8484 into investigational new drug (IND)-enabling studies, marking the next critical step on the path to clinical development. With its promising preclinical data, S-8484 represents a potentially transformative therapeutic approach for allergic diseases driven by IgE-mediated immune dysfunction.
“The data we are presenting at AAAAI/WAO support the differentiated efficacy of S-8484, driven by chronic IgE degradation,” said Otipoby. “We are eager to continue our work and bring this novel therapeutic candidate closer to the clinic, where it has the potential to make a profound impact on patients suffering from allergic conditions.”
As Seismic Therapeutic moves forward with its research, the company remains committed to pioneering machine learning-driven immunology to develop innovative treatments for immune-driven diseases. The poster presentation and additional data on S-8484 are available on Seismic’s website, providing further insights into the promising future of IgE-targeting protease therapies.
